CHAPTER 06 ENDOCRINE SYSTEM

06.01 DRUGS USED IN DIABETES

Diabetes
Diabetes is classified as type 1 diabetes (previously referred to as insulin-dependent diabetes mellitus, IDDM); type 2 diabetes (previously referred to as non–insulin-dependent diabetes mellitus, NIDDM); gestational diabetes and other specific types, e.g. secondary to endocrine disorders or pancreatic disease. Only type 1 and type 2 diabetes are discussed here.

Prevention of diabetes
Lifestyle changes (diet improvement, weight reduction and increase in physical activity) delay onset of type 2 diabetes in people with impaired glucose tolerance.
Consider screening for diabetes in patients with hypertension, hyperlipidaemia, obesity, family history of diabetes or history of gestational diabetes.

Diabetes is a strong risk factor for cardiovascular disease. Other risk factors for cardiovascular disease such as smoking, hypertension, obesity , and hyperlipidaemia should be addressed. The use of an ACE inhibitor , of low-dose aspirin and of a lipid-regulating drug can be beneficial in patients with diabetes and a high risk of cardiovascular disease

Rationale for drug use
Essential for life in type 1 diabetes.
Symptom relief (eg polyuria, polydipsia).
Control of blood glucose concentration.
Prevention and treatment of acute complications (ketoacidosis).
Prevention and treatment of long term complications (nephropathy, neuropathy, retinopathy, macrovascular disorders).
Before starting treatment
Insulin treatment may be required in an emergency, especially in children, because of risk of fatal ketoacidosis.
In type 2 diabetes, develop a healthy eating plan and exercise/activity program; there should be a 3-month trial before considering drug treatment.
Plan appropriate investigations and assessment (renal function, eye examination).
Assess risk factors for cardiovascular complications (smoking, hypertension, dyslipidaemia, obesity).
Consider referrals to dietitian, diabetes educator, endocrinologist, podiatrist and ophthalmologist.
Drug choice
Two large controlled trials, The Diabetes Control and Complications Trial (DCCT) in people with type 1 diabetes and the UK Prospective Diabetes Study (UKPDS) in people with type 2 diabetes, showed that tight blood glucose control reduces risk of diabetes-related microvascular complications, eg retinopathy and nephropathy. It may have a beneficial effect on the risk of macrovascular complications.
Contrary to previous results in people with type 2 diabetes, sulfonylureas or insulin did not increase cardiovascular morbidity and mortality.
Type 1 diabetes
Insulin is a lifelong treatment. Intensive treatment reduces the risk of microvascular complications but with a greater risk of hypoglycaemia and weight gain. An intensive regimen cannot be used in young children because of possible long term adverse effects of hypoglycaemia on cerebral development.
Continuous SC insulin infusion has similar or better efficacy than intensive regimens with multiple injections.
Type 2 diabetes
Antidiabetic treatment is not a substitute for a healthy diet and exercise, which should always be encouraged.
Consider antidiabetic treatment:

·         if appropriate glycaemic control is not achieved after a 3-month period of healthy eating and regular exercise/activity

·         when severe symptoms are present or blood glucose concentrations are consistently >20 mmol/L.

In non-obese patients consider sulfonylureas or metformin first. In the UKPDS study, glibenclamide significantly reduced the incidence of diabetes-related events in non-obese patients; however, it has a higher risk of hypoglycaemia compared to other sulfonylureas. Equivalent long term efficacy data are not available for other sulfonylureas. Insulin has a similar efficacy but a greater risk of hypoglycaemia and weight gain than sulfonylureas.
In obese patients consider metformin first as it significantly reduces the incidence of diabetes-related events and mortality.
Efficacy of a single oral antidiabetic drug will decline over time (secondary failure); substitution of one oral drug for another does not usually improve glucose control.
When a first line treatment fails, there is currently no alternative with proven long term benefits. Sulfonylurea with metformin is the most widely used combination. There is controversial evidence that this combination may increase risk of diabetes-related and all-cause mortality. Addition of bedtime isophane insulin to oral treatment (metformin, sulfonylurea or metformin with sulfonylurea combination) reduces glycated haemoglobin similarly to multiple daily insulin injections but with a smaller weight increase. Further data are required to define the best combinations of antidiabetic treatments.
Acarbose, repaglinide and thiazolidinediones have only been assessed in terms of blood glucose control; long term comparative trials with morbidity and mortality outcomes are required to define their role in diabetes treatment.
Sulfonylureas
Include glibenclamide, gliclazide, glimepiride and glipizide.
Risk of weight gain.
Risk of hypoglycaemia, particularly in the elderly and in people with renal or hepatic impairment; avoid use of glibenclamide in these people.
Metformin
No risk of hypoglycaemia when used alone.

Metformin is the drug of first choice in overweight patients in whom strict dieting has failed to control diabetes, if appropriate it may also be considered as an option in patients who are not overweight. It is also used when diabetes is inadequately controlled with sulphonylurea treatment.
GI adverse effects can occur; may be reduced by titrating slowly.
Lactic acidosis is the most serious adverse effect but is rare (0.03 cases per 1000 patient years); occurs mainly with high dose and in people with renal impairment (including situations with a risk of altered renal function, eg dehydration, severe infection, ketoacidosis, surgery, use of iodinated contrast media), hepatic impairment, alcohol misuse, old age and heart failure.
Acarbose

Less effective than sulfonylureas and metformin; it has a small but significant effect in lowering blood glucose ; may be used as monotherapy or with  sulfonylurea, metformin (increased GI adverse effects) or insulin.
GI adverse effects (diarrhoea, flatulence) can occur, particularly at start of treatment; may be reduced by starting on low dose and titrating slowly.
Hypoglycaemia may occur in combination with sulfonylureas, repaglinide or insulin; give glucose but not sucrose (cane sugar) because of delayed absorption of sucrose.

Flatulence deters some from using acarbose although this side-effect tends to decrease with time.
Repaglinide
May be used as monotherapy; no improvement expected in patients who have been inadequately controlled with sulfonylureas.
Risk of hypoglycaemia seems similar to that with sulfonylureas.
Limited data evaluating combinations with other oral antidiabetic drugs exist; combination with metformin or insulin may improve glycaemic control but at increased risk of hypoglycaemia.
Thiazolidinediones
Include rosiglitazone and pioglitazone.
Rosiglitazone and pioglitazone are currently marketed for use as monotherapy or in combination with sulfonylureas or metformin or insulin. However, there are no adequate comparative data on clinical outcomes with either metformin or sulfonylureas that could justify their use as monotherapy. It should be noted that in European countries combination with insulin is contraindicated because of increased risk of heart failure.
Up to one-third of patients do not respond to thiazolidinediones; combinations of a thiazolidinedione plus either metformin or a sulfonylurea seem to control blood glucose similarly to metformin with a sulfonylurea but are not better tolerated.
Insulin, alone or with metformin or a sulfonylurea, has a better benefit to risk ratio than triple therapy of a thiazolidinedione with metformin and a sulfonylurea.
Weight increase and oedema are common adverse effects of thiazolidinediones. Caution is required in patients with heart failure or at risk of heart failure.
Hepatotoxicity may occur with rosiglitazone and pioglitazone; close monitoring of liver enzymes is required.

Insulin
May be used with oral antidiabetic drugs in type 2 diabetes or as monotherapy.
Risk of weight gain and hypoglycaemia.
Control of other risk factors
Controlling other vascular risk factors, in particular smoking, hypertension, obesity and dyslipidaemia, may be more important than tight glycaemic control in decreasing diabetes-related morbidity and mortality.
Hypertension

Reducing BP decreases diabetes-related complications and mortality; aim to keep BP <130/85 mm Hg.
Microalbuminuria

Improvement in glycaemic control and reduction of BP reduces progression of renal disease.
ACE inhibitors delay microalbuminuria in hypertensive patients and reduce progression of microalbuminuria to overt nephropathy in normotensive patients. Losartan and irbesartan reduce progression of renal disease in patients who have type 2 diabetes with hypertension and proteinuria; irbesartan is also approved for use when microalbuminuria is present.
Cardiovascular disease prevention
Low dose aspirin is recommended in patients at high risk of cardiovascular disease; its benefit may be offset by risk of GI adverse effects in diabetic patients without other cardiovascular risk factors.
Ramipril reduces risk of MI, stroke, cardiovascular death or need for revascularisation procedures in diabetic patients >55 years with one or more risk factors. Consider using statins in patients with LDL >3.4 mmol/L or with cardiovascular disease.
Special cases
Pregnancy: Tell patient to seek advice several months before planned conception to optimise glucose control. Tight blood glucose control, especially at the time of conception and early in pregnancy, reduces risk of spontaneous abortion and congenital malformations. Replace oral antidiabetic drugs with insulin (insulin may also be required in gestational diabetes).
Treatment endpoints
Adjust treatment endpoints individually; intensive treatment may be inappropriate, eg when risk of (and from) hypoglycaemia is unacceptable, in presence of severe concomitant disease, in children, adolescents and the very elderly.
Ideal treatment endpoints proposed by the Australian Diabetes Society:

·         fasting blood glucose, <6 mmol/L

·         random blood glucose, 4–8 mmol/L

·         glycated haemoglobin concentration (HbA1c), 7% (or less).

Monitoring
Blood glucose self-monitoring

Useful to identify and treat hyperglycaemia and hypoglycaemia and to adjust insulin dosage

·         Blood glucose meters give more accurate reading than visual strips, but are more expensive.
Frequency and pattern of monitoring depends on clinical situation; consider referral to diabetes educator to plan a self-monitoring schedule:

·         in people on an intensive insulin regimen, advise monitoring 4 times daily, ie before each meal and at bedtime; postprandial monitoring may also be useful

·         whether self-monitoring is useful in people with type 2 diabetes who are not treated with insulin is controversial; monitoring may be considered at different times of the day 1–2 days a week; may be useful when HbA1c suggests poor control, during the 2 weeks before a clinic visit or when symptoms are suggestive of hyper- or hypoglycaemia

·         monitor more frequently during illness or stress and after changes in treatment.

Ketone self-monitoring

Essential for identification of impending ketoacidosis in type 1 diabetes; blood glucose concentrations may be deceptively normal during illness with severe ketonuria.
Most commonly performed on urine; blood ketone testing is also possible with some blood glucose meters.
Advise monitoring when symptoms of ketoacidosis are present, during acute illness or stress, with persistent high glucose concentrations (>15 mmol/L), or in pregnant women with pre-existing type 1 diabetes.

Glycated haemoglobin

Glycated haemoglobin indicates glycaemic control during preceding 2–3 months; there is a continuous relationship between the risk of microvascular complications and level of glycated haemoglobin.
Monitor glycated haemoglobin every 3–6 months.
Glycated haemoglobin results vary between laboratories; use the same laboratory for repeated testing.

Drugs affecting blood glucose

Many drugs affect blood glucose concentration and may alter control of diabetes or increase risk of hypoglycaemia when used with insulin or oral antidiabetic drugs.
Drugs which may decrease blood glucose concentration: aspirin (analgesic doses), disopyramide, octreotide, pentamidine, perhexiline, quinine, quinolones.
Drugs which may increase blood glucose concentration: adrenaline, arsenic trioxide, baclofen, beta2 agonists (high dose, eg IV salbutamol), busulfan (high dose), chlorpromazine, clozapine, combined oral contraceptives, colaspase, cyclosporin, diazoxide, fludarabine, glucocorticoids, haloperidol, HRT, interferon alfa, isoniazid, isotretinoin, nicotinic acid (lipid-lowering doses), octreotide, olanzapine, pentamidine, phenytoin, PIs, quetiapine, quinolones, risperidone, somatropin, tacrolimus, TCAs, thiazide diuretics (high dose).
When introducing or withdrawing a drug that influences blood glucose concentration, close monitoring of blood glucose and adjustment of insulin or antidiabetic drug dosage are required.
Alcohol: decreases blood glucose concentration by inhibiting hepatic glucose output; increases risk of hypoglycaemia and can also mask its warning symptoms. Limit alcohol intake and take food with alcohol.
Beta-blockers: may mask some hypoglycaemic warning symptoms and increase incidence and severity of hypoglycaemia but data are conflicting; choose beta1 selective beta-blockers, such as atenolol, which has been shown to be safe and effective in patients with type 2 diabetes.
Diabetic ketoacidosis
Diabetic ketoacidosis is caused by absolute or relative lack of insulin; it may occur at the onset of type 1 diabetes or during intercurrent illness.
Prevention of ketoacidosis in type 1 diabetes
Patients should monitor their urine ketones when symptoms of ketoacidosis are present (eg nausea, vomiting, weakness, rapid breathing, sweet breath odour), during acute illness or stress, and when persistent high blood glucose concentrations are present (>15 mmol/L).
Give patients an emergency contact number and an individualised sick day management plan:

·         monitor blood glucose frequently (at least 3–4 times daily, and as often as every hour)

·         increase insulin dosage according to blood glucose monitoring

·         do not stop insulin even if not eating

·         monitor urine ketones, particularly when blood glucose is >15 mmol/L (blood ketone testing is available with some blood glucose meters)

·         sip sweetened fluids frequently if not able to tolerate solid food

·         seek medical advice when persistent urine ketones and high glucose concentrations are present, or if repeated vomiting occurs.

Treatment of ketoacidosis
Fluid and electrolyte replacement: start fluid replacement with IV infusion of sodium chloride 0.9%; adjust dosage of potassium chloride according to plasma potassium concentrations; sodium chloride 0.45% can then be used if corrected serum sodium is normal or elevated. Use sodium bicarbonate only in cases of extreme acidosis and/or shock.
Insulin: blood glucose concentration should be reduced slowly. Give short acting insulin by IV infusion at a rate of 5–10 units/hour in adults and 0.1 units/kg/hour in children (diluted to 1 unit/mL in sodium chloride 0.9%). Dosage may need to be decreased, especially in young children, when blood glucose has fallen to 10 mmol/L. Intermittent IM injection is an alternative only if circulatory state is satisfactory. Begin glucose infusion once blood glucose has fallen to 10–15 mmol/L, while continuing insulin infusion until urine ketones are no longer detectable.
Treatment of hyperosmolar hyperglycaemic non-ketotic coma
Occurs mainly in elderly people with type 2 diabetes. Infection is the most common precipitating factor.
Clinical management is broadly similar to management of diabetic ketoacidosis. Use sodium chloride 0.45% for fluid and electrolyte replacement. Lower insulin dosage than for diabetic ketoacidosis has been recommended (0.01–0.05 units/kg/hour).

 

06.01.01 Insulin’s

Mode of action
Increase or restore ability to metabolise glucose by enhancing cellular glucose uptake; inhibit endogenous glucose output and lipolysis.
Comparative information
Origin
Available preparations are either purified bovine insulins or human insulins obtained by recombinant DNA technology; initial concern about reduced awareness of hypoglycaemia with human insulin has not been confirmed.
Onset and duration of action
See
Table 06-1 Insulins: comparative information
Ultra-short and short acting insulins are soluble insulins (clear solution).
Insulin lispro and insulin aspart are human insulin analogues; their ultra-short onset of action allows them to be given immediately before meals.
Intermediate acting insulins (cloudy solution) have a prolonged duration of action (eg isophane insulin).
Mixed insulins (also called biphasic insulins) combine a short or ultra-short acting insulin in varying proportions (20–50%) with an intermediate acting insulin.

Insulin glargine (clear solution) is a human insulin analogue which provides a constant basal insulin level over 24 hours allowing for once-daily dosing.
Safety

Ultra-short acting insulins seem to reduce the frequency of severe hypoglycaemia compared to short acting insulin but evidence is limited.
There is some evidence of decreased nocturnal hypoglycaemia with insulin glargine compared to once daily isophane insulin in patients with type 2 diabetes. Insulin glargine is more painful to inject than isophane insulin. Post-marketing surveillance data are required to monitor local reactions as some animal studies have identified risk of local toxicity.
Presentation
All preparations contain 100 units/mL and are suitable for SC injection. Short acting insulins and insulin lispro can be given IV, eg in diabetic ketoacidosis.
Most preparations are available in vials for use with a syringe (0.3 mL, 0.5 mL or 1 mL). Most ultra-short, short and intermediate acting human insulins are also available in cartridges for use with a pen injection device. Pen devices are more convenient than syringes and avoid the need to draw up insulin. Some preparations are available as disposable pen devices.

Examples of recommended insulin regimens

·         Short-acting insulin mixed with intermediate-acting insulin: twice daily (before meals)

·         Short-acting insulin mixed with intermediate-acting insulin: before breakfast

·         Short-acting insulin: before evening meal

·         Intermediate-acting insulin: at bedtime

·         Short-acting insulin: three times daily (before breakfast, midday, and evening meal)

·         Intermediate-acting insulin: at bedtime

·         Intermediate-acting insulin with or without short-acting insulin: once daily either before breakfast or at bedtime suffices for some patients with type 2 diabetes who need insulin, sometimes in combination with oral hypoglycaemic drugs

06.01.01.01 Short-Acting Insulin’s

 

Products

INSULIN, HUMAN, SOLUBLE VIAL 100 IU/ML   10 ML VIAL (ACTRAPID®, HUMULIN R®, GENSULIN R®)

INSULIN, HUMAN, ASPART VIAL 100 IU/ML   10 ML VIAL (NOVORAPID®)

06.01.01.02 Intermediate-Acting Insulin’s

Products
INSULIN, HUMAN, BIPHASIC ASPART, RECOMBINANT HUMAN INSULIN ANALOGUE 100 IU/ML (30% INSULIN ASPART+70% INSULIN ASPART PROTAMINE) (NOVOMIX®)
INSULIN, HUMAN, BIPHASIC ISOPHANE PENFILL [100 IU/ML (30+70)]   3 ML (GENSULIN M 30®, MIXTARD 30®)
INSULIN, HUMAN, ISOPHANE VIAL 100 IU/ML   10 ML VIAL (HUMULIN NPH®, GENSULIN N®, INSULATARD®)
INSULIN, HUMAN, ISOPHANE VIAL 100 IU/ML 10 ML VIAL (GENSULIN M 30®, HUMILIN 70/30®, MIXTARD 30®)

06.01.01.03 Long-acting insulin’s

Insulin glargine and insulin detemir should be available as an option for patients with type 1 diabetes.

Insulin glargine and insulin detemir are not recommended for routine use in patients with type 2 diabetes who require insulin, but it may be considered in type 2 diabetes for those:

·         who require assistance with injecting their insulin; or

·         whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemia; or

·         who would otherwise need twice-daily basal insulin injections in combination with oral antidiabetic drugs

Products

INSULIN, HUMAN, DETEMIR, RECOMBINANT HUMAN INSULIN ANALOGUE 100 IU/ML (LEVEMIR®)

INSULIN, HUMAN, GLARGINE, RECOMBINANT HUMAN INSULIN ANALOGUE 100 IU/ML (LANTUS®)

 

06.01.02 Oral Antidiabetic Drugs 

Oral antidiabetic drugs are used for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. They should be prescribed only if the patient fails to respond adequately to at least 3 months’ restriction of energy and carbohydrate intake and an increase in physical activity. They should be used to augment the effect of diet and exercise, and not to replace them.

06.01.02.01 Sulfonylureas

The sulphonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present; during long-term administration they also have an extrapancreatic action. All may cause hypoglycaemia but this is uncommon and usually indicates excessive dosage. Sulphonylurea-induced hypoglycaemia may persist for many hours and must always be treated in hospital.

Sulphonylureas are considered for patients who are not overweight, or in whom metformin is contra-indicated or not tolerated. Several sulphonylureas are available and choice is determined by side-effects and the duration of action as well as the patient’s age and renal function. The long-acting sulphonylureas like glibenclamide is  associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly and shorter-acting alternatives, such as gliclazide, should be used instead. Chlorpropamide also has more side-effects than the other sulphonylureas (see below) and therefore it is no longer recommended.

When the combination of strict diet and sulphonylurea treatment fails other options include:

·         combining with metformin (reports of increased hazard with this combination remain unconfirmed);

·         combining with acarbose , which may have a small beneficial effect, but flatulence can be a problem;

·         combining with pioglitazone or rosiglitazone.

·         combining with bedtime isophane insulin but weight gain and hypoglycaemia can occur.

Insulin therapy should be instituted temporarily during intercurrent illness (such as myocardial infarction, coma, infection, and trauma). Sulphonylureas should be omitted on the morning of surgery; insulin is required because of the ensuing hyperglycaemia in these circumstances.

Cautions

Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting; metformin is considered the drug of choice in obese patients. Caution is needed in the elderly and in those with mild to moderate hepatic and renal impairment because of the hazard of hypoglycaemia. The short-acting tolbutamide may be used in renal impairment, as may gliquidone and gliclazide which are principally metabolised in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the smallest possible dose that produces adequate control of blood glucose.

 

GLIBENCLAMIDE

Mode of action
Increase pancreatic insulin secretion; may decrease insulin resistance.
Indications
Type 2 diabetes (includes combination with
metformin).
Contraindications
Ketoacidosis; Type 1 diabetes.
Specific considerations
Porphyria: risk of acute attacks.
Intercurrent illness (eg MI, coma, infection, trauma): monitor blood glucose and urine ketones; substitute insulin treatment if glycaemic control is inadequate.

Renal impairment: Increased risk of hypoglycaemia; avoid use.
Hepatic impairment: Increased risk of hypoglycaemia; avoid use.
Elderly: Increased risk of hypoglycaemia; avoid use.
Surgery: Substitute insulin treatment before surgery.
Pregnancy: Avoid use (replace with insulin); ADEC category C.
Breastfeeding: Avoid use.
Adverse effects

Common: weight gain, hypoglycaemia.
Infrequent: nausea, diarrhoea, metallic taste, headache, rash.
Rare: blood disorders (thrombocytopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia), allergic reaction, erythema multiforme, exfoliative dermatitis, photosensitivity, hepatotoxicity.
Dosage
2.5–20 mg daily in 1–2 doses; up to 10 mg as single dose.
Counselling
Take tablets with food to minimise risk of low blood glucose (hypoglycaemia).
Drinking alcohol decreases your blood glucose. It can also mask warning symptoms of hypoglycaemia. Avoid binge drinking and have something to eat when you drink alcohol.
Make sure that you, and your friends and family, know how to recognise and treat hypoglycaemia; ask your doctor or diabetes educator if you are unsure.
Practice points

·         start with low dose and increase at weekly intervals until control achieved

·         increasing dosage at the upper limit of dose range may achieve little additional hypoglycaemic effect

·         substitution with, or addition of, another sulfonylurea does not usually improve glucose control; instead, consider combined treatment with other classes of oral antidiabetic drugs or insulin, or monotherapy with insulin

Products
GLIBENCLAMIDE TABS 5 MG (EUGLUCON®
, GLIBEMIDE®, GLIBESYN®, GLIBIL®, GLUCANA®, GLUCOMID®, GLUNIL®, MELIX®, RIVECLAMIDE®)

 

GLICLAZIDE

Mode of action

Same as Glibenclamide .
Indications

Type 2 diabetes (includes combination with metformin)
Contraindications
Ketoacidosis; Type 1 diabetes.
Specific considerations
Same as Glibenclamide.

Adverse effects

Common: weight gain, hypoglycaemia.
Infrequent: nausea, diarrhoea, metallic taste, headache, rash.
Rare: blood disorders (thrombocytopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia), allergic reaction, erythema multiforme, exfoliative dermatitis, photosensitivity, hepatotoxicity.

Dosage
40–320 mg daily in 1–2 doses; up to 160 mg as single dose.
Controlled release formulation, initially 30 mg once daily; increase dose, according to response, by 30 mg once daily at not less than 2-week intervals; maximum daily dose 120 mg.
Practice points

·         30 mg of the controlled release formulation is equivalent to 80 mg of the conventional tablet

·         start with low dose and increase at weekly intervals until control achieved

·         increasing dosage at the upper limit of dose range may achieve little additional hypoglycaemic effect

·         substitution with, or addition of, another sulfonylurea does not usually improve glucose control; instead, consider combined treatment with other classes of oral antidiabetic drugs or insulin, or monotherapy with insulin

Products
GLICLAZIDE TABS 30 MG (DEBADAY MR®, DIAMICRON MR®
)

GLICLAZIDE TABS 80 MG (DEBADAY®, DIAMICRON®, DIAMID®,MICROZIDE®)


GLIMEPIRIDE

Mode of action

Same as Glibenclamide
Indications

Type 2 diabetes (includes combination with metformin).
Contraindications
Ketoacidosis; Type 1 diabetes.
Specific considerations
Adverse effects

Same as Glibenclamide.
Dosage
Initially, 1 mg once daily, adjusted according to response in 1 mg steps at 1–2 week intervals up to 4 mg once daily.
Counselling
Take tablets with food to minimise risk of low blood glucose (hypoglycaemia).
Drinking alcohol decreases your blood glucose. It can also mask warning symptoms of hypoglycaemia. Avoid binge drinking and have something to eat when you drink alcohol.
Make sure that you, and your friends and family, know how to recognise and treat hypoglycaemia; ask your doctor or diabetes educator if you are unsure.
Practice points

Same as Glibenclamide
Products
GLIMEPIRIDE TABS 1 MG (AMARYL®, DIAPRIDE®, GLIMERYL®, GLITRA®, GLORION®
)

GLIMEPIRIDE TABS 2 MG (AMARYL®, DIAPRIDE®, GLEMAX®, GLIMERYL®, GLITRA®, GLORION® )

GLIMEPIRIDE TABS 3 MG (AMARYL®, DIAPRIDE®, GLEMAX®, GLIMERYL®, GLITRA®, GLORION® )

GLIMEPIRIDE TABS 4 MG (AMARYL®, DIAPRIDE®, GLEMAX®, GLIMERYL®, GLITRA®, GLORION® ).

06.01.02.02 Biguanides

METFORMIN

Mode of action
Reduces hepatic glucose production; increases peripheral utilisation of glucose.
Indications
Marketed: Type 2 diabetes as monotherapy or in combination with glibenclamide.
Accepted: With clomiphene for anovulatory infertility due to polycystic ovary syndrome (unresponsive to clomiphene alone) and body mass index >25, under specialist supervision.

Contraindications

Moderate-to-severe heart failure; Respiratory failure; Severe infection or trauma; Dehydration; Alcohol misuse; Type 1 diabetes; Ketoacidosis; Conditions predisposing to lactic acidosis.
Specific considerations
Renal impairment: Increases risk of lactic acidosis; reduce maximum dose in mild impairment, do not use when creatinine clearance is <30 mL/minute. Replace with insulin if possible.
Hepatic impairment: Avoid use; risk of lactic acidosis.
Surgery: Stop metformin 2 days before, during, and for 2 days after, surgery; monitor blood glucose concentrations; replace with insulin as required.

Elderly: use cautiously; avoid use in very old people, i.e. >85 years.
Avoid combination with glibenclamide (the fixed-dose combination is particularly unsuitable as dose titration is difficult).
Pregnancy: Usually replaced with insulin; some clinical use; ADEC category C.
Breastfeeding: Safe to use.
Adverse effects
Common: malabsorption of vitamin B12, nausea, vomiting, anorexia, diarrhea.
Infrequent: rash.
Rare: acute hepatitis.

Lactic acidosis

Rare, but often fatal. Caused by metformin accumulation when contraindications are overlooked, or in high risk situations (eg major illness, surgery). Early symptoms include anorexia, nausea, vomiting, abdominal pain, cramps, malaise and weight loss.

Dosage
Type 2 diabetes: 500 mg 1–3 times daily; may be increased up to 850 mg 2–3 times daily according to response. Maximum daily dose 3 g.
Polycystic ovary syndrome: 500 mg 2–3 times daily as tolerated has been used, may be increased up to 2 g daily.
Renal impairment: A reduced maximum dose is suggested based on creatinine clearance:

·         60–90 mL/minute, 2 g daily

·         30–60 mL/minute, 1 g daily.

Combination with glibenclamide
Initially 1 tablet of 500 mg metformin with 2.5 mg glibenclamide daily with breakfast. Increase by 1 tablet every 2 weeks or longer according to response, to a maximum of 1 tablet of 500 mg metformin with 5 mg glibenclamide 3 times a day.
Elderly, the manufacturer suggests an initial dose of 250 mg metformin with 1.25 mg glibenclamide daily. Give with breakfast and increase dose according to response as above.
Counselling
Take with meals to reduce stomach upset and the risk of low blood glucose (hypoglycaemia).
Tell your doctor immediately if you have loss of appetite, nausea, vomiting, abdominal pain, cramps, malaise, diarrhoea or weight loss.
Drinking alcohol decreases your blood glucose. It can also mask warning symptoms of hypoglycaemia and increase the risk of serious side effects. Limit your alcohol intake, avoid binge drinking and have something to eat when you drink alcohol.
Combination with glibenclamide
Ensure that you, and your friends and family, know how to recognise and treat hypoglycaemia; ask your doctor or diabetes educator if you are unsure.
Practice points

·         slow onset of effect; control may take up to 2 weeks to establish

·         monitor plasma creatinine before starting treatment and every 4–6 months

·         increase dosage slowly to limit GI adverse effects; reduce or stop treatment if symptoms persist

·         consider temporarily stopping treatment if illness occurs which may alter renal function (eg dehydration, shock, sepsis) or increase risk of tissue hypoxia and acidosis (eg MI, pulmonary embolism)

·         use of iodinated contrast media increases risk of lactic acidosis; stop metformin 2 days before, during, and for 2 days after, administration of contrast media

Combination with glibenclamide

·         monitor blood glucose when switching from standard tablets to fixed-dose combination because tablets are not bioequivalent

·         do not use the previous doses of metformin and glibenclamide to start fixed-dose combination therapy

Products
METFORMIN TABS 500 MG (AS HCL) (DIAMET®, DIPHAGE®,FORMET®,GLUCOPHAGE®, GLYFORMIN®,GLYMET®, METFORAL®, METFORAL®, RIVOMET®
)

METFORMIN TABS 850 MG (AS HCL) (DIABAMYL®, DIAMET®, DIPHAGE®, GLUCOPHAGE®, GLYMET®, METFORAL®, RIVOMET®)

METFORMIN TABS 1000 MG (AS HCL) (FORMET®, GLUCOPHAGE®).

 

06.01.02.03 Thiazolidinediones

 

PIOGLITAZONE

Mode of action
Increase the sensitivity of peripheral tissues to insulin; decrease hepatic glucose output.
Indications
Type 2 diabetes, as monotherapy or with metformin, sulfonylureas or insulin.
Contraindications
Ketoacidosis; Type 1 diabetes; Heart failure NYHA class III and  IV.

Specific considerations
Mild-to-moderate heart failure (NYHA Class I or II): may worsen heart failure; start with a low dose and monitor carefully.
Treatment with insulin: increases risk of heart failure; use combination with caution.
Premenopausal anovulatory state, polycystic ovary syndrome: may restore fertility; consider contraception.
Intercurrent illness (eg MI, coma, infection, trauma): monitor blood glucose and urine ketones; substitute insulin treatment if glycaemic control is not adequate.
Hepatic impairment: Avoid use when transaminase levels are >2.5 times the upper limit of normal.
Surgery: Substitute insulin treatment before surgery.
Pregnancy: Avoid use; no human data; ADEC category B3.
Breastfeeding: Avoid use; no human data.
Adverse effects
Common: peripheral oedema, weight gain, headache, dizziness, arthralgia, decrease in haemoglobin and haematocrit.
Rare: elevated liver enzymes, hepatocellular injury, heart failure, pulmonary oedema.
Dosage
15–30 mg once daily; may be increased to a maximum dose of 45 mg once daily after 6–8 weeks of treatment if effect is inadequate.
Wait several months before increasing dose in people with mild-to-moderate heart failure.
Counselling
Tell your doctor immediately if you have swollen feet or ankles, breathlessness, nausea, vomiting, abdominal pain, fatigue, loss of appetite or dark urine.
Practice points

·         there are no data to justify use as monotherapy

·         stop treatment if no effect after 6 months

·         monitor liver enzymes at the start of treatment, then every 2 months for the first year and periodically thereafter

·         check liver enzymes at the first symptoms suggestive of hepatic dysfunction

·         stop treatment if ALT rises >3 times the upper limit of normal or if the patient has jaundice

·         weight gain and pedal oedema are common adverse effects; assess risk of fluid retention before increasing dosage; consider stopping treatment if a diagnosis of heart failure is made

Products
PIOGLITAZONE TABS 15 MG (AS HCL) (ACTOS®
)

PIOGLITAZONE TABS 30 MG (AS HCL) (ACTOS®, UNIGLIT®)

 

ROSIGLITAZONE

Mode of action
Increase the sensitivity of peripheral tissues to insulin; decrease hepatic glucose output.
Indications
Type 2 diabetes, as monotherapy or with metformin, sulfonylureas, or insulin.
Contraindications
Ketoacidosis; Type 1 diabetes; Heart failure NYHA class III and  IV

Specific considerations

Same as Pioglitazone.
Adverse effects

Common: peripheral oedema, weight gain, headache, dizziness, arthralgia, decrease in haemoglobin and haematocrit, increase in total and HDL cholesterol.

Rare: elevated liver enzymes, hepatocellular injury, heart failure, pulmonary oedema.

Dosage
Initially, 4 mg once daily; may be increased to 8 mg daily in 1 or 2 doses if effect is inadequate after 6–8 weeks of treatment; Wait several months before increasing dose in people with mild-to-moderate heart failure.
Counselling
Tell your doctor immediately if you have swollen feet or ankles, breathlessness, nausea, vomiting, abdominal pain, fatigue, loss of appetite or dark urine.
Practice points

Same as Pioglitazone

Products
ROSIGLITAZONE TABS 4 MG (AS MALEATE) (AVANDIA®
)

 

Note: On 26th September 2010, JFDA has suspended the registration of products containing Rosiglitazone as an active ingredient (according to article 15 of adverse drug reactions regulations and drug related problems 2010) based on EMA decision on 23 September 2010. EMA concluded that the benefits of rosiglitazone no longer outweigh its risks based on the availability of recent studies in addition to previous clinical trials, observational studies and published literature that support an increased cardiovascular risk of rosiglitazone. The suspension decision will remain in effect until the company can supply convincing data to identify a patient population in which the clinical benefits of rosiglitazone-containing medicines clearly outweigh their risks.

 

06.01.02.04 Dipeptidylpeptidase inhibitors

 
SITAGLIPTIN

Mode of action
competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4).

Indications
Type 2 diabetes, as monotherapy or with metformin, or with sulfonylureas, or with thiazolidinedione.

Contraindications
Ketoacidosis; Type 1 diabetes; Kidney problems.

Specific considerations.
Renal impairment: Avoid use if eGFR less than 50 ml/minute/1.73 m
2.
Pregnancy: Avoid use; toxicity in animal studies.
Breastfeeding: Avoid use; present in milk in animal study.
Adverse effects
Common: gastro-intestinal disturbances; peripheral oedema; upper respiratory tract infection; nasopharyngitis; pain; osteoarthritis.
Infrequent: dry mouth, anorexia, headache, drowsiness, dizziness, hypoglycaemia, osteoarthritis.

Rare: pancreatitis, rash, cutaneous vasculitis, Stevens-Johnson syndrome.
Dosage
adult over 18 years, 100 mg once daily.

Counselling

Tell your doctor immediately if you have feel very weak and tired, have unusual (not normal) muscle pain, trouble breathing, unexplained stomach or intestinal problems with nausea and vomiting or diarrhea, feel cold  especially in your arms and legs.You feel dizzy or lightheaded or you  have a slow or irregular heart beat.

Products
SITAGLIPTIN TABS 100 MG (AS Phosphate) (JANUVIA®
)

 

VILDAGLIPTIN

Mode of action
competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4).

Indications
Type 2 diabetes, in combination with metformin, or with sulfonylureas, or with thiazolidinedione.
Contraindications
Ketoacidosis; Type 1 diabetes; Kidney problems; Hepatic impairment

Specific considerations.
Elderly: monitor liver function

Heart failure: avoid if moderate or severe.

Hepatic impairment: avoid.

Renal impairment: Avoid use if eGFR less than 50 ml/minute/1.73 m2
Pregnancy: Avoid use; toxicity in animal studies
Breastfeeding: Avoid use; present in milk in animal study.
Adverse effects
Common: nausea, peripheral oedema, headache, tremor, asthenia, dizziness.
Infrequent: constipation, hypoglycaemia.

Rare: hepatic dysfunction, nasopharyngitis, upper respiratory tract infection, arthralgia.
Dosage
adult over 18 years, in combination with metformin or a thiazolidinedione, 50 mg twice daily.

In combination with a sulphonylurea, 50 mg daily in the morning.

Counselling

Tell your doctor immediately if you have feel very weak and tired, have unusual (not normal) muscle pain, trouble breathing, unexplained stomach or intestinal problems with nausea and vomiting or diarrhea, loss of appetite, darkened urine or yellowing of the eyes or skin.

Products
VILDAGLIPTIN TABS 50 MG (GALVUS®
)

06.01.02.05 Meglitinides (Glinides)

 

REPAGLINIDE

Mode of action
Increases pancreatic insulin secretion.
Indications
Type 2 diabetes,  as monotherapy or combined with metformin or insulin.
Contraindications
Ketoacidosis; Severe hepatic impairment; Pregnancy and breast-feeding; Type 1 diabetes; Treatment with gemfibrozil.
Specific considerations
Intercurrent illness (eg MI, coma, infection, trauma): monitor blood glucose and urine ketones; substitute insulin treatment if glycaemic control is not adequate.
Renal impairment: Lower dosage required in severe impairment; titrate dose carefully in mild and moderate impairment.
Hepatic impairment: No data in severe impairment; titrate dose carefully in mild and moderate impairment.
Surgery: Substitute with insulin treatment.
Elderly: No data for people >75 years.
Children: Contraindicated in children <12 years.
Pregnancy: Avoid use; no data; ADEC category C.
Breastfeeding: Avoid use; no data.
Adverse effects

Common: hypoglycemia, nausea, vomiting, abdominal pain, diarrhoea, constipation,

Infrequent: rash, increase in liver enzymes.
Dosage
Initially, 0.5 mg 3 times daily; increase every 1–2 weeks according to blood glucose control up to 4 mg 3 times daily. Maximum dose 16 mg daily.
Changing from another oral antidiabetic drug
Initially, 1 mg 3 times daily.
Counselling
Take immediately before meals. Do not take a dose if you are skipping a meal.
Drinking alcohol decreases your blood glucose. It can also mask warning symptoms of hypoglycaemia. Avoid binge drinking and have something to eat when you drink alcohol.
Make sure that you, and your friends and family, know how to recognise and treat low blood glucose  (hypoglycaemia); ask your doctor or diabetes educator if you are unsure.
Products
REPAGLINIDE TABS 1 MG (NOVONORM®
)

06.01.03 Treatment of Hypoglycemia

Hypoglycaemia
Hypoglycaemia can occur in people with diabetes receiving insulin, sulfonylureas or repaglinide.
Mild hypoglycaemia will respond to oral administration of glucose or sucrose; give glucose (eg glucose tablets), not sucrose (cane sugar), to people treated with acarbose because of delayed absorption of sucrose.
Treat severe hypoglycaemia in a person unable to take oral food or fluids with glucagon. If glucagon is not available or if there is no response in 10–15 minutes, give 20 mL of glucose 50% injection (into a secure IV cannula in an antecubital vein because of risk of superficial thrombophlebitis). In children, give glucose 10% injection (2 mL/kg over 3 minutes, followed by 0.1 mL/kg/minute until recovery). Recheck blood glucose as continued glucose boluses may render a young child hyperosmolar, with the risk of cerebral oedema.
Prolonged treatment with glucose infusion may be required for hypoglycaemia due to a long acting sulfonylurea. Octreotide (SC 50 micrograms) may be used in patients with persisting hypoglycaemia despite glucose infusion.
When the person has responded, give longer acting carbohydrates to prevent recurrent hypoglycaemia.

 

GLUCAGON

Mode of action
Increases blood glucose concentration by activating hepatic glucose production; decreases GI motility.
Indications
Marketed: Hypoglycaemia induced by insulin or oral hypoglycaemic agents in people unable to take food or fluid orally; Diagnostic aid for GI radiological examination.
Accepted: Adjunct in treatment of beta-blocker or calcium channel blocker overdose.

Contraindications
Insulinoma; Glucagonoma; Phaeochromocytoma.
Specific considerations
Chronic hypoglycaemia, adrenal insufficiency, starvation: glucagon is ineffective.
Pregnancy: Safe to use; ADEC category B2.
Breastfeeding: Safe to use.
Adverse effects
Nausea, vomiting, hypokalaemia (large doses), allergic reactions.
Dosage
Hypoglycaemia
Adult, child >5 years, 1 mg SC, IM or IV.
Child <5 years, 0.5 mg SC, IM or IV.
Diagnostic aid

IV/IM, 0.2–2 mg depending on radiological technique and route.
Counselling
Make sure that your friends and family know how to recognise low blood glucose (hypoglycaemia) and how to give glucagon injection; ask your doctor or diabetes educator if you are unsure.
Practice points

·         person should respond to glucagon within 10–15 minutes; if there is no response, give IV glucose

·         give oral carbohydrates when person has responded to prevent recurrent hypoglycaemia

      

              Products
GLUCAGON VIALS 1 MG/VIAL (AS HCL) (GLUCAGEN®
)

 

06.02 DRUGS FOR THYROID DISORDERS

06.02.01 Thyroid Hormones

Thyroid hormones are used in hypothyroidism (myxoedema), and also in diffuse non-toxic goitre, Hashimoto's thyroiditis (lymphadenoid goitre), and thyroid carcinoma. Neonatal hypothyroidism requires prompt treatment for normal development.

Levothyroxine sodium (thyroxine sodium) is the treatment of choice for maintenance therapy. The initial dose should not exceed 100 micrograms daily, preferably before breakfast, or 25 to 50 micrograms in elderly patients or those with cardiac disease, increased by 25 to 50 micrograms at intervals of at least 4 weeks. The usual maintenance dose to relieve hypothyroidism is 100 to 200 micrograms daily which can be administered as a single dose.

In infants and children doses of thyroxine, for congenital hypothyroidism and juvenile myxoedema, should be titrated according to clinical response, growth assessment, and measurements of plasma thyroxine and thyroid-stimulating hormone.

 

LEVOTHYROXINE (THYROXINE Sodium )

Also known as T4 
Indications
Hypothyroidism; Block-replace regimen in hyperthyroidism; Suppressive regimen in thyroid cancer and euthyroid goiter.
Contraindications
Untreated hyperthyroidism; Thyrotoxicosis.
Specific considerations
Hypopituitarism and adrenal insufficiency: risk of acute adrenal crisis if used without glucocorticoid replacement.

Cardiovascular disorders: risk of worsening ischaemic symptoms; risk of arrhythmias,
Diabetes: may require adjustment of insulin or antidiabetic drug dosage when beginning treatment with thyroid hormones.
Elderly: quire slower dosage adjustment; risk of cardiovascular adverse effects.
Children: thyroxine preferred; liothyronine rarely required. Try to avoid liothyronine because of preferential use of thyroxine by the developing brain.
Pregnancy: thyroxine is safe to use; increased dose (by about 25–40%) likely to be required; check thyroid function at least once each trimester; ADEC category A.
Try to avoid using liothyronine in pregnancy because of preferential use of thyroxine by the developing brain.
Breastfeeding: Safe to use.
Adverse effects
Usually associated with excessive dosage; correspond to symptoms of hyperthyroidism, eg tachycardia, arrhythmia, excitability, insomnia, flushing, sweating, diarrhoea and excessive weight loss.
Worsening ischaemic symptoms may occur in those with ischaemic heart disease, even at reduced doses.
Decreased bone density has been reported, particularly in over treated postmenopausal women and in suppressive regimens.
Infants treated with excessive doses may develop craniosynostosis and advancement of bone age.
Benign intracranial hypertension with headache, vomiting and papilloedema has been reported rarely in children in the first few weeks of treatment.
Dosage
Adult
Initially, 50–100 micrograms daily; increase by 25–50 micrograms daily every 3–4 weeks if necessary, according to TSH. Maintenance, 100–200 micrograms daily.
Child
<6 months, 8–10 micrograms/kg daily; up to 15 micrograms/kg daily in athyrosis.
7–12 months, 6–8 micrograms/kg daily.
1–5 years, 5–6 micrograms/kg daily.
6–12 years, 4–5 micrograms/kg daily (around 100 micrograms/m2 daily).
Elderly, ischaemic heart disease, severe hypothyroidism
Initially, 25–50 micrograms daily; increase daily dose by 25 micrograms every 6–8 weeks (or more frequently in severe cases) if necessary. Usual maintenance, 50–200 micrograms daily.
Counselling
Take thyroxine on an empty stomach, usually before breakfast.
Tell your doctor if symptoms of hyperthyroidism occur, e.g. palpitations, excitability, insomnia, flushing, sweating or weight loss.
Infants, the tablets can be easily dispersed in a small amount of milk or water.
Practice points

·         if hyperthyroidism occurs, stop thyroxine for a week and restart at lower dosage

Products
LEVOTHYROXINE TABS  50 MCG (ELTROXIN®
, EUTHYROX®, THYROXINE®)

LEVOTHYROXINE TABS 100 MCG (ELTROXIN®, EUTHYROX®, THYROXINE®)

 

06.02.02 Antithyroid Drugs

Antithyroid drugs are used for hyperthyroidism either to prepare patients for thyroidectomy or for long-term management. Carbimazole is the most commonly used drug. Propylthiouracil may be used in patients who suffer sensitivity reactions to carbimazole as sensitivity is not necessarily displayed to both drugs. Both drugs act primarily by interfering with the synthesis of thyroid hormones.

CSM warning (neutropenia and agranulocytosis)

Doctors are reminded of the importance of recognising bone marrow suppression induced by carbimazole and the need to stop treatment promptly.

Patient should be asked to report symptoms and signs suggestive of infection, especially sore throat.

A white blood cell count should be performed if there is any clinical evidence of infection.

Carbimazole should be stopped promptly if there is clinical or laboratory evidence of neutropenia.

 

CARBIMAZOLE

Mode of action
Block thyroid hormone synthesis; propylthiouracil also inhibits peripheral conversion of T4 to T3.
Indications
Graves' disease; Short term treatment before thyroid surgery, or before and after radioactive iodine treatment; Thyroid storm.
Contraindications
Agranulocytosis with antithyroid drug.
Specific considerations
Children: neonatal thyrotoxicosis may occur as a rare complication of maternal Graves' disease.
Pregnancy: Use the lowest effective dosage; may induce fetal hypothyroidism; propylthiouracil preferred; do not use block-replace regimen; ADEC category C. Check TSH and free thyroid hormone every 6 weeks.
Carbimazole given during pregnancy has been linked to aplasia cutis, a rare congenital defect of the scalp, but the association has been questioned. Other increases in abnormalities may form part of a rare carbimazole embryopathy.
Breastfeeding: Propylthiouracil preferred because of lower secretion in breast milk; use the lowest effective dosage with appropriate monitoring of infant.
Adverse effects
Occur most often during the first 8 weeks of treatment. Itching and mild rashes may respond to antihistamines while continuing treatment; if a change in treatment is needed, the 2 drugs can often be interchanged without recurrence of adverse effects (unless agranulocytosis occurred, in which case seek specialist advice for future management).
Common: itching, rash, mild leucopenia, nausea, vomiting, gastric discomfort, headache, arthralgia.
Rare: agranulocytosis, hypoprothrombinaemia and bleeding, myositis, hepatitis, vasculitis, lupus-like syndrome.

Dosage
Hyperthyroidism
Adult; Initially, 20–40 mg daily (up to 60 mg daily in severe cases) in divided doses for 3–4 weeks.
Adjusted regimen, maintenance dose is usually 5–15 mg daily (but highly variable, range 2.5–40 mg daily) in single or divided doses according to response.
Block-replace regimen, continue initial dosage and add 100–150 micrograms thyroxine when T4 in normal range.
Thyroid storm
Adult, 60–80 mg daily, gradually reduced.
Counselling
Tell your doctor immediately if you develop a fever, mouth ulcers, sore throat or a rash.

Products
CARBIMAZOLE TABS  5 MG (CARBIMAZOLE®
, NEOMERCAZOL®)

 

06.03 DRUGS AFFECTING BONE METABOLISM

Osteoporosis

Osteoporosis occurs most commonly in postmenopausal women and in those taking long-term oral corticosteroids (glucocorticosteroids). Other risk factors for osteoporosis include; low body weight, cigarette smoking, excess alcohol intake, lack of physical activity, family history of osteoporosis, and early menopause.

Those at risk of osteoporosis should maintain an adequate intake of calcium and vitamin D and any deficiency should be corrected by increasing dietary intake or taking supplements.

Elderly patients, especially those who are housebound or live in residential or nursing homes, are at increased risk of calcium and vitamin D deficiency and may benefit from supplements. Reversible secondary causes of osteoporosis such as hyperthyroidism, hyperparathyroidism, osteomalacia or hypogonadism should be excluded, in both men and women, before treatment for osteoporosis is initiated.

Postmenopausal osteoporosis

The bisphosphonates (alendronic acid, disodium etidronate, and risedronate) are effective for preventing postmenopausal osteoporosis. Hormone replacement therapy (HRT) is an option where other therapies are contra-indicated, cannot be tolerated, or if there is a lack of response. The CSM has advised that HRT should not be considered first-line therapy for long-term prevention of osteoporosis in women over 50 years of age. HRT is of most benefit for the prophylaxis of postmenopausal osteoporosis if started early in menopause and continued for up to 5 years, but bone loss resumes (possibly at an accelerated rate) on stopping HRT. Calcitonin may be considered for those at high risk of osteoporosis for whom a bisphosphonate is unsuitable. Women of Afro-Caribbean origin appear to be less susceptible to osteoporosis than those who are white or of Asian origin.

Postmenopausal osteoporosis may be treated with a bisphosphonate. The bisphosphonates (such as alendronate, etidronate, and risedronate) decrease the risk of vertebral fracture; alendronate and risedronate have also been shown to reduce non-vertebral fractures. If bisphosphonates are unsuitable calcitriol or calcitonin may be considered. Calcitonin [unlicensed indication] may also be useful for pain relief for up to 3 months after a vertebral fracture if other analgesics are ineffective.

Corticosteroid-induced osteoporosis

To reduce the risk of osteoporosis doses of oral corticosteroids should be as low as possible and courses of treatment as short as possible. The risk of osteoporosis may be related to cumulative dose of corticosteroids; even intermittent courses can therefore increase the risk. The greatest rate of bone loss occurs during the first 6–12 months of corticosteroid use and so early steps to prevent the development of osteoporosis are important. Long-term use of high-dose inhaled corticosteroids may also contribute to corticosteroid-induced osteoporosis.

Patients taking (or who are likely to take) the equivalent of prednisolone 7.5 mg or more each day for 3 months or longer should be assessed and where necessary given prophylactic treatment; those aged over 65 years are at greater risk. Patients taking oral corticosteroids who have sustained a low-trauma fracture should receive treatment for osteoporosis.

Rationale for drug use
To prevent fractures and associated morbidity in people with low bone density or history of fracture.
Before starting treatment
Exclude other diseases that may cause bone fragility, eg metastatic cancer, multiple myeloma, osteomalacia.
Consider specific causes, eg hypogonadism, hyperthyroidism, hyperparathyroidism, liver disease, malabsorption syndromes, Cushing's disease, especially in men or where bone density is >2.5 standard deviations (SD) below young mean value.
Evaluate risk factors and manage when possible:

·         calcium intake, sunlight exposure, physical activity

·         smoking, alcohol, medications, eg thyroxine, corticosteroids, some antiepileptic drugs, heparin

·         age, gender, weight

·         menstrual history, eg early menopause

·         history of low-trauma fracture

·         family history of low-trauma fracture.

Consider fall prevention, eg regular weight-bearing physical activity, balance training, medication management (reduce use of sedatives), improving poor vision, and home and environment modification.
Moderate activity levels, including walking, may lower hip fracture risk in postmenopausal women.
Evidence for efficacy of hip protectors is still conflicting; further data are required before recommending their use.
When to start treatment
Consider treatment in people with presence or history of osteoporotic fracture or when bone density is >2.5 SD below young mean value, especially if they have other risk factors for fracture.
Drug choice
Calcium
Adequate calcium intake should be part of routine management; total intake (including diet) should be 1200–1500 mg daily in postmenopausal women.
Supplementation may reduce bone loss in osteoporosis, particularly in late postmenopausal women with a low dietary calcium intake; less effective than other treatments when used as sole therapy.
Vitamin D
Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2)
Increase bone density and reduce falls in older people.
In a study in institutionalised elderly women, vitamin D with calcium decreased risk of hip and vertebral fracture; however, results from other studies are conflicting. Vitamin D with calcium may not be effective for secondary prevention of low-trauma fractures in elderly people living in the community.
Calcitriol
Is the active form of vitamin D.
Reduces rate of bone density loss in postmenopausal osteoporosis; may reduce risk of vertebral fractures in women with a history of vertebral fracture; further efficacy data are required.
Monitor plasma calcium concentration regularly because of risk of hypercalcaemia and hypercalciuria.
Bisphosphonates
First line treatment of established postmenopausal osteoporosis. Alendronate and risedronate decrease risk of vertebral and non-vertebral fractures in postmenopausal women with a history of fracture.
Alendronate is also marketed for prevention of postmenopausal osteoporosis; however, it has not been shown to decrease risk of fractures in postmenopausal women with bone density <2.5 SD below young mean value.
Calcium and vitamin D supplements should be given with alendronate and risedronate if dietary intake is inadequate.
They are poorly absorbed orally. There is a risk of oesophageal adverse effects with alendronate and a risk of osteomalacia with continuous use and high doses of etidronate (intermittent administration in cycles alternating with calcium is required).
Optimal duration of treatment with bisphosphonates is uncertain. There is limited evidence of additional protective effect after 5 years of treatment. Long term effects on bones due to skeletal retention are yet to be determined. Harmful effects such as delayed or absent fracture healing has been reported in long term users.
Raloxifene
Is a selective oestrogen receptor modulator.
Increases bone density in postmenopausal women (but less than oestrogen); decreases risk of vertebral fractures, but not risk of non-vertebral fractures in postmenopausal women with osteoporosis.
Increases risk of VTE similar to that with HRT.
Long term data are needed to confirm that raloxifene decreases risk of breast cancer and does not increase risk of endometrial cancer.
Improves lipid profile; lowers LDL cholesterol but no effect on HDL cholesterol and triglycerides.
Reduces cardiovascular morbidity in women at risk of cardiovascular disease.
Does not cause vaginal bleeding and breast discomfort but may aggravate hot flushes.
May be useful as second line treatment of postmenopausal osteoporosis in women at risk of breast cancer.
Hormone replacement therapy
The Women's Health Initiative study, a randomised trial in >16 000 postmenopausal women, confirmed benefit of HRT for prevention of hip and vertebral fractures. Risk of colorectal cancer was also slightly decreased. However, there was an increased risk of coronary heart disease, breast cancer, stroke and thromboembolism. The benefit of fracture reduction does not outweigh increased risk of cardiovascular disease and breast cancer.
In postmenopausal women who have had a hysterectomy use of unopposed oestrogens decreased risk of hip fracture and increased risk of stroke and VTE, but did not appear to increase risk of coronary heart disease and breast cancer.
Teriparatide (human parathyroid hormone)
Teriparatide increases bone density and decreases risk of vertebral fractures in postmenopausal women with established osteoporosis. There are fewer data in men with primary osteoporosis. Further data are needed to determine its place in treatment for osteoporosis. Currently it is used when other agents are unsuitable and there is a high risk of fracture.
Treatment is restricted to a total of 18 months (teriparatide caused osteosarcoma in animal studies).
Strontium
Decreases risk of vertebral fractures in postmenopausal women with established osteoporosis or risk factors for osteoporosis. A significant effect on hip fracture has not been shown.
No comparative data with bisphosphonates.
Long term safety data on consequences of skeletal uptake of strontium and possible muscular, thromboembolic and neurological adverse effects are required.
Other drug treatment
Calcitonins are not marketed for osteoporosis in Australia. There is limited evidence for long term prevention of fractures. Expense, adverse effects and difficulties with administration limit their use.
Androgens should not be used for osteoporosis because of lack of documented efficacy in preventing fractures and risk of serious adverse effects.
Fluoride should not be used for osteoporosis unless further studies show effective and safe regimens.
Special cases
Corticosteroid-induced osteoporosis
Measure bone density in people starting corticosteroids if they are likely to take these long term; look for corticosteroid-induced hypogonadism in men.
To minimise risks:

·         use lowest effective dose of corticosteroids

·         use topical or inhaled preparations instead of oral preparations when possible

·         maintain adequate calcium intake, using calcium and vitamin D supplementation if necessary.

Most treatments used for corticosteroid-induced osteoporosis may prevent bone loss but further data are needed to assess their efficacy for preventing fractures.
Alendronate, etidronate and risedronate are marketed for prevention and treatment of corticosteroid-induced osteoporosis. There is some evidence that alendronate and risedronate prevent radiographic vertebral fractures.
Calcitriol is marketed for prevention of corticosteroid-induced osteoporosis; the risk of hypercalcaemia limits its use.

Osteoporosis in men
Secondary causes of osteoporosis are more common (eg hypogonadism, excess alcohol) and need specific treatment.
Limited data are available about specific prevention and treatment of osteoporosis in men. Consider fall prevention and supplementation with calcium and vitamin D.
Alendronate and calcitriol are marketed for treatment of osteoporosis in men; alendronate may reduce risk of vertebral fractures; there is no evidence of benefit for calcitriol in men.

 

Paget's disease of bone
Rationale for drug use
Relieve bone pain.
Prevent complications, eg bone deformities, pathological fractures, secondary osteoarthritis, neurological syndromes.
Preparation for orthopaedic surgery.
When to start treatment
Only 5% of people with Paget's disease have symptoms and/or complications that require drug treatment.
Time to start treatment is influenced by:

·         pain severity and persistence

·         disease location and extent

·         presence of complications

·         age of person

·         increase in biochemical markers of disease, eg plasma ALP, urinary hydroxyproline (may be normal in people with monostotic disease).

Drug choice
Bisphosphonates and calcitonins inhibit bone resorption, relieve bone pain and decrease biochemical markers.
Bisphosphonates
First line treatment.
Prolonged therapeutic effect (months to years).
Poor oral absorption; some may be given by intermittent IV infusion.
Risk of oesophageal adverse effects (which may be severe) with alendronate.
Etidronate can impair bone mineralisation, which limits dosage and treatment duration; avoid use in people with osteolytic lesions or fissure fractures of weight-bearing bones.
Long term effects on bones due to skeletal retention of the drugs remain to be determined.
Salcatonin
Rapid onset of analgesic effect (days to weeks).
Clinical response to treatment varies; limited biochemical effect (biochemical markers may not be reduced to the normal range).
Resistance to treatment may develop with rebound increase in biochemical markers during treatment; antibody-mediated resistance is rare despite frequent development of antibodies to salcatonin.
Short duration of remission after stopping treatment (some months); relapses tend to be increasingly resistant to repeated courses.
Adverse effects are common but usually improve with continuing drug use.
Available only as an injection.
Practice points

·         monitor plasma ALP and urinary hydroxyproline concentrations before treatment and every 3 months

·         ensure adequate calcium and vitamin D intake, especially during treatment with bisphosphonates, because of risk of osteomalacia

·         initiate retreatment when symptoms recur or, in some circumstances, when biochemical markers increase by 20–25% above the minimum achieved after previous course

 

06.03.01  Bipphosphonates 

Bisphosphonates are adsorbed onto hydroxyapatite crystals in bone, slowing both their rate of growth and dissolution, and therefore reducing the rate of bone turnover. Bisphosphonates have an important role in the prophylaxis and treatment of osteoporosis and corticosteroid-induced osteoporosis; alendronic acid or risedronate sodium are considered the drugs of choice for these conditions, but disodium etidronate may be considered if these drugs are unsuitable or not tolerated .

Bisphosphonates are also used in the treatment of Paget's disease, hypercalcaemia of malignancy, and in bone metastases in breast cancer . Disodium etidronate can impair bone mineralisation when used continuously or in high doses (such as in the treatment of Paget’s disease).

 

ALENDRONIC ACID 

Mode of action
Decrease bone resorption by inhibiting osteoclasts.
Indications
Paget's disease of bone; Prevention and treatment of osteoporosis (including postmenopausal and corticosteroid-induced); Hypercalcaemia of malignancy; Osteolytic bone metastases from breast cancer or multiple myeloma.
Contraindications
Oesophageal disorders (active oesophagitis, oesophageal ulceration, stricture, achalasia); Inability to stand or sit upright for at least 30 minutes after drug administration; Hypocalcaemia.

Specific considerations
Upper GI conditions (eg dysphagia, oesophageal disease, gastritis), concomitant use of NSAIDs: increase risk of oesophageal adverse effects.
Renal impairment: Excreted unchanged mainly via the kidney. Limited data in patients with renal impairment. Deterioration of renal function has been reported; avoid use in severe impairment; reduce infusion rate during IV administration. Dose reduction may be required when creatinine clearance is <35 mL/minute.
Pregnancy: No data available; avoid use ADEC category B3.
Breastfeeding: No data available; avoid use.
Adverse effects
Common: nausea, vomiting, diarrhoea, musculoskeletal pain, headache
I.V: fever, flu-like symptoms, injection site reaction, increased creatinine concentration, hypophosphataemia, hypomagnesaemia, hypocalcaemia, bone pain, myalgia, hypertension.
Infrequent: oesophagitis, oesophageal erosions and ulcers (mainly with alendronate), gastritis, duodenitis, glossitis, iritis, uveitis, scleritis, rash.
Rare: heart failure, renal impairment, osteonecrosis of the jaw, allergic reaction.
Dosage
Paget's disease: 40 mg once daily for up to 6 months.
Treatment of postmenopausal osteoporosis and osteoporosis in men: 10 mg once daily or 70 mg once a week.
Prevention of postmenopausal osteoporosis: 5 mg once daily.
Treatment and prevention of corticosteroid-induced osteoporosis: 5 mg once daily; 10 mg once daily for postmenopausal women not receiving oestrogen.
Counselling
Take in the morning with a full glass of water at least 30 minutes before food or drink. Remain upright during this time and until after you eat. Swallow whole; do not chew or suck on the tablet.
Do not take antacids, calcium, iron or mineral supplements within 30 minutes of alendronate as they may interfere with its absorption.
Stop tablets and see your doctor promptly if there is pain on swallowing, or new or worsening heartburn.
Practice points

·         limited data available about multiple courses of alendronate in Paget's disease

·         for osteoporosis and Paget's disease, ensure adequate intake of calcium and vitamin D; if necessary prescribe supplements (to be taken at a different time of day)

·         complete dental procedures before treatment with IV bisphosphonates to minimise risk of osteonecrosis of the jaw

Products
ALENDRONIC ACID TABS 10 MG (ALENDOMAX®
, BONMAX®, CALIDRON®, DROLATE®, FOSAMAX® )

ALENDRONIC ACID TABS 70 MG (ALFRA-PROSIS®, DROLATE®, FOSAMAX®, OSTEO-MEPHA® )

PAMIDRONIC ACID

Disodium PAMIDRONATE
Mode of action

Same as Alendronic Acid .
Indications

Same as Alendronic Acid .
Contraindications
Hypocalcaemia

Specific considerations
Cardiac disease: risk of heart failure.
Predisposition to renal impairment (eg hypercalcaemia of malignancy, multiple myeloma): monitor renal function because of risk of acute renal failure.
Previous thyroid surgery: risk of hypocalcaemia.
Hepatic impairment: No data in severe impairment. Manufacturer suggests infusing at <20 mg/hour in mild-to-moderate impairment.
Renal impairment: Excreted unchanged mainly via the kidney. If creatinine clearance <30 mL/minute, avoid use unless life-threatening hypercalcaemia is present. In less severe impairment infuse at <20 mg/hour.
Pregnancy: No data available; avoid use ADEC category B3.
Breastfeeding: No data available; avoid use.
Adverse effects
Common: nausea, vomiting, diarrhoea, musculoskeletal pain, headache
IV, fever, flu-like symptoms, injection site reaction, increased creatinine concentration, hypophosphataemia, hypomagnesaemia, hypocalcaemia, bone pain, myalgia, hypertension
Infrequent: oesophagitis, oesophageal erosions and ulcers (mainly with alendronate), gastritis, duodenitis, glossitis, iritis, uveitis, scleritis, rash
Rare: heart failure, renal impairment, osteonecrosis of the jaw, allergic reaction
Dosage
Paget's disease of bone
60 mg by slow IV infusion (15 mg/hour); optimal dosing regimen (interval between doses and total dose per treatment episode) adjusted individually according to response.
Hypercalcaemia of malignancy
Slow IV infusion (<60 mg/hour), dose adjusted according to initial plasma calcium concentration:

·         <3.0 mmol/L, 30 mg

·         3.0–3.5 mmol/L, 30–60 mg

·         3.5–4.0 mmol/L, 60–90 mg

·         >4.0 mmol/L, 90 mg.

Repeat dose every 2–3 weeks as necessary.
Bone metastases
Slow IV infusion (2 hours in breast cancer, 4 hours in multiple myeloma), 90 mg every 3–4 weeks.
Administration instructions
Dilute with sodium chloride 0.9% or glucose 5%.
Insert injection cannula carefully into a relatively large vein because of risk of local reactions.
Practice points

·         monitor plasma concentrations of electrolytes, including calcium, magnesium and phosphate during treatment

·         measure serum creatinine before each dose; if renal function deteriorates, withhold further dose until serum creatinine returns to within 10% of baseline value unless there is life-threatening hypercalcaemia

·         restore and maintain adequate hydration with sodium chloride 0.9% in hypercalcaemia

·         for osteoporosis and Paget's disease, ensure adequate intake of calcium and vitamin D; if necessary prescribe supplements (to be taken at a different time of day)

·         complete dental procedures before treatment with IV bisphosphonates to minimise risk of osteonecrosis of the jaw

Products
PAMIDRONIC ACID VIAL 15 MG/VIAL (AREDIA®
, PAMIDRONATE®)

PAMIDRONIC ACID VIAL 30 MG/VIAL (AREDIA®, PAMIDRONATE®)

PAMIDRONIC ACID VIAL 90MG/VIAL (PAMIDRON®, PAMIDRONATE®)

 

RISEDRONIC ACID 

Risedronate Sodium
Mode of action

Same asAlendronic Acid.
Indications

Same asAlendronic Acid.
Contraindications
Hypocalcaemia; Inability to stand or sit upright for at least 30 minutes.

Specific considerations

History of oesophageal disorders, concomitant use of NSAIDs: increase risk of oesophageal adverse effects.
Renal impairment: Excreted unchanged mainly via the kidney Not recommended in moderate-to-severe impairment.
Pregnancy: No data available; avoid use; ADEC category B3.
Breastfeeding: No data available; avoid use.
Adverse effects
Common: nausea, vomiting, diarrhoea, musculoskeletal pain, headache.

Infrequent: oesophagitis, oesophageal erosions and ulcers (mainly with alendronate), gastritis, duodenitis, glossitis, iritis, uveitis, scleritis, rash.
Rare: heart failure, renal impairment, osteonecrosis of the jaw, allergic reaction.
Dosage
Paget's disease: 30 mg once daily for 2 months.
Postmenopausal osteoporosis: 5 mg once daily or 35 mg once a week.
Corticosteroid-induced osteoporosis: 5 mg once daily.
Counselling
Take in the morning with a full glass of water at least 30 minutes before food or drink. Remain upright during this time and until after you eat. Swallow whole; do not chew or suck on the tablet.
Do not take antacids, calcium, iron or mineral supplements within 2 hours of risedronate as they may interfere with its absorption.
Stop tablets and see your doctor promptly if there is pain on swallowing, or new or worsening heartburn.
Practice points

·         for osteoporosis and Paget's disease, ensure adequate intake of calcium and vitamin D; if necessary prescribe supplements (to be taken at a different time of day)

·         complete dental procedures before treatment with IV bisphosphonates to minimise risk of osteonecrosis of the jaw

 Products

RISEDRONIC ACID TABS 5 MG (ACTONEL®)

RISEDRONIC ACID TABS 35 MG (ACTONEL®)

 

ZOLEDRONIC ACID

Mode of action.

Same asAlendronic Acid.
Indications
Hypercalcaemia of malignancy; Prevention of skeletal-related events in patients with advanced malignancies involving bone; Paget's disease of bone; Prevention and treatment of osteoporosis (including postmenopausal and corticosteroid-induced).
Contraindications
Hypocalcaemia; Oregnancy and breast feeding; Not recommended for children.
Specific considerations
Renal impairment: Excreted unchanged mainly via the kidney . No dosage adjustment required in mild impairment; avoid use in moderate-to-severe impairment.
reduce infusion rate during IV administration.
Pregnancy: No data available; avoid use; ADEC category B3.
Breastfeeding: No data available; avoid use.
Adverse effects
Common: nausea, vomiting, diarrhoea, musculoskeletal pain, headache.
I.V:  fever, flu-like symptoms, injection site reaction, increased creatinine concentration, hypophosphataemia, hypomagnesaemia, hypocalcaemia, bone pain, myalgia, hypertension.
Infrequent: oesophagitis, oesophageal erosions and ulcers (mainly with alendronate), gastritis, duodenitis, glossitis, iritis, uveitis, scleritis, rash.
Rare: heart failure, renal impairment, osteonecrosis of the jaw, allergic reaction.
Dosage
Hypercalcaemia of malignancy
Initial treatment, 4 mg by IV infusion over 15 minutes.
Repeated treatment, 8 mg by IV infusion over 15 minutes at least 1 week after initial treatment in patients who are refractory to initial treatment or who subsequently relapse.
Prevention of skeletal-related events: 4 mg by IV infusion over no less than 15 minutes, repeated every 3–4 weeks.
Administration instructions
Dilute with 100 mL sodium chloride 0.9% or glucose 5%.
Practice points

·         restore and maintain adequate hydration with sodium chloride 0.9% in hypercalcaemia

·         monitor calcium, phosphate and magnesium during treatment

·         measure serum creatinine before each dose; if renal function deteriorates, withhold further dosing until serum creatinine returns to within 10% of baseline value unless there is life-threatening hypercalcaemia

·         give supplements of 500 mg calcium and 10 micrograms (400 units) vitamin D daily to patients with advanced bone malignancies

·         for osteoporosis and Paget's disease, ensure adequate intake of calcium and vitamin D; if necessary prescribe supplements (to be taken at a different time of day)

·         complete dental procedures before treatment with IV bisphosphonates to minimise risk of osteonecrosis of the jaw

Products
ZOLEDRONIC ACID VIAL 4 MG/VIAL (ZOMETA®
)

 

06.03.02   Vitamin D Substances

ERGOCALCIFEROL

Also known as vitamin D2.
Mode of action
Regulate calcium homeostasis and bone metabolism. Increase intestinal absorption and renal reabsorption of calcium and phosphate. Promote bone mineralisation.
Indications
Prevention and treatment of vitamin D deficiency (osteomalacia in adults and rickets in children); Hypocalcaemia in hypoparathyroidism, hypophosphataemic rickets, renal osteodystrophy, chronic renal dialysis; Treatment of osteoporosis; Prevention of corticosteroid-induced osteoporosis.
Contraindications
Hypercalcaemia.
Specific considerations
Renal impairment: Avoid use in severe impairment (inability to convert ergocalciferol to active form).
Hyperphosphataemia: risk of ectopic calcification; restrict dietary phosphate and/or give phosphate binders.
Pregnancy: Safe to use at physiological doses; seek specialist advice for use at pharmacological doses; fetal risk with untreated maternal vitamin D deficiency may be greater than risk of vitamin D-related hypercalcaemia in the infant.
Breastfeeding: Safe to use at physiological doses; risk of hypercalcaemia in the infant at pharmacological doses.
Adverse effects
Most adverse effects are due to effects of hypercalcaemia; increased risk with calcitriol because of its high potency.
Early symptoms of hypercalcaemia include nausea, vomiting, constipation, anorexia, apathy, headache, thirst, sweating and polyuria.
Renal and cardiovascular damage may occur because of ectopic calcification.
Dosage
Treatment of moderate-to-severe vitamin D deficiency
75–125 micrograms (3000–5000 international units) daily for 6–12 weeks then 25 micrograms (1000 international units) daily.
Prevention of vitamin D deficiency, osteoporosis: 10–20 micrograms (400–800 international units) daily.
Dose equivalence: 1 international unit is equivalent to 0.025 micrograms.
Counselling
Avoid taking other medications (including over-the-counter and health food preparations) that contain vitamin D. Check with your pharmacist or doctor if you are unsure.
Practice points

·         some multivitamin products contain 10 micrograms (400 international units)

Products

ERGOCALCIFEROL (CALCIFEROL D2) AMPS 600,000 IU/AMP

ERGOCALCIFEROL (CALCIFEROL D2) BOTTLE  2000 MCG/BOTTLE

 

06.03.03 Other Drugs Affecting Bone

CALCITONIN 

Also known as salcatonin

Calcitonin is involved with parathyroid hormone in the regulation of bone turnover and hence in the maintenance of calcium balance and homoeostasis. Calcitonin (salmon) (salcatonin, synthetic or recombinant salmon calcitonin) is used to lower the plasma-calcium concentration in some patients with hypercalcaemia (notably when associated with malignant disease). Calcitonin is licensed for treatment of Paget’s disease of bone. It can also be used in the prevention and treatment of postmenopausal osteoporosis

Mode of action
Calcitonin is a natural hormone involved in calcium regulation and bone metabolism. It inhibits bone resorption; increases urinary excretion of calcium and phosphate.
Indications
Paget's disease of bone; Hypercalcaemia.
Specific considerations
Renal impairment: May require dosage reduction.
Children: Used in juvenile Paget's disease (hyperphosphatasia); dosing information limited, seek specialist advice.
Pregnancy: Does not cross placenta; ADEC category B2.
Breastfeeding: Safe to use.
Adverse effects
Common: flushing, nausea, vomiting, dizziness
Infrequent: inflammatory reaction at injection site
Rare: tingling of hands, increased urinary frequency, allergic reactions, including rash and anaphylaxis.
Dosage

Paget's disease
SC/IM, 50–100 units daily for 3–6 months.
Hypercalcaemia
5–10 units/kg daily by slow IV infusion over at least 6 hours, or by slow IV injection in 2–4 divided doses. Administration instructions
Dilute with 500 mL sodium chloride 0.9% for IV infusion.
Patient counselling
This medication can cause dizziness; avoid driving or operating machinery.
Practice points

·         common adverse effects last for 1–2 hours after administration and usually improve with continuing drug use

·         incidence of adverse effects may be reduced by giving SC rather than IM, administration at bedtime, giving once daily rather than twice daily, or use of an antiemetic

·         antibodies may develop after prolonged treatment; while the development of resistance to calcitonins is not uncommon, antibody-mediated resistance to treatment is rare

·         modest and transient effect seen in hypercalcaemia; tachyphylaxis typically develops over several days

Products
CALCITONIN AMPS 100 IU/AMP   1 ML AMP (CALCO®
, MIACALCIC®)

 

CALCITONIN NASAL SPRAY 200 IU/PUFF   2ML (14 PUFF) PER BOTTLE (CALCO®, MIACALCIC®, RAFACALCIN®)

 

CALCIUM

Indications
Marketed: Calcium deficiency; Adjunctive treatment in osteoporosis, osteomalacia and rickets; Acute hypocalcaemia and hypocalcaemic tetany; Hyperphosphataemia associated with renal failure (as phosphate binding agent); Severe hyperkalaemia not due to digoxin toxicity; Magnesium toxicity; Hydrofluoric acid burns, Antacid.
Accepted: Acute verapamil and diltiazem poisoning.

Combination with cholecalciferol (vitamin D3), Osteoporosis.
Contraindications
Hypercalcaemia; Hypercalciuria; Digoxin toxicity.
Specific considerations
Hyperparathyroidism: use cautiously as a phosphate binder in renal impairment (monitor calcium concentration).
Treatment with digoxin: combination may lead to arrhythmias; avoid using calcium injection solutions; monitor clinical effects, ECG and calcium concentrations if using oral calcium.
Treatment with calcitriol: increases risk of hypercalcaemia; avoid combination unless dietary intake is clearly inadequate.
Renal impairment: Monitor plasma calcium concentration; if necessary, reduce dosage or stop.
Pregnancy: Safe to use.
Breastfeeding: Safe to use.
Adverse effects
Common: belching, flatulence, abdominal distension, constipation.
Infrequent: hypercalcaemia, alkalosis, hypophosphataemia.
Rare: renal calculi, milk-alkali syndrome.

IV skin necrosis (extravasation), irritation.

Milk-alkali syndrome
Presents acutely with headache, nausea, irritability and weakness or chronically with uraemia, alkalosis and hypercalcaemia; usually triggered by concomitant vomiting and/or sodium bicarbonate ingestion.
Dosage
Calcium deficiency, adjunctive treatment in osteoporosis, osteomalacia, rickets
Oral, adjust dose individually; the recommended daily intake of calcium for adults is 800 mg, 1100–1200 mg during pregnancy and lactation, and 1200–1500 mg in postmenopausal women.
Acute hypocalcaemia:

IV, 2.25–4.5 mmol of elemental calcium (10–20 mL calcium gluconate injection 10%) by slow injection; then adjust according to plasma calcium concentration.
Hyperphosphataemia:

Oral, 168–1200 mg elemental calcium (given as 420–3000 mg calcium carbonate) with each meal according to clinical response.
Combination with cholecalciferol (vitamin D3):

Oral, 1–2 tablets daily.
Administration instructions
Do not inject calcium solutions IM or SC as they are extremely irritant. Avoid extravasation during IV injection.
Counselling
Phosphate binder, if you skip a meal save your dose and take it when you next eat.
Practice points

·         differences in formulation of calcium products (eg chewable tablet, effervescent tablet) may influence patient compliance

Products

CALCIUM CAPS 500 MG (AS DOPESILATE) (DOBESIL®, DOXIUM®)

 

STRONTIUM RANELATE 

Mode of action
Increases bone formation and reduces bone resorption.
Indications
Treatment of postmenopausal osteoporosis.
Specific considerations
History of, or increased risk of, VTE—increases risk of VTE.
Phenylketonuria—product contains aspartame which is metabolised to phenylalanine.
Renal impairment: not recommended if creatinine clearance <30 mL/minute.

Adverse effects
Common: nausea, diarrhoea, headache, dermatitis, increased creatine kinase concentration.
Rare: deep vein thrombosis, pulmonary embolism, CNS effects including disturbed consciousness, memory loss or seizures.
Dosage

2 g once daily at bedtime.

Patient counselling
This medication is best taken at bedtime, at least 2 hours after eating, because food and drink (especially calcium-containing products such as milk) can reduce its absorption. Mix the granules in water and drink immediately.

Practice points

Products
STRONTIUM RANELATE GRANULES 2 G/SACHET (PROTELOS®
)

 

06.04 DRUGS FOR ADRENAL INSUFFICIENCY

Corticosteroids Therapy

The adrenal cortex normally secretes hydrocortisone (cortisol) which has glucocorticoid activity and weak mineralocorticoid activity. It also secretes the mineralocorticoid aldosterone.

In deficiency states, physiological replacement is best achieved with a combination of hydrocortisone and the mineralocorticoid fludrocortisone; hydrocortisone alone does not usually provide sufficient mineralocorticoid activity for complete replacement.

In Addison's disease or following adrenalectomy, hydrocortisone 20 to 30 mg daily by mouth is usually required. This is given in 2 doses, the larger in the morning and the smaller in the evening, mimicking the normal diurnal rhythm of cortisol secretion. The optimum daily dose is determined on the basis of clinical response. Glucocorticoid therapy is supplemented by fludrocortisone 50 to 300 micrograms daily.

In acute adrenocortical insufficiency, hydrocortisone is given intravenously (preferably as sodium succinate) in doses of 100 mg every 6 to 8 hours in sodium chloride intravenous infusion 0.9%.

In hypopituitarism glucocorticoids should be given as in adrenocortical insufficiency, but since the production of aldosterone is also regulated by the renin-angiotensin system a mineralocorticoid is not usually required. Additional replacement therapy with levothyroxine and sex hormones should be given as indicated by the pattern of hormone deficiency.

Corticosteroids regulate gene expression which results in:

·         glucocorticoid effects, eg gluconeogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses

·         mineralocorticoid effects, eg hypertension, sodium and water retention, potassium loss.

Corticosteroids may have predominantly glucocorticoid effects (eg dexamethasone), mineralocorticoid effects (fludrocortisone), or a combination of both (eg hydrocortisone).

In comparing the relative potencies of corticosteroids in terms of their anti-inflammatory (glucocorticoid) effects it should be borne in mind that high glucocorticoid activity in itself is of no advantage unless it is accompanied by relatively low mineralocorticoid activity (see Disadvantages of Corticosteroids below). The mineralocorticoid activity of fludrocortisone is so high that its anti-inflammatory activity is of no clinical relevance. The table below shows equivalent anti-inflammatory doses.

Equivalent anti-inflammatory doses of corticosteroids

 

This table takes no account of mineralocorticoid effects, nor does it take account of variations in duration of action

Prednisolone 5 mg

Betamethasone 750 micrograms

Cortisone acetate 25 mg

Dexamethasone 750 micrograms

Hydrocortisone 20 mg

Methylprednisolone 4 mg

Triamcinolone 4 mg

 

The relatively high mineralocorticoid activity of cortisone and hydrocortisone, and the resulting fluid retention, make them unsuitable for disease suppression on a long-term basis. However, they can be used for adrenal replacement therapy ; hydrocortisone is preferred because cortisone requires conversion in the liver to hydrocortisone. Hydrocortisone is used on a short-term basis by intravenous injection for the emergency management of some conditions. The relatively moderate anti-inflammatory potency of hydrocortisone also makes it a useful topical corticosteroid for the management of inflammatory skin conditions because side-effects (both topical and systemic) are less marked ; cortisone is not active topically.

Prednisolone has predominantly glucocorticoid activity and is the corticosteroid most commonly used by mouth for long-term disease suppression.

Betamethasone and dexamethasone have very high glucocorticoid activity in conjunction with insignificant mineralocorticoid activity. This makes them particularly suitable for high-dose therapy in conditions where fluid retention would be a disadvantage.

Betamethasone and dexamethasone also have a long duration of action and this, coupled with their lack of mineralocorticoid action makes them particularly suitable for conditions which require suppression of corticotropin (corticotrophin) secretion (e.g. congenital adrenal hyperplasia). Some esters of betamethasone and of beclometasone (beclomethasone) exert a considerably more marked topical effect (e.g. on the skin or the lungs) than when given by mouth; use is made of this to obtain topical effects whilst minimising systemic side-effects (e.g. for skin applications and asthma inhalations).

Disadvantages of Corticosteroids

Overdosage or prolonged use may exaggerate some of the normal physiological actions of corticosteroids leading to mineralocorticoid and glucocorticoid side-effects.

Mineralocorticoid side-effects include hypertension, sodium and water retention and potassium loss. They are most marked with fludrocortisone, but are significant with cortisone, hydrocortisone, corticotropin, and tetracosactide (tetracosactrin). Mineralocorticoid actions are negligible with the high potency glucocorticoids, betamethasone and dexamethasone, and occur only slightly with methylprednisolone, prednisolone, and triamcinolone.

Glucocorticoid side-effects include diabetes and osteoporosis , which is a danger, particularly in the elderly, as it may result in osteoporotic fractures for example of the hip or vertebrae; in addition high doses are associated with avascular necrosis of the femoral head. Mental disturbances may occur; a serious paranoid state or depression with risk of suicide may be induced, particularly in patients with a history of mental disorder. Euphoria is frequently observed. Muscle wasting (proximal myopathy) may also occur. Corticosteroid therapy is also weakly linked with peptic ulceration (the potential advantage of soluble or enteric-coated preparations to reduce the risk is speculative only).

High doses of corticosteroids may cause Cushing's syndrome, with moon face, striae, and acne; it is usually reversible on withdrawal of treatment, but this must always be gradually tapered to avoid symptoms of acute adrenal insufficiency .

In children, administration of corticosteroids may result in suppression of growth.

Adrenal Suppression

During prolonged therapy with corticosteroids, adrenal atrophy develops and may persist for years after stopping. Abrupt withdrawal after a prolonged period may lead to acute adrenal insufficiency, hypotension or death (see Withdrawal of Corticosteroids, below). Withdrawal may also be associated with fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and weight loss.

To compensate for a diminished adrenocortical response caused by prolonged corticosteroid treatment, any significant intercurrent illness, trauma, or surgical procedure requires a temporary increase in corticosteroid dose, or if already stopped, a temporary re-introduction of corticosteroid treatment. Anaesthetists must therefore know whether a patient is taking or has been taking a corticosteroid, to avoid a precipitous fall in blood pressure during anaesthesia or in the immediate postoperative period. A suitable regimen for corticosteroid replacement, in patients who have taken more than 10 mg prednisolone daily (or equivalent) within 3 months of surgery, is:

·         Minor surgery under general anaesthesia: usual oral corticosteroid dose on the morning of surgery or hydrocortisone 25–50 mg (usually the sodium succinate) intravenously at induction; the usual oral corticosteroid dose is recommenced after surgery

·         Moderate or major surgery: usual oral corticosteroid dose on the morning of surgery and hydrocortisone 25–50 mg intravenously at induction, followed by hydrocortisone 25–50 mg 3 times a day by intravenous injection for 24 hours after moderate surgery or for 48–72 hours after major surgery; the usual pre-operative oral corticosteroid dose is recommenced on stopping hydrocortisone injections

Infections

Prolonged courses of corticosteroids increase susceptibility to infections and severity of infections; clinical presentation of infections may also be atypical. Serious infections e.g. septicaemia and tuberculosis may reach an advanced stage before being recognised, and amoebiasis or strongyloidiasis may be activated or exacerbated (exclude before initiating a corticosteroid in those at risk or with suggestive symptoms). Fungal or viral ocular infections may also be exacerbated.

Chickenpox

Unless they have had chickenpox, patients receiving oral or parenteral corticosteroids for purposes other than replacement should be regarded as being at risk of severe chickenpox . Manifestations of fulminant illness include pneumonia, hepatitis and disseminated intravascular coagulation; rash is not necessarily a prominent feature.

Passive immunisation with varicella–zoster immunoglobulin is needed for exposed non-immune patients receiving systemic corticosteroids or for those who have used them within the previous 3 months; varicella–zoster immunoglobulin should preferably be given within 3 days of exposure and no later than 10 days. Confirmed chickenpox warrants specialist care and urgent treatment . Corticosteroids should not be stopped and dosage may need to be increased.

Topical, inhaled or rectal corticosteroids are less likely to be associated with an increased risk of severe chickenpox.

Measles

Patients taking corticosteroids should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Use of Corticosteriods

Dosage of corticosteroids varies widely in different diseases and in different patients. If the use of a corticosteroid can save or prolong life, as in exfoliative dermatitis, pemphigus, acute leukaemia or acute transplant rejection, high doses may need to be given, because the complications of therapy are likely to be less serious than the effects of the disease itself.

When long-term corticosteroid therapy is used in some chronic diseases, the adverse effects of treatment may become greater than the disabilities caused by the disease. To minimise side-effects the maintenance dose should be kept as low as possible.

When potentially less harmful measures are ineffective corticosteroids are used topically for the treatment of inflammatory conditions of the skin . Corticosteroids should be avoided or used only under specialist supervision in psoriasis.

Corticosteroids are used both topically (by rectum) and systemically (by mouth or intravenously) in the management of ulcerative colitis and Crohn's disease.

Use can be made of the mineralocorticoid activity of fludrocortisone to treat postural hypotension in autonomic neuropathy.

Although very high doses of corticosteroids have been given by intravenous injection in septic shock, a study of high-dose methylprednisolone sodium succinate did not demonstrate efficacy and, moreover, suggested a higher mortality in some subsets of patients given the high-dose corticosteroid therapy. However, there is evidence that administration of lower doses of hydrocortisone (50 mg intravenously every 6 hours) and fludrocortisone 50 micrograms daily by mouth) is of benefit in patients who have adrenocortical insufficiency as a consequence of septic shock.

Dexamethasone and betamethasone have little if any mineralocorticoid action and their long duration of action makes them particularly suitable for suppressing corticotropin secretion in congenital adrenal hyperplasia where the dose should be tailored to clinical response and by measurement of adrenal androgens and 17-hydroxyprogesterone. In common with all glucocorticoids their suppressive action on the hypothalamic-pituitary-adrenal axis is greatest and most prolonged when they are given at night. In most normal subjects a single dose of 1 mg of dexamethasone at night, is sufficient to inhibit corticotropin secretion for 24 hours. This is the basis of the ‘overnight dexamethasone suppression test' for diagnosing Cushing's syndrome.

Betamethasone and dexamethasone are also appropriate for conditions where water retention would be a disadvantage.

A corticosteroid may be used in the management of raised intracranial pressure or cerebral oedema that occurs as a result of malignancy; high doses of betamethasone or dexamethasone are generally used. However, a corticosteroid should not be used for the management of head injury or stroke because it is unlikely to be of benefit and may even be harmful

In acute hypersensitivity reactions such as angioedema of the upper respiratory tract and anaphylactic shock, corticosteroids are indicated as an adjunct to emergency treatment with adrenaline (epinephrine). In such cases hydrocortisone (as sodium succinate) by intravenous injection in a dose of 100 to 300 mg may be required.

Corticosteroids are preferably used by inhalation in the management of asthma but systemic therapy in association with bronchodilators is required for the emergency treatment of severe acute asthma.

Corticosteroids may also be useful in conditions such as auto-immune hepatitis, rheumatoid arthritis and sarcoidosis; they may also lead to remissions of acquired haemolytic anaemia , and some cases of the nephrotic syndrome (particularly in children) and thrombocytopenic purpura .

Corticosteroids can improve the prognosis of serious conditions such as systemic lupus erythematosus, temporal arteritis, and polyarteritis nodosa; the effects of the disease process may be suppressed and symptoms relieved, but the underlying condition is not cured, although it may ultimately remit. It is usual to begin therapy in these conditions at fairly high dose, such as 40 to 60 mg prednisolone daily, and then to reduce the dose to the lowest commensurate with disease control.

For other references to the use of corticosteroids see Prescribing in Palliative Care, (immunosuppresion), (rheumatic diseases), (eye), (otitis externa), (allergic rhinitis), and (aphthous ulcers).

Pregnancy and breast-feeding

Following a review of the data on the safety of systemic corticosteroids used in pregnancy and breast-feeding the CSM has concluded:

·         corticosteroids vary in their ability to cross the placenta; betamethasone and dexamethasone cross the placenta readily while 88% of prednisolone is inactivated as it crosses the placenta;

·         there is no convincing evidence that systemic corticosteroids increase the incidence of congenital abnormalities such as cleft palate or lip;

·         when administration is prolonged or repeated during pregnancy, systemic corticosteroids increase the risk of intra-uterine growth restriction; there is no evidence of intra-uterine growth restriction following short-term treatment (e.g. prophylactic treatment for neonatal respiratory distress syndrome);

·         any adrenal suppression in the neonate following prenatal exposure usually resolves spontaneously after birth and is rarely clinically important;

·         prednisolone appears in small amounts in breast milk but maternal doses of up to 40 mg daily are unlikely to cause systemic effects in the infant; infants should be monitored for adrenal suppression if the mothers are taking a higher dose.

Administration

Whenever possible local treatment with creams, intra-articular injections, inhalations, eye-drops, or enemas should be used in preference to systemic treatment. The suppressive action of a corticosteroid on cortisol secretion is least when it is given as a single dose in the morning. In an attempt to reduce pituitary-adrenal suppression further, the total dose for two days can sometimes be taken as a single dose on alternate days; alternate-day administration has not been very successful in the management of asthma . Pituitary-adrenal suppression can also be reduced by means of intermittent therapy with short courses. In some conditions it may be possible to reduce the dose of corticosteroid by adding a small dose of an immunosuppressive drug.

 Withdrawal of corticosteroids

The CSM has recommended that gradual withdrawal of systemic corticosteroids should be considered in those whose disease is unlikely to relapse and have

·         recently received repeated courses (particularly if taken for longer than 3 weeks)

·         taken a short course within 1 year of stopping long-term therapy

·         other possible causes of adrenal suppression

·         received more than 40 mg daily prednisolone (or equivalent)

·         been given repeat doses in the evening

·         received more than 3 weeks’ treatment

Systemic corticosteroids may be stopped abruptly in those whose disease is unlikely to relapse and who have received treatment for 3 weeks or less and who are not included in the patient groups described above.

During corticosteroid withdrawal the dose may be reduced rapidly down to physiological doses (equivalent to prednisolone 7.5 mg daily) and then reduced more slowly. Assessment of the disease may be needed during withdrawal to ensure that relapse does not occur.

 

DEXAMETHASONE

Indications
Where corticosteroids are indicated, e.g. cerebral oedema, prevention of neonatal respiratory distress syndrome, chemotherapy-induced nausea and vomiting, croup
Adrenal insufficiency
Immunosuppression in transplantation and autoimmune diseases
As an anti-inflammatory, eg in inflammatory bowel disease, asthma, allergy and skin conditions
Antepartum to prevent respiratory distress syndrome in premature infants
Adjunctive treatment of chemotherapy-induced nausea and vomiting
Contraindications
Except when used for adrenal insufficiency:
Uncontrolled infection, Active peptic ulcer disease, Recent exposure to shingles, chickenpox or measles without prior immunity.

Intra-articular injection

Infective arthritis, Skin and soft tissue infections near joint (risk of introducing bacteria into joint), Prosthetic joint.
Specific considerations
Except when used for adrenal insufficiency:
Altered glucose tolerance: may increase insulin requirement or precipitate the need for insulin.
Hypertension, heart failure: may be worsened by sodium and water retention (mineralocorticoid effect) and enhanced vascular reactivity; more likely to occur with cortisone or hydrocortisone (consider using alternative corticosteroid).
Psychiatric disorders: may exacerbate psychosis and mood swings.
Glaucoma: may increase intraocular pressure.
Latent tuberculosis: may be reactivated; consider treatment with antitubercular drugs.
Osteoporosis: may be exacerbated.
Myasthenia gravis: increased muscle weakness may occur during treatment with corticosteroids; seek specialist advice.
Clotting disorders or anticoagulant treatment: risk of joint haemorrhage with intra-articular injection, seek specialist advice.
Surgery: Patients with hypothalamic–pituitary–adrenal (HPA) suppression or taking replacement doses of corticosteroids require corticosteroid protection against adrenal crisis during surgery and for 24–48 hours afterwards.
Wound healing may be delayed by pharmacological doses of corticosteroids.
Tight blood glucose control for 48 hours after surgery may reduce risk of wound infection.
Dental procedures should be performed before immunosuppression or with antibacterial cover during immunosuppressive treatment.
Children: Chronic use of corticosteroids may retard bone growth; follow growth and development carefully; catch-up growth may occur after corticosteroid withdrawal.
Pregnancy: Safe to use; ADEC category A.

Breastfeeding: Limited data available; consider using alternative corticosteroid, eg prednisolone.
Adverse effects
These adverse effects occur when corticosteroids are used for indications other than adrenal insufficiency.
Incidence of adverse effects is related to dose, route of administration and duration of treatment. Systemic effects may result from inhaled, intra-articular and topical treatment.
Short courses of high dose systemic treatment cause fewer adverse effects than prolonged courses of lower doses.
Common: dyspepsia, increased susceptibility to infection (eg oral, vaginal and intertriginous candidiasis), masking of signs of infection, acne, oedema, hypertension, hypokalaemia, hyperglycaemia, osteoporosis, spontaneous fractures, increased appetite, delayed wound healing, skin atrophy, growth retardation in children, myopathy, muscle weakness and wasting (particularly symptomatic on drug withdrawal), fat redistribution (producing cushingoid appearance), amenorrhoea, psychosis, euphoria, depression, adrenal suppression, bruising
Infrequent: burning and tingling in perineal area (high dose IV treatment); vertebral compression fractures and aseptic necrosis of the talus, or femoral and humoral heads
Intra-articular injection: headache, flushing, rashes, acute post-injection flare reactions, injection site irritation, joint discomfort (brief), increased blood glucose concentration (temporary)
Rare: peptic ulceration with short courses of high doses, posterior subcapsular cataracts, glaucoma, hypersensitivity reactions
Intra-articular injection: periarticular calcification (reversible), arthropathies, progressive cartilage damage, muscle wasting, skin and subcutaneous tissue atrophy, skin pigmentation changes, sterile abscess formation
Adrenal crisis
Acute cardiovascular collapse may occur when corticosteroids are abruptly stopped or if adrenal response is inadequate in periods of stress such as infection, trauma, surgery and blood loss.
Dosage
Adult
Cerebral oedema, IV 10 mg, then IM 4 mg every 6 hours; reduce dose over 5–7 days.
Prevention of neonatal respiratory distress syndrome, IM 6 mg every 12 hours for 4 doses (if delivery has not occurred).
Chemotherapy-induced nausea and vomiting, IV 8 mg, then oral 4 mg every 6 hours.
Bacterial meningitis, IV 10 mg every 6 hours for 4 days; start before or at the same time as antibacterials.
Child
Cerebral oedema, IV 1.5 mg/kg (maximum 10 mg), then 0.25 mg/kg every 4–6 hours; reduce dose over 5–7 days.
Croup, initially IV/IM 0.6 mg/kg, then oral for 2–3 days.
Chemotherapy-induced nausea and vomiting, IV/oral 0.2 mg/kg (maximum 8 mg), then 0.1 mg/kg (maximum 4 mg) every 6 hours.
Bacterial meningitis, IV 0.4 mg/kg every 12 hours for 2 days or 0.15 mg/kg every 6 hours for 4 days; start before or at the same time as antibacterials.
In adrenal insufficiency corticosteroids are used in doses which approximate physiological need (replacement doses); all other indications use doses that are supraphysiological (pharmacological doses).
Adjust dose according to response; higher doses are required for active disease than for maintenance treatment.
Counselling
Take the tablets or oral liquid with food to help reduce stomach upset.
Tell your doctor immediately if you have any signs of infection.
This medication may affect your mood, eg you may feel happy or sad; talk to your doctor if you have any concerns.
If you have been on this medication for more than 3 weeks the dose should be reduced gradually, not suddenly, when stopping treatment.
Tell all doctors, surgeons and dentists treating you that you are taking corticosteroids (or have taken them in the past). Consider wearing a Medic Alert® bracelet and carrying a card with the details of your treatment.
Practice points

·         can also be given by intra-articular or soft tissue injection for local effect

·         use of adjuvant IV dexamethasone (starting before or at the same time as IV antibacterials), reduces mortality and rate of complications of bacterial meningitis; when treating penicillin-resistant pneumococcal meningitis consider reduced CSF penetration of vancomycin due to corticosteroids

·         corticosteroids are used for a wide range of conditions often without substantial evidence of their effectiveness

When using pharmacological doses

·         measure blood glucose, weight, BP and electrolytes at baseline, then each week for the first month of treatment

·         watch for signs/symptoms of infection; signs of infection may be masked

·         avoid contact with faeces from a patient vaccinated with oral polio vaccine within the last 6 weeks as systemic infection may occur

·         consider treatment to suppress gastric acid when dose >15 mg daily of prednisolone or equivalent for >1 month

·         measure bone mineral density at baseline if likely to require repeat courses or chronic treatment

·         consider prevention of osteoporosis when beginning chronic treatment

Stress and HPA suppression

·         use of pharmacological doses of corticosteroids may result in an inadequate adrenal response in periods of stress, eg infection, trauma, blood loss, because of HPA suppression

·         degree of suppression depends on many factors and is particularly likely to occur with prolonged treatment (>3 weeks) and high doses

·         adrenal response may be depressed for >1 year after corticosteroid-induced HPA suppression

·         minimise suppression by giving corticosteroid doses in the morning or on alternate mornings

·         during stress may need to give extra corticosteroid in addition to the usual dose, see Drugs for adrenal insufficiency

Intra-articular injection

·         used for joints that fail to respond to systemic treatment

·         use a sterile technique, aspirate fluid from joint if possible (do not proceed with the corticosteroid if you have any suspicion that there is infection)

·         do not give >4 injections into any single joint over 1 year as there is a risk of developing progressive cartilage damage; seek specialist advice

·         avoid further intra-articular injections if there is no response after 2 consecutive injections

·         giving an intra-articular injection to a big toe affected by gout is generally not recommended because the procedure is very painful

·         some practitioners use a mixture of local anaesthetic and corticosteroid to reduce discomfort following intra-articular injection

·         instruct patients not to overuse the joint following intra-articular injection to avoid the risk of further joint deterioration and reduced beneficial effects

Prevention of neonatal respiratory distress syndrome

·         give antenatal corticosteroid therapy to women 24–34 weeks gestation at risk of preterm delivery within 7 days

·         betamethasone and dexamethasone are both effective in preventing neonatal respiratory distress syndrome

·         repeat courses of corticosteroids should not be used routinely; evidence of a significant benefit is lacking; trials are ongoing.

Products
DEXAMETHASONE ELIXER 0.5 MG/5ML  100 ML BOTTLE (DECADRON®
)

DEXAMETHASONE TABS 0.5 MG (DECADRON®, DEXAMED®)

DEXAMETHASONE AMPS 4 MG/ML (DEXAMED®, DEXAMETASONE RICHMOND®, DEXAMETASONE®, F-CORTEN®, FORTECORTINE®, ZENOS®, METHASONE®, DEXONIUM®)

 

FLUDROCORTISONE

Mineralocorticoid
Indications
Marketed: Mineralocorticoid replacement in adrenal insufficiency, with a glucocorticoid, Salt-losing congenital adrenal hyperplasia, with a glucocorticoid.
Accepted: Orthostatic hypotension.
Specific considerations
Heart failure: may be exacerbated by electrolyte changes and fluid retention; monitor and adjust fludrocortisone dosage carefully.
Low potassium concentrations: may be exacerbated by fludrocortisone-induced increase in potassium loss via the kidneys; monitor and treat accordingly (potassium supplementation may be needed).
Pregnancy: Safe to use; ADEC category A.
Breastfeeding: No data available.
Adverse effects
When used as mineralocorticoid replacement, adverse effects usually indicate that the dose (and/or salt intake) is too high.
Common: sodium and water retention, oedema, hypokalaemia, hypertension.
Rare: hypokalaemic alkalosis, heart failure.
Dosage
Adrenal conditions: 50–100 micrograms once or twice daily, adjust as needed.
Orthostatic hypotension: Adult, initially 100 micrograms daily, increasing to 200 micrograms daily if necessary.
Counselling
Take this medicine with food to help reduce stomach upset.
Do not stop taking this medicine suddenly. Tell your doctor if you develop swelling of the feet or ankles, headaches or weakness.
Products
FLUDROCORTISONE TABS 100 MCG AS ACETATE

 

HYDROCORTISONE

Glucocorticoid
Indications
Glucocorticoid replacement in adrenal insufficiency; Acute adrenal insufficiency.
Dosage
Replacement therapy: Adult, child, oral, 8–20 mg/m2 daily (8–30 mg daily in adults) given in 2 doses with two-thirds of the dose in the morning and one-third in the evening; may be doubled or trebled and given more frequently (every 6–8 hours) during intercurrent illness.
Acute adrenal insufficiency: Adult, IV/IM, 100 mg repeated every 4–8 hours for 24 hours. Child, IV/IM, 25–50 mg/m2 every 4–8 hours for 24 hours.
Practice points

·         patients and carers should know how to give IM hydrocortisone when oral intake is impossible and medical care is not available; this may be life saving

Products
HYDROCORTISONE TABS 10 MG (AS SUCCINATE)

HYDROCORTISONE TABS 20 MG (AS SUCCINATE) (HYDROSONE®)

HYDROCORTISONE VIAL 100 MG/VIAL (AS SUCCINATE) (HYDROCORTISONE®, HYDROCORTISONE MEDO®, HYDROCORTISONE SOD SUCC®, STANDACILLIN®)

 

PREDNISOLONE (PREDNISONE)

Mode of action
Corticosteroids regulate gene expression which results in:

·         glucocorticoid effects, eg gluconeogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses

·         mineralocorticoid effects, eg hypertension, sodium and water retention, potassium loss.

Indications

Same as Dexamethasone.
Contraindications

Same as Dexamethasone.
Specific considerations

Hepatic impairment: In severe impairment the conversion of prednisone to prednisolone may be diminished.
Breastfeeding: Safe to use; take dose immediately after a feed and wait 4 hours before the next feed. Doses up to 80 mg have been studied.
Adverse effects

Same as Dexamethasone.
Dosage
Once condition has stabilised, reduce to the minimum required to maintain control of disorder.
Adult
Initial autoimmune or inflammatory disease control, 1–2 mg/kg once daily and taper according to response.
Rheumatoid arthritis, 5–10 mg once daily.
Acute liver transplant rejection, 200 mg once daily for 3 days.
Acute gout, 20–50 mg once daily for 3–5 days, then taper dose over 7–10 days.
In tertiary syphilis (with benzylpenicillin), 20 mg every 12 hours for 3 doses to reduce Jarisch–Herxheimer reaction.
Child: Autoimmune disease, initially 2 mg/kg once daily, reducing over 2 months to nil or the minimum required to sustain remission.
Nephrotic syndrome, 60 mg/m2 daily (maximum 80 mg) until remission, then reducing over 3–4 months to nil.
Acute asthma, 1 mg/kg once daily for 3–5 days. Croup, 1 mg/kg every 12 hours for 1–2 doses.
In adrenal insufficiency corticosteroids are used in doses which approximate physiological need (replacement doses); all other indications use doses that are supraphysiological (pharmacological doses).
Adjust dose according to response; higher doses are required for active disease than for maintenance treatment.
Counselling

Same as Dexamethasone.
Practice points

·         prednisone is converted to the pharmacologically active prednisolone in the liver

·         Additional points: same as dexamethasone

Products

METHYL PREDNISOLONE AMPS 40 MG/AMP (AS ACETATE) (DEPOMEDROL®, EPIZOLONE®, MEDROLON®)

METHYL PREDNISOLONE AMPS 40 MG/AMP (AS ACETATE) (SOLU-MEDROL®)

PREDNISOLONE TABS 5 MG (AS ACETATE) (CORTOPE 5®, PREDNISOLONE®)

 

TETRACOSACTRIN

Corticotrophin analogue
Mode of action
Stimulates synthesis and release of corticosteroids.
Indications
Diagnostic aid for adrenocortical insufficiency; Hypsarrhythmia and/or infantile spasms (long acting suspension)
Specific considerations
Allergic disorders: risk of allergic reactions.
Pregnancy: Avoid use; ADEC category D.
Breastfeeding: Inactive orally; safe to use.
Adverse effects
Allergic reactions including anaphylaxis, adrenal haemorrhage (isolated cases).
Dosage
Diagnosis of adrenal insufficiency, solution, IM 0.25 mg as a single dose.
Practice points

·         failure to observe an adequate rise in plasma cortisol concentration (>500–650 nanomoles/L depending on the assay used) 30 minutes after administration of tetracosactrin (0.25 mg) may reflect adrenal insufficiency

Products

TETRACOSACTRIN AMPS  250 MCG/AMP (AS ACETATE)   1 ML AMP

 

 

06.05 DRUGS FOR INFERTILITY

Infertility
Treatment of infertility is highly specialised and depends on the cause.
Anovulatory infertility and polycystic ovary syndrome are commonly treated with clomiphene and occasionally with metformin or tamoxifen. Gonadotrophins (follicle stimulating hormones) may be used in women in whom clomiphene has been unsuccessful.
Women with hypopituitarism require FSH and LH. Multiple pregnancy is a major risk following ovulation induction with gonadotrophins. Risks of multiple pregnancies can be reduced by careful monitoring of follicle development by oestradiol measurement and ultrasound in a specialised unit.
Assisted reproduction techniques including in vitro fertilisation (IVF) and gamete intrafallopian transfer (GIFT) usually require down regulation with GnRH analogues (leuprorelin or nafarelin) or with newer GnRH antagonists (ganirelix and cetrorelix) and artificial stimulation of ovarian follicle growth by gonadotrophins.
HCG is commonly used in gonadotrophin-induced ovulation, IVF and GIFT to time release of eggs from the ovarian follicles and for luteal phase support. The combination of GnRH analogues, gonadotrophins and HCG is associated with a risk of serious ovarian hyperstimulation.
Progesterone is used for luteal phase support in assisted conception cycles when HCG is not recommended because of the risks of ovarian hyperstimulation. It is essential in assisted conception cycles when ovulation and natural progesterone production do not occur, eg treatment with donor oocytes; it is rarely indicated in natural conceptions.
Bromocriptine or cabergoline may be used to normalise prolactin levels and induce ovulation in women with hyperprolactinaemia where surgical treatment is not indicated.
HCG and/or FSH may be used in infertile males with hypopituitarism.

 

06.05.01 Gonadotrophines

 

Human CHORIONIC GONADOTROPHIN 

Also known as HCG.

Mode of action
Biological product; acts as LH
.
Indications
Induction of ovulation in infertility and assisted reproduction techniques; Prepubertal cryptorchidism; Hypogonadotrophic hypogonadism.

Contraindications
Ovarian cysts or enlargement not due to polycystic ovary syndrome; Genital bleeding of unknown origin; Ovarian, prostate, uterine or breast cancer; Hypothalamic or pituitary tumours; Fibroids incompatible with pregnancy.
Specific considerations

Asthma, epilepsy, migraine, cardiovascular and renal disorders: risk of androgen-induced fluid retention.
Prepubertal boys: risk of premature closure of epiphyses.
Pregnancy: Contraindicated; ADEC category B3.
Breastfeeding: Avoid use.
Adverse effects
Common: local reaction at injection site, abdominal or pelvic pain, breast pain, nausea, headache, ovarian cyst, multiple pregnancy.
Rare: allergic reaction.
Ovarian hyperstimulation syndrome
Symptoms usually mild with slight ovarian enlargement and abdominal pain. Rarely, a severe, life-threatening syndrome occurs with large ovarian cysts prone to rupture, ascites, pleural effusion, thromboembolic disorders and death.
Dosage
Induction of ovulation
IM 5000–10 000 units as a single dose.
Cryptorchidism, hypogonadism
IM 500–4000 units 3 times a week.

Practice points

·         use of these drugs is restricted to specialists; in assisted reproduction techniques, close monitoring of follicular development and oestrogen secretion is necessary for adjustment of dose and prevention of ovarian hyperstimulation syndrome

 Products
CHORIONIC GONADOTROPHIN AMPS/VIAL 5000 IU/AMP (CHORIOMON®
, CHORAGON®, GONACOR®, PREGNYL®)

 

MENOTROPHIN LH+FSH (HUMAN MENOPAUSAL GONADOTROPHINS)

Uses and Administration

Human menopausal gonadotrophins possess both follicle-stimulating hormone (FSH) activity and luteinising hormone (LH) activity at equal proportions. It is of pituitary origin obtained from the urinr of postmenopausal urine.

Human menopausal gonadotrophins are used in the treatment of male and female infertility due to hypogonadism. In anovulatory infertility unresponsive to clomifene, human menopausal gonadotrophins are administered to induce follicular maturation and are followed by treatment with chorionic gonadotrophin to stimulate ovulation and corpus luteum formation. In women with polycystic ovary syndrome a gonadorelin analogue may be given beforehand to suppress pituitary gonadotrophin production.

The dosage and schedule of treatment for female infertility must be determined according to the needs of each patient; it is usual to monitor response by studying the patient's urinary oestrogen excretion or by ultrasonic visualisation of follicles, or both. Human menopausal gonadotrophins may be given daily by intramuscular or subcutaneous injection to provide a dose of 75 to 150 units of FSH and gradually adjusted if necessary until an adequate response is achieved. Treatment is then stopped and followed after 1 or 2 days by single doses of chorionic gonadotrophin 5000 to 10 000 units. In menstruating patients treatment should be started within the first 7 days of the menstrual cycle. In the UK it has been suggested that the treatment course should be abandoned if no response is seen in 3 weeks although in the US the manufacturers recommend that an individual course should not exceed 12 days. This course may be repeated at least twice more if necessary.

An alternative schedule is to give three equal doses by intramuscular or subcutaneous injection, each providing 225 to 375 units of FSH on alternate days followed by chorionic gonadotrophin one week after the first dose.

In fertilisation procedures in vitro, or other assisted conception techniques, human menopausal gonadotrophins are used with chorionic gonadotrophin and sometimes also clomifene citrate or a gonadorelin analogue. Stimulation of follicular growth is produced by human menopausal gonadotrophins given by intramuscular or subcutaneous injection, in a dose providing 75 to 300 units of FSH daily, usually beginning on the 2nd or 3rd day of the menstrual cycle. An example of a combined regimen involves clomifene citrate 100 mg on days 2 to 6, with human menopausal gonadotrophins beginning on day 5 in a dose providing 150 to 225 units of FSH daily. Treatment is continued until an adequate response is obtained and the final injection of human menopausal gonadotrophins is followed 1 to 2 days later with up to 10 000 units of chorionic gonadotrophin. Oocyte retrieval is carried out about 32 to 36 hours later.

In men with infertility due to hypogonadotrophic hypogonadism, spermatogenesis is stimulated with chorionic gonadotrophin and then human menopausal gonadotrophins are added in a dose of 75 or 150 units of FSH two or three times weekly by intramuscular or subcutaneous injection. Treatment should be continued for at least 3 or 4 months.

Adverse Effects

Human menopausal gonadotrophins may cause dose-related ovarian hyperstimulation varying from mild ovarian enlargement and abdominal discomfort to severe hyperstimulation with marked ovarian enlargement or cyst formation, acute abdominal pain, ascites, pleural effusion, hypovolaemia, shock and thromboembolic disorders. Rupture of ovarian cysts and intraperitoneal haemorrhage has occurred, usually after pelvic examination. Fatalities have been reported.

Hypersensitivity reactions and local reactions at the injection site may occur. Nausea and vomiting, joint pains and fever have been reported; gynaecomastia, acne, and weight gain have occurred in men.

Precautions

Human menopausal gonadotrophins should not be given to pregnant patients. Use should be avoided in patients with abnormal genital bleeding, hormone sensitive malignancies such as those of the breast, uterus, prostate, ovaries or testes, or ovarian cysts or enlargement not caused by the polycystic ovary syndrome. Pituitary or hypothalamic lesions, adrenal or thyroid disorders, and hyperprolactinaemia should be treated appropriately to exclude them as causes of infertility before attempting therapy with human menopausal gonadotrophins. Patients who experience ovarian enlargement are at risk of rupture; pelvic examinations should be avoided or carried out with care and the recommendation has been made that sexual intercourse should be avoided while there is such a risk.

There is a risk of multiple births.

Interactions

In women who show evidence of excessive ovarian stimulation while receiving human menopausal gonadotrophins the use of drugs with luteinising-hormone (LH) activity increases the risk of ovarian hyperstimulation syndrome.

Products

MENOTROPHIN (LH+FSH)  (HUMAN MENOPAUSAL GONADOTROPHINS) AMPS 75+75 IU/AMP (MENOGON®, MENOPUR ®)

 

06.05.02 Gonadotrophin-releasing hormone analogues

Gonadorelin when injected intravenously in normal subjects leads to a rapid rise in plasma concentrations of both luteinising hormone (LH) and follicle-stimulating hormone (FSH). It has not proved to be very helpful, however, in distinguishing hypothalamic from pituitary lesions. Gonadorelin analogues are indicated in endometriosis and infertility and in breast and prostate cancer

Adverse Effects

Gonadorelin and its analogues are generally well tolerated but may cause gastrointestinal adverse effects, usually nausea and abdominal pain or discomfort. There may be headache or lightheadedness, and an increase in menstrual bleeding. Continued therapy with gonadorelin analogues results in paradoxical suppression of the pituitary gonadal axis; in premenopausal women this may produce menopausal symptoms, including vaginal dryness, hot flushes, and loss of libido. If sufficiently prolonged the suppression of circulating oestrogens may lead to osteoporosis. In men, hot flushes and sexual dysfunction have occurred. Breast swelling and tenderness in men have been reported infrequently with gonadorelin analogues. Other adverse effects reportedly associated with gonadorelin analogue therapy, and presumably related to changes in the hormonal milieu, include mood changes, nervousness, palpitations, acne and dry skin, alterations in liver function tests and blood lipids, decreased glucose tolerance, and changes in scalp and body hair. Ovarian hyperstimulation (as seen with chorionic gonadotrophin,, although rare, has occurred in women given gonadorelin.

Reactions or pain may occur at the site of injection with rash (local or generalised), thrombophlebitis, swelling, or pruritus. Hypersensitivity reactions, including bronchospasm and anaphylaxis, have been reported.

Other effects may be a consequence of the particular use of gonadorelin or its analogues. Tumour flare, due to an initial surge in testosterone concentrations, has been reported in the initial stages of treatment for cancer of the prostate and concomitant anti-androgen therapy may be given prophylactically. Flare may manifest as an increase in bone pain; occasionally there has been spinal cord compression, or a worsening of urinary-tract symptoms with haematuria and urinary obstruction. Acute degeneration of submucous fibroids with severe bleeding has been reported following use of leuprorelin. An initial increase in signs and symptoms has also been reported in women with breast cancer receiving gonadorelin analogues; hypercalcaemia has occurred in those with metastatic disease.

Precautions

Gonadorelin or its analogues should not generally be used in patients with pituitary adenoma as haemorrhagic infarction (pituitary apoplexy) has sometimes occurred. It has also been recommended that patients with weight-related amenorrhoea should not receive these drugs until their weight is corrected. While it has been recommended by at least one manufacturer that gonadorelin should not be used in women with polycystic ovary disease or with endometriotic cysts, gonadorelin and its analogues have produced improvement in polycystic disease and in uterine fibroids, and gonadorelin analogues have been used with benefit in endometriosis. Gonadorelin or its analogues should be discontinued if the patient becomes pregnant. Contraceptive measures should be taken to protect against unwanted ovulation. Men at risk from tumour flare should be carefully monitored in the first month of therapy.

Interactions

Drugs affecting pituitary secretion of gonadotrophins may alter the response to gonadorelin or its analogues; other hormonal therapy and corticosteroids can affect the response. Spironolactone and levodopa can stimulate gonadotrophins while phenothiazines, dopamine antagonists, digoxin, and sex hormones can inhibit gonadotrophin secretion.

Gonadorelin, or more usually its analogues such as buserelin, goserelin, leuprorelin, nafarelin, and triptorelin (which are more potent and have a longer duration of action) are used in cryptorchidism, malignant neoplasms (especially of the prostate), and in delayed and precocious puberty.

Gonadorelin is sometimes used as the hydrochloride or acetate.

Benign prostatic hyperplasia: The gonadorelin analogues have been tried in the management of benign prostatic hyperplasia but are considered unsatisfactory for indefinite use.

Cryptorchidism: Whether gonadorelin or its analogues have a role in the management of cryptorchidism is a matter of debate; surgery remains the treatment with the best success rate, but hormonal therapy, with gonadorelin or chorionic gonadotrophin or both, is widely employed. Meta-analysis has suggested a success rate of about 20% overall, although this may be reduced when care is taken to exclude retractile testes.

Premenstrual syndrome

In women in whom other drug treatments for premenstrual syndrome are ineffective, use of a gonadorelin analogue, usually with HRT to prevent menopausal symptoms, may be considered. Short-term therapy (3 months) has been used to confirm the diagnosis of premenstrual syndrome, or to predict the response to bilateral oophorectomy when this is being considered.

 

GONADORELIN (Gonadotropin –releasing hormone;GnRH;LH-RH)
Mode of action
GnRH stimulates synthesis of FSH and LH; continuous administration of GnRH analogues inhibits gonadotrophin production, suppressing ovarian and testicular steroidogenesis and inhibiting the growth of certain hormone-dependent tumours.

Uses and Administration

Gonadorelin is a synthetic form of hypothalamic gonadotrophin-releasing hormone. It stimulates the synthesis and release of follicle-stimulating hormone and, in particular, luteinising hormone in the anterior lobe of the pituitary. The secretion of endogenous gonadotrophin-releasing hormone is pulsatile and is controlled by several factors including circulating sex hormones. Gonadotrophic hormones (gonadotrophins), released from the pituitary gland in response to gonadorelin, stimulate secretion of sex hormones from the gonads. A single dose of gonadorelin or one of its analogues has the effect of increasing circulating sex hormones; continued administration leads to down-regulation of gonadorelin-receptor synthesis in the pituitary and results in a paradoxical reduction in sex-hormone secretion.

Gonadorelin is used in the diagnosis of hypothalamic-pituitary-gonadal dysfunction. Assessment is usually based on the response to a dose of gonadorelin of 100 micrograms by intravenous or subcutaneous injection. In females, where possible, it should be given early in the follicular stage of the menstrual cycle.

Gonadorelin is also used in the treatment of amenorrhoea and infertility associated with hypogonadotrophic hypogonadism and multifollicular ovaries. Weight-related amenorrhoea should have been corrected by diet. Treatment in such conditions is based on an intermittent pulse pump providing 5 to 20 micrograms over one minute every 90 minutes for up to 6 months or until conception.

Indications

Endometriosis; Uterine fibroids; Endometrial thinning before endometrial ablation; Pituitary down regulation to prepare for controlled ovarian stimulation; Advanced prostate cancer (stages C and D); Advanced breast cancer in premenopausal women; Precocious puberty.
Contraindications
Pituitary tumour; Undiagnosed vaginal bleeding.
Specific considerations
Urinary tract obstruction, metastatic vertebral lesions (prostatic cancer): risk of aggravation caused by tumour flare.
Women at risk of decreased bone mass, eg weight-related amenorrhoea, immobilisation, corticosteroid use, family history of osteoporosis: risk of decreased bone mass.
Polycystic ovarian disease: risk of cystic enlargement at the beginning of the treatment.
Pregnancy: Contraindicated; ADEC category D.
Breastfeeding: Contraindicated.
Adverse effects
Common: hot flushes, sweating, amenorrhoea, withdrawal bleeding, sexual dysfunction, reduced libido, vaginal dryness, changes in breast size, breast tenderness, arthralgia, myalgia, peripheral oedema, dizziness, headache, nausea, vomiting, constipation, mood changes, injection site reaction, thrombophlebitis, decreased bone mass.
Infrequent: bronchospasm, rash.
Rare: paraesthesia, depression.
Flare
A flare may develop during the first 2 weeks of treatment which may cause increased bone pain, and rarely ureteric obstruction or spinal cord compression, in patients with prostate cancer; and increased endometriotic symptoms and lesions in patients with endometriosis.
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome may occur, mainly when GnRH analogues are used with FSH in assisted reproduction techniques. Symptoms are usually mild with slight ovarian enlargement and abdominal pain. Rarely, a severe and life-threatening syndrome can occur with large ovarian cysts prone to rupture, ascites, pleural effusion, thromboembolic disorders and death.
Practice points

·         in non-cancer indications (eg endometriosis), courses >6 months and repeat courses are not recommended due to risk of decreased bone mass

·         in women of child-bearing age, give first injection during menstruation or shortly afterwards to exclude pregnancy (except in some dosing schedules used for assisted reproduction); use non-hormonal methods of contraception to avoid unwanted pregnancy in the event of missed doses

·         in infertility, monitor follicular development and oestrogen secretion to adjust dose and prevent ovarian hyperstimulation

·         in controlled ovarian stimulation before in-vitro fertilisation, stop treatment at least 3 days before fertilised embryos are placed in the uterus

Products

GONADORELIN LH-RH AMPS 100 MCG/AMP

 

GOSERELIN

Mode of action

Same as Gonadorelin.
Indications
Marketed: Advanced prostate cancer (stages C and D); Advanced breast cancer in premenopausal women; Adjuvant treatment in early breast cancer in pre- and peri-menopausal women; Endometriosis; Uterine fibroids; Endometrial thinning before endometrial ablation; Pituitary down regulation to prepare for controlled ovarian stimulation
Accepted: Precocious puberty, seek specialist advice; Advanced prostate cancer (stages C and D).
Contraindications
Pituitary tumour; Undiagnosed vaginal bleeding.
Specific considerations
Same as Gonadorelin.
Adverse effects

Rare: transient changes in BP, hypercalcemia ( in patients with metastatic breast cancer).

Others: Same as Gonadorelin.
Dosage
Endometrial thinning
SC, single 3.6 mg implant followed by surgery at 4 weeks, or two 3.6 mg implants inserted 4 weeks apart followed by surgery within 2–4 weeks of insertion of the second implant.
Endometriosis, uterine fibroids, assisted reproduction, breast cancer
SC, single 3.6 mg implant every 4 weeks (up to 6 months for endometriosis, for 3–6 months for uterine fibroids).
Prostate cancer

SC, single 3.6 mg implant every 4 weeks, or single 10.8 mg implant every 12 weeks.
Administration instructions
Insert SC into the anterior abdominal wall.
Practice points

Same as Gonadorelin.

Products

GOSERELIN PFS  3.6 MG (AS ACETATE) (ZOLADEX®)

GOSERELIN PFS 10.8 MG (AS ACETATE) (ZOLADEX®)

 

LEUPRORELIN

Mode of action

Same as Gonadorelin and Goserlin
Indications
Marketed: Advanced prostate cancer (stages C and D).
Accepted: Precocious puberty, seek specialist advice; Pituitary down regulation to prepare for controlled ovarian stimulation, seek specialist advice; Endometriosis; Uterine fibroids; Endometrial thinning before endometrial ablation; Advanced breast cancer in premenopausal women.
Contraindications

Same as Gonadorelin and Goserlin.
Specific considerations
Same as Gonadorelin and Goserlin.
Adverse effects

Same as Gonadorelin and Goserlin.
Dosage
Prostate cancer: Immediate release injection, SC, 1 mg daily.
Depot injection: 7.5 mg every month, 22.5 mg every 3 months, 30 mg every 4 months or 45 mg every 6 months.
Administration instructions
Alternate injection sites.
Practice points

·         consider starting treatment with daily leuprorelin injection rather than depot injection to facilitate treatment withdrawal if necessary; however, it is not known whether withdrawal will decrease flare reactions

·         depot injections have different release rates, eg one-third of a 22.5 mg injection is not equivalent to the 7.5 mg injection

·         dose for precocious puberty depends on clinical status

Products

LEUPRORELIN VIAL 3.75 MG/VIAL (AS ACETATE) (LUPRON®)

LEUPRORELIN VIAL 22.5 MG/VIAL (AS ACETATE) (LUPRON®)

 

TRIPTORELIN

Uses and Administration

Triptorelin is an analogue of gonadorelin with similar properties. It is used for the suppression of gonadal sex hormone production in the treatment of malignant neoplasms of the prostate, in precocious puberty, and in the management of endometriosis, female infertility, and uterine fibroids. Triptorelin may be used as the base, acetate, diacetate, or embonate, although for preparations containing the acetate or diacetate it is not always obvious which has been used.

Dosage

Doses are usually given in terms of the base, and the following are each approximately equivalent to 1 mg of triptorelin:

·         triptorelin acetate, 1.05 mg

·         triptorelin diacetate, 1.09 mg

·         triptorelin embonate, 1.30 mg

It is given as a daily subcutaneous injection, or as an intramuscular depot preparation lasting a month or longer.

In the treatment of prostate cancer, a dose equivalent to triptorelin 3 or 3.75 mg is given intramuscularly as a depot preparation every 4 weeks; the first dose may be preceded by 100 micrograms daily for 7 days by subcutaneous injection. A longer-acting depot preparation that contains the equivalent of triptorelin 11.25 mg is given once every 12 to 13 weeks. An anti-androgen such as cyproterone acetate may be given for several days before beginning therapy with triptorelin and continued for about 3 weeks to avoid the risk of a disease flare.

Similar doses of the 3 or 3.75 mg depot preparations may be given for up to 6 months in the management of endometriosis or uterine fibroids, with treatment begun during the first 5 days of the menstrual cycle. In the management of female infertility doses of 100 micrograms subcutaneously daily, with gonadotrophins, have been recommended from the second day of the menstrual cycle for about 10 to 12 days.

In children with precocious puberty a dose equivalent to triptorelin 50 micrograms/kg from the 3-mg depot preparation may be given intramuscularly every 4 weeks. Alternatively, using the 3.75-mg preparation, doses of 1.875 mg for children weighing less than 20 kg, 2.5 mg for children of 20 to 30 kg, or 3.75 mg for children of more than 30 kg may be given; the first 3 doses should be given at 14-day intervals, with further doses given every 4 weeks.

Delayed and precocious puberty.

Gonadorelin analogues such as triptorelin1-4 are used in the management of central precocious puberty. They may also be effective in delayed puberty although they are most likely to be helpful where this is due to hypogonadism. Triptorelin has been used to differentiate gonadotrophin deficiency from constitutional delayed puberty.

Disturbed behaviour.

Combined therapy with triptorelin, which suppressed testosterone secretion by inhibiting the pituitary-gonadal axis, and supportive psychotherapy, has been tried in the treatment of men with paraphilias: a reduction in abnormal sexual thoughts and behaviours has been reported, although the study was uncontrolled.

Endometriosis.

Gonadorelin analogues are effective in the management of endometriosis, but the need for long-term therapy to prevent recurrence limits their value because of the risk of osteoporosis; 'add-back' therapy, with concomitant hormone replacement, can be used to prevent this.

Fibroids.

Gonadorelin analogues have been used as an alternative to surgery in the treatment of uterine fibroids, despite some concern that this may complicate the diagnosis of malignancy.

Infertility.

Gonadorelin analogues are used in the management of infertility related to hypogonadotrophic hypogonadism in both men and women.

Malignant neoplasms.

Triptorelin, like other gonadorelin analogues, may be used in the production of androgen blockade in patients with prostate cancer.

Porphyria.

Triptorelin has been used successfully to suppress premenstrual exacerbations of acute intermittent porphyria, in doses of 3.75 mg by intramuscular depot injection given monthly.1,2 To reduce the risk of osteoporosis, 'add-back' therapy with topical oestrogen and oral calcium was used in one case,1 and tibolone in another

Pharmacokinetics

Triptorelin is rapidly absorbed following subcutaneous injection, with peak plasma concentrations achieved about 40 minutes after a dose. The biological half-life has been stated to be about 7.5 hours, although longer half-lives have been reported in patients with prostate cancer, and shorter half-lives in some groups of healthy subjects.

Adverse Effects and Precautions

As for Gonadorelin.

Effects of Buserelin Acetate

Products

TRIPTORELIN VIAL 3.75 MG/VIAL (AS ACETATE) (DECAPEPTYL®, GONAPEPTYL®)

TRIPTORELIN VIAL 11.25 MG/VIAL (AS ACETATE) (DECAPEPTYL®)

 

06.05.03 Treatments of Anovulatory Infertility

Anti-oestrogens

The anti-oestrogens clomifene (clomiphene) and tamoxifen are used in the treatment of female infertility due to oligomenorrhoea or secondary amenorrhoea (e.g. associated with polycystic ovarian disease). They induce gonadotrophin release by occupying oestrogen receptors in the hypothalamus, thereby interfering with feedback mechanisms; chorionic gonadotrophin is sometimes used as an adjunct. Patients should be warned that there is a risk of multiple pregnancy (rarely more than twins).

 

CLOMIPHENE CITRATE

Mode of action
Competitively antagonises oestrogen receptors in the hypothalamus. This interferes with normal negative feedback mechanisms and increases the release of pituitary gonadotrophins, especially LH, inducing ovulation.
Indications
Anovulatory infertility
Contraindications
Abnormal uterine bleeding (determine cause before starting treatment); Endometrial carcinoma.
Specific considerations
Ovarian cysts: may enlarge during treatment.
Hepatic impairment: Avoid use in severe impairment.
Pregnancy: Avoid use; ADEC category B3.
Breastfeeding: May reduce milk supply.
Adverse effects
Common: hot flushes, abdominal discomfort, visual blurring, reversible ovarian enlargement and cyst formation.
Infrequent: abnormal uterine bleeding, nausea, vomiting.
Rare: hair loss (reversible), ovarian hyperstimulation syndrome (see Practice points).
Dosage
50–100 mg daily for days 2–6 of the menstrual cycle. Specialist guidance necessary.
Counselling
Stop taking this medicine and tell your doctor if your vision becomes blurred; avoid driving or using machinery if you are affected.
Practice points

·         check liver function before starting treatment

·         clomiphene is used for polycystic ovary syndrome, but there is a significantly increased risk of multiple pregnancy if it is successful

·         ovarian hyperstimulation syndrome may occur in women with polycystic ovary syndrome, especially if pregnancy occurs in the cycle where clomiphene is given; pregnancy rates are poor in severe polycystic ovary syndrome

Products

CLOMIFENE TABS 50 MG (AS CITRATE) (CLOMID®, CLOMIFERT®, DUINUM®, FERTILINE®, INFANTRIL®, OVAMIT®, PROLIFEN®)

 

 

06.06 DRUGS FOR OTHER ENDOCRINE DISORDERS

06.06.01 Growth Hormone

Growth hormone is used to treat deficiency of the hormone in children and in adults (see NICE guidance below). In children it is used in Prader-Willi syndrome, Turner’s syndrome and in chronic renal insufficiency; growth hormone has also recently been licensed for use in short children considered small for gestational age at birth.

Growth hormone of human origin (HGH; somatotrophin) has been replaced by a growth hormone of human sequence, somatropin, produced using recombinant DNA technology.

NICE guidance (somatropin in children with growth failure)

NICE has recommended (May 2002) treatment with somatropin for children with:

·         proven growth-hormone deficiency;

·         Turner’s syndrome;

·         Prader-Willi syndrome;

·         chronic renal insufficiency before puberty.

Treatment should be initiated and monitored by a paediatrician with expertise in managing growth-hormone disorders; treatment can be continued under a shared-care protocol by a general practitioner.

Treatment should be discontinued if the response is poor (i.e. an increase in growth velocity of less than 50% from baseline) in the first year of therapy.

In children with chronic renal insufficiency, treatment should be stopped after renal transplantation and not restarted for at least a year

NICE guidance (somatropin for adults with growth hormone deficiency)

NICE has recommended (August 2003) somatropin in adults only if the following 3 criteria are fulfilled:

·         Severe growth hormone deficiency, established by an appropriate method,

·         Impaired quality of life, measured by means of a specific questionnaire,

·         Already receiving treatment for another pituitary hormone deficiency.

Somatropin treatment should be discontinued if the quality of life has not improved sufficiently by 9 months.

Severe growth hormone deficiency developing after linear growth is complete but before the age of 25 years should be treated with growth hormone; treatment should continue until adult peak bone mass has been achieved. Treatment for adult-onset growth hormone deficiency should be stopped only when the patient and the patient’s physician consider it appropriate.

Treatment with somatropin should be initiated and managed by a physician with expertise in growth hormone disorders; maintenance treatment can be prescribed in the community under a shared-care protocol.

 

SOMATROPIN

Synthetic human growth hormone
Mode of action
Promotes growth of skeletal, muscular and other tissues; stimulates protein anabolism and influences fat and mineral metabolism.
Indications
Short stature in children due to growth hormone deficiency, Turner's syndrome, chronic renal insufficiency, Prader–Willi syndrome or intrauterine growth retardation without spontaneous catch up by age 2
To correct neonatal hypoglycaemia due to growth hormone deficiency
Growth hormone deficiency and precocious puberty, irrespective of height and growth velocity
Growth hormone deficiency in adults
Contraindications
Active intracranial tumour or malignancy; Children with closed epiphyses; Acute critical illness due to trauma, abdominal or open heart surgery, or respiratory failure; With Prader–Willi syndrome, severe obesity, history of respiratory impairment, sleep apnoea, or unidentified respiratory infection; Allergy to somatropin or excipients.
Specific considerations
Diabetes: risk of hyperglycaemia; adjust dosage of insulin or oral antidiabetic drugs.
Hypothyroidism: can reduce response to soma-tropin, monitor thyroid function and give thyroxine if necessary.
Reduced thyroid stimulating hormone reserve (eg multiple pituitary hormone deficiencies): somatropin treatment may lead to secondary hypothyroidism.
Previous intracranial tumour: monitor for progression and recurrence.
Children post-renal transplant: seek specialist advice.
Pregnancy: Avoid use; ADEC category B2.
Breastfeeding: Avoid use.
Adverse effects
Common: local skin reaction (at injection site), peripheral oedema, arthralgia, growing pains in shins, carpal tunnel syndrome (in adults), paraesthesia (in adults)
Infrequent: hyperglycaemia, lipodystrophy (at injection site), exacerbation of scoliosis, increase in number and size of naevi, acral enlargement, excessive loss of central body fat, slipped capital epiphysis
Rare: papilloedema, benign intracranial hypertension, systemic allergic reaction
Dosage
1 mg somatropin is equivalent to 3 units. Individualise dosage according to response.
Adult: Initially, 40 micrograms/kg each week, divided into daily SC injections; up to 80 micrograms/kg each week.
Child: 4.5–7.5 mg/m2/week, divided into daily SC injections. Up to 9.5 mg/m2/week in Turner's syndrome and chronic renal insufficiency.
Administration instructions
Rotate injection site to prevent lipodystrophy.
Practice points

·         reports of Creutzfeldt–Jakob disease in people who received growth hormone extracted from human pituitary glands resulted in withdrawal of pituitary-derived preparations; because of the long incubation period new cases of infection may still be reported

·         gradual increase in dosage (eg starting at half or one-third of the recommended dosage) seems to minimise risk of adverse effects

·         watch for limping as this may indicate development of a slipped capital epiphysis

·         check for papilloedema if severe or recurrent headache, visual problems, nausea or vomiting occur

·         all products are now synthesised by recombinant DNA technology; however, synthesis and purification processes are different for each brand; do not change formulation during treatment because it may increase antibody response and complicate long term follow-up of drug safety

·         somatropin antibodies may develop in some people; they do not usually affect somatropin activity; however, testing for antibodies can be performed in people who fail to respond to treatment

Products
SOMATROPIN VIAL IU/ML  4-16 I.U (GENOTROPIN®
, GROWTROPIN®, HUMATROPE®, NORDITROPIN®, NORDILET®, SAIZEN®)

 

06.06.02 Somatostatin Analogues

Octreotide and lanreotide are analogues of the hypothalamic release-inhibiting hormone somatostatin. They are indicated for the relief of symptoms associated with neuroendocrine (particularly carcinoid) tumours and acromegaly. Additionally, lanreotide is licensed for the treatment of thyroid tumours and octreotide is also licensed for the prevention of complications following pancreatic surgery; octreotide may also be valuable in reducing vomiting in palliative care and in stopping variceal bleeding (unlicensed indication )

Cautions

Growth hormone-secreting pituitary tumours can expand causing serious complications; during treatment with somatostatin analogues patients should be monitored for signs of tumour expansion (e.g. visual field defects). Ultrasound examination of the gallbladder is recommended before treatment and at intervals of 6–12 months during treatment (avoid abrupt withdrawal of short-acting octreotide: see Side-effects below). In insulinoma an increase in the depth and duration of hypoglycaemia may occur (observe patients when initiating treatment and changing doses); in diabetes mellitus, insulin or oral antidiabetic requirements may be reduced.

 

LANREOTIDE

Mode of action
Inhibit release of growth hormone and of various peptides of the gastroenteropancreatic endocrine system; have a more prolonged duration of action than somatostatin (natural growth hormone inhibiting peptide).
Indications
Acromegaly where surgery, radiotherapy or dopamine agonist treatment have failed to control disease; Relief of symptoms associated with carcinoid tumours.
Specific considerations
Insulinoma: possible increase in severity and duration of hypoglycaemia.
Diabetes: variable effect on blood glucose; adjust dose of insulin and oral antidiabetic drugs.
Gastroenteropancreatic endocrine tumours: occasional sudden escape from symptomatic control with rapid recurrence of severe symptoms.
Pregnancy: Avoid use; may produce fetal growth retardation, probably due to suppression of growth hormone; ADEC category C.
Breastfeeding: Avoid use.
Adverse effects
Common: abdominal pain, flatulence, nausea, vomiting, diarrhoea, gallstones, fatigue, hyperglycaemia, hypoglycaemia, hair loss, transient local reaction at injection site.
Rare: hypothyroidism, pancreatitis, hepatic dysfunction.
Dosage
Acromegaly: IM, initially 30 mg every 2 weeks. Maintenance, adjust dosing intervals according to response.
No previous treatment with a somatostatin analogue, initially SC 60 mg once every 28 days. Maintenance, adjust dose strength according to response.
Previous treatment with Somatuline

·         every 14 days, initial dose SC 60 mg every 28 days

·         every 10 days, initial dose SC 90 mg every 28 days

·         every 7 days, initial dose SC 120 mg every 28 days.

Maintenance, adjust dose strength according to response.
Carcinoid tumours: Initially, SC 60–120 mg every 28 days, then adjust dose according to response.
Administration instructions
Rotate injection sites, should be given in the upper outer quadrant of the buttock.
Practice points

·         monitor thyroid function during long term treatment

·         ultrasound of the gall bladder before, and every 6–12 months during, treatment is recommended by the manufacturers

Products

LANREOTIDE VIAL 30 MG/VIAL (AS ACETATE) (SOMATULINE®)

LANREOTIDE VIAL 120 MG/VIAL (AS ACETATE) (SOMATULINE®)

 

OCTREOTIDE

Mode of action

Same as Lanreotide
Indications
Marketed: Acromegaly where surgery or radiotherapy are contraindicated or have failed to control disease, or until radiotherapy becomes fully effective; Relief of symptoms associated with gastroenteropancreatic tumours, e.g. carcinoid tumours, VIPomas; Prevention of complications following pancreatic surgery (SC octreotide only).
Accepted: Glucagonomas.
Specific considerations
Same as  Lanreotide.
Adverse effects
Common: abdominal pain, flatulence, nausea, vomiting, diarrhoea, gallstones, fatigue, hyperglycaemia, hypoglycaemia, hair loss, transient local reaction at injection site.
Rare: hypothyroidism, pancreatitis, hepatic dysfunction.
Dosage
Acromegaly
SC, initially, 50–100 micrograms every 8–12 hours. Maintenance, 200–300 micrograms daily.
IM, initially, 20 mg every 4 weeks for 3 months. Start the day after the last dose of SC octreotide. Maintenance, adjust dosage according to clinical and biological response.
Gastroenteropancreatic tumours
SC, initially, 50 micrograms once or twice daily. Maintenance, up to 200 micrograms 3 times daily. Higher doses may be required.
IM, initially, 20 mg every 4 weeks for 3 months. Continue octreotide SC for 2 weeks after first dose of long acting IM octreotide. Maintenance, adjust dosage according to clinical and biological response.
Pancreatic surgery:

SC, 100 micrograms 3 times daily for 7 days from the day of operation.
Administration instructions
Rotate injection sites. Give long acting octreotide by deep intragluteal injection only; avoid deltoid injection because of significant discomfort.
Practice points

·         GI adverse effects may occur at start of treatment and usually subside spontaneously in 10–14 days; they may be reduced by injecting between meals or at bedtime

·         avoid abrupt withdrawal of SC octreotide; risk of biliary colic and pancreatitis

·         monitor thyroid function during long term treatment

·         ultrasound of the gall bladder before, and every 6–12 months during, treatment is recommended by the manufacturers

Products

OCTREOTIDE AMPS 0.1 MG/AMP   1 ML AMP (SANDOSTATIN®)

OCTREOTIDE AMPS 0.5 MG/AMP   1 ML AMP

OCTREOTIDE AMPS 10 MG/PFS   1 ML PFS (SANDOSTATIN®)

OCTREOTIDE AMPS 20 MG/PFS   1 ML PFS (SANDOSTATIN®)

 

06.06.03 Antidiuretic Hormone Analogues and Antagonists

DESMOPRESSIN

Also known as DDAVP
Mode of action
Increases tubular reabsorption of water; increases factor VIII and von Willebrand's factor coagulation activity.
Indications
Diagnostic aid for differential diagnosis of polyuria; Pituitary diabetes insipidus, Nocturnal enuresis; Control of bleeding in patients with mild or moderate haemophilia and type I von Willebrand's disease; Control of bleeding in surgery in people with certain platelet disorders.
Contraindications
Heart failure; Type IIb von Willebrand's disease (high doses); Hyponatraemia.
Specific considerations
Fluid and/or electrolyte imbalance, treatment with diuretics, NSAIDs or drugs known to induce SIADH, or at risk of increased intracranial pressure: take precautions to avoid hyponatraemia and/or fluid overload.
Renal impairment: Creatinine clearance <50 mL/minute, although use of tablets is contraindicated by the manufacturer, it is used IV in specialist centres in patients with factor VIII deficiency or end stage renal failure to correct bleeding time before certain procedures.
Pregnancy: Seek specialist advice; ADEC category B2.
Breastfeeding: Safe to use.
Adverse effects
Common: headache, nausea, abdominal cramps, hyponatraemia, Injection, pain and swelling at injection site
Intranasal, local irritation and rhinitis.
Infrequent: water intoxication, seizures.
Dosage
Diabetes insipidus
Adult
Intranasal, 10–40 micrograms daily in 1 or 2 doses.
SC/IM/IV, 1–4 micrograms daily in 1 or 2 doses
Oral, 100–200 micrograms 3 times daily (range 200 micrograms – 1.2 mg daily).
Child

Intranasal, 2.5–20 micrograms daily in 1 or 2 doses
SC/IM/IV, up to 0.4 micrograms 3 times daily.
Oral, 100–200 micrograms 3 times daily
Renal function testing
Adult, intranasal, up to 40 micrograms; parenteral, up to 4 micrograms.
Child, intranasal, up to 20 micrograms
Infant, intranasal, up to 10 micrograms.
Dose equivalence: Intranasal dosage is approximately 10 times parenteral dosage.
Counselling
Tell your doctor immediately if you have headache, nausea, vomiting or weight gain
Practice points

·         spray or rhinyle delivery system (supplied with nasal solution and gives more flexibility in dosage than the spray) can be used for nasal administration

·         for diabetes insipidus, the larger dose is usually given at night to prevent nocturia and the smaller dose during the day

·         restrict fluid intake when giving desmopressin for renal function testing or nocturnal enuresis

·         monitor water balance, especially when the response to thirst is not functioning (eg sedated, unconscious or postoperative patients) or in patients with craniopharyngiomas or hypothala-mic lesions

Products
DESMOPRESSIN AMPS 4 MCG/AMPS (AS ACETATE) (MINIRIN®
) 

DESMOPRESSIN NASAL SPRAY  0.1 MG (AS ACETATE) (MINIRIN®, NOCTISSIN®)

DESMOPRESSIN TABS 60 MCG (AS ACETATE) (MINIRIN®)

DESMOPRESSIN TABS 120 MCG (AS ACETATE) (MINIRIN®)

 

06.06.04 Dopamine Agonists

Bromocriptine is a stimulant of dopamine receptors in the brain; it also inhibits release of prolactin by the pituitary. Bromocriptine is used for the treatment of galactorrhoea and cyclical benign breast disease, and for the treatment of prolactinomas (when it reduces both plasma prolactin concentration and tumour size). Bromocriptine also inhibits the release of growth hormone and is sometimes used in the treatment of acromegaly, but somatostatin analogues (such as octreotide) are more effective.

Cabergoline has actions and uses similar to those of bromocriptine, but its duration of action is longer. Its side-effects appear to differ from that of bromocriptine and patients intolerant of bromocriptine may be able to tolerate cabergoline (and vice versa).

Fibrotic reactions

The CSM has advised that ergot-derived dopamine-receptor agonists, bromocriptine, cabergoline, lisuride, and pergolide have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions.

Before starting treatment with these ergot derivatives it may be appropriate to measure the erythrocyte sedimentation rate and serum creatinine and to obtain a chest X-ray. Patients should be monitored for dyspnoea, persistent cough, chest pain, cardiac failure, and abdominal pain or tenderness. If long-term treatment is expected, then lung-function tests may also be helpful.

Quinagolide has actions and uses similar to those of ergot-derived dopamine agonists, but its side-effects differ slightly.

Suppression of lactation

Although bromocriptine and cabergoline are licensed to suppress lactation, they are not recommended for routine suppression (or for the relief of symptoms of postpartum pain and engorgement) that can be adequately treated with simple analgesics and breast support. If a dopamine-receptor agonist is required, cabergoline is preferred. Quinagolide is not licensed for the suppression of lactation.

Sudden onset of sleep

Excessive daytime sleepiness and sudden onset of sleep can occur with dopaminergic drugs.

Patients starting treatment with these drugs should be warned of the possibility of these effects and of the need to exercise caution when driving or operating machinery.

Patients who have suffered excessive sedation or sudden onset of sleep, should refrain from driving or operating machines, until those effects have stopped recurring.

 

BROMOCRIPTIN

Mode of action
Stimulate dopamine receptors; inhibit prolactin secretion; reduce size of prolactinomas; decrease growth hormone concentration in people with acromegaly.
Indications
Acromegaly where surgery or radiotherapy are contraindicated or failed to control disease, or until radiotherapy becomes fully effective; Hyperprolactinaemia, including prolactinomas; Prevention of onset of lactation in the puerperium for clearly defined medical reasons; Parkinson's disease.
Contraindications
Symptoms and/or history of serious psychiatric disorders; Pre-eclampsia, postpartum hypertension.
Specific considerations
Treatment with ergot alkaloids, vasoconstrictive sympathomimetics: possible increased risk of cardiovascular adverse effects; avoid combination.

Compromised cerebral or cardiac circulation: risk of hypotension and collapse.
Peptic ulcer: risk of gastric haemorrhage in people with acromegaly.
Dopamine antagonists (eg some antipsychotics, metoclopramide): avoid combined use (mutual antagonism).
Pregnancy: Safe to use; ADEC category A.
Breastfeeding: Inhibits lactation. Bromocriptine should not be used for suppression of established lactation because of possible severe adverse effects, eg stroke.
Hepatic impairment: Limited data; dosage reduction may be required in severe impairment.
Adverse effect 

Common: nausea, vomiting, abdominal pain, constipation, headache, dizziness, orthostatic hypotension, weakness, fatigue, nasal congestion, digital vasospasm, erythromelalgia, dyskinesia, psychiatric disorders (hallucination, confusion, delusion, psychotic episode), drowsiness, sudden sleep onset (particularly in patients with Parkinson's disease).
Rare: pleural effusion, retroperitoneal fibrosis (long term treatment with high doses of the ergot-derived dopamine agonists); gastric haemorrhage (in patients with acromegaly); hypertension, MI, seizure, stroke (in patients receiving bromocriptine for suppression of lactation); cardiac valvulopathy (infrequent with pergolide).

Dosage

Acromegaly
1.25 mg daily, increased gradually up to 10–30 mg daily according to response.
Hyperprolactinaemia
1.25 mg 2–3 times daily, increased gradually up to 2.5 mg 2–3 times daily according to response (up to 15 mg daily in divided doses in prolactinomas).
Prevention of onset of lactation
2.5 mg twice daily for 14 days (not until 4 hours after delivery and when vital signs are stable).

Counselling
Daily doses should be taken at night, especially when starting treatment.
Sometimes bromocriptine's side effects can be made worse by taking alcohol; avoid alcohol if this happens to you.
This medicine may cause dizziness or drowsiness; if affected, do not drive or operate machinery.
Be careful when you stand up as this medicine might make you feel dizzy if you stand up too quickly.
Take with food to lessen the chance of nausea or stomach upset.
Practice points

·         start treatment at low dose with the evening meal and increase gradually to limit adverse effects

·         consider contraceptive measures if pregnancy is unwanted in women treated for hyperprolactinaemia; oral hormonal contraceptives are safe to use when plasma prolactin concentration is in the normal range

·         monitor for pituitary enlargement, particularly during pregnancy (eg by checking visual fields)

·         monitor for symptoms of progressive fibrotic disorders in patients on long term treatment with ergot-derived dopamine agonists

Products

BROMOCRIPTINE TABS 2.5 MG (AS MESILATE) (PARLODEL®, RONALIN®)

 

CABERGOLINE

Mode of action

Same as Bromocriptin.
Indications

Same as Bromocriptin.
Contraindications

Same as Bromocriptin.
Specific considerations
Treatment with ergot alkaloids: possible increased risk of cardiovascular adverse effects; avoid combination.
Pregnancy: Limited data available; ADEC category B1.
Breastfeeding: Inhibits lactation.
Compromised cerebral or cardiac circulation: risk of hypotension and collapse.
Peptic ulcer: risk of gastric haemorrhage in people with acromegaly.
Dopamine antagonists (eg some antipsychotics, metoclopramide): avoid combined use (mutual antagonism).
Hepatic impairment: Limited data; dosage reduction may be required in severe impairment.
Adverse effects

Common: nausea, vomiting, abdominal pain, constipation, headache, dizziness, orthostatic hypotension, weakness, fatigue, nasal congestion, digital vasospasm, erythromelalgia, dyskinesia, psychiatric disorders (hallucination, confusion, delusion, psychotic episode), drowsiness, sudden sleep onset (particularly in patients with Parkinson's disease).
Rare: pleural effusion, retroperitoneal fibrosis (long term treatment with high doses of the ergot-derived dopamine agonists); gastric haemorrhage (in patients with acromegaly); hypertension, MI, seizure, stroke (in patients receiving bromocriptine for suppression of lactation); cardiac valvulopathy (infrequent).

Dosage

Hyperprolactinaemia
0.5 mg each week in 1 or 2 doses, increase gradually by 0.5 mg at monthly intervals up to 2 mg each week.
Prevention of onset of lactation

1 mg as a single dose during the first day postpartum.

Counselling
This medicine may cause dizziness or drowsiness; if affected, do not drive or operate machinery.
Be careful when you stand up as this medicine might make you feel dizzy if you stand up too quickly.
Take with food to lessen the chance of nausea or stomach upset.
Practice points

Same as Bromocriptin.

Products

CABERGOLINE TABS 0.5 MG (DOSTINEX®)

 

QUINAGOLIDE

Mode of action

Stimulate dopamine receptors; inhibit prolactin secretion; reduce size of prolactinomas; decrease growth hormone concentration in people with acromegaly.
Indications

Hyperprolactinaemia, including prolactinomas.
Contraindications

Symptoms and/or history of serious psychiatric disorders; Pre-eclampsia, postpartum hypertension.
Specific considerations
Pregnancy: Limited data available; ADEC category B3.
Breastfeeding:Inhibits lactation

Adverse effects

Common: nausea, vomiting, abdominal pain, constipation, headache, dizziness, orthostatic hypotension, weakness, fatigue, nasal congestion, digital vasospasm, erythromelalgia, dyskinesia, psychiatric disorders (hallucination, confusion, delusion, psychotic episode), drowsiness, sudden sleep onset (particularly in patients with Parkinson's disease)
Rare: pleural effusion, retroperitoneal fibrosis (long term treatment with high doses of the ergot-derived dopamine agonists); gastric haemorrhage (in patients with acromegaly); hypertension, MI, seizure, stroke (in patients receiving bromocriptine for suppression of lactation); cardiac valvulopathy (infrequent with pergolide), syncope

Dosage

25 micrograms daily (at bedtime) for 3 days, then 50 micrograms daily for 3 days, then 75 micrograms daily, then increase dose at intervals of at least 1 week until optimal response achieved. Usual maintenance dose 75–150 micrograms daily.
If >300 micrograms daily required, dosage increases of 75–150 micrograms should be made at intervals of at least 4 weeks.

Counselling
This medicine may cause dizziness or drowsiness; if affected, do not drive or operate machinery.
Be careful when you stand up as this medicine might make you feel dizzy if you stand up too quickly.
Take with food to lessen the chance of nausea or stomach upset.
Practice points

Products

QUINAGOLIDE TABS 75 MCG (NORPROLAC®)

 

06.06.05 Male Sex Hormones and Antagonists (Androgens And Anti-Androgens)

06.06.05.01 Androgens 

Androgens cause masculinisation; they may be used as replacement therapy in castrated adults and in those who are hypogonadal due to either pituitary or testicular disease. In the normal male they inhibit pituitary gonadotrophin secretion and depress spermatogenesis. Androgens also have an anabolic action which led to the development of anabolic steroids .

Androgens are useless as a treatment of impotence and impaired spermatogenesis unless there is associated hypogonadism; they should not be given until the hypogonadism has been properly investigated. Treatment should be under expert supervision.

When given to patients with hypopituitarism they can lead to normal sexual development and potency but not to fertility. If fertility is desired, the usual treatment is with gonadotrophins or pulsatile gonadotrophin-releasing hormone which will stimulate spermatogenesis as well as androgen production.

Caution should be used when androgens or chorionic gonadotrophin are used in treating boys with delayed puberty since the fusion of epiphyses is hastened and may result in short stature.

Intramuscular depot preparations of testosterone esters are preferred for replacement therapy. Testosterone enantate, propionate or undecanoate, or alternatively Sustanon®, which consists of a mixture of testosterone esters and has a longer duration of action, may be used. Satisfactory replacement therapy can sometimes be obtained with 1 mL of Sustanon 250®, given by intramuscular injection once a month, although more frequent dose intervals are often necessary. Implants of testosterone can be used for hypogonadism; the implants are replaced every 4 to 5 months. Menopausal women are also sometimes given implants of testosterone (in a dose of 50–100 mg every 4–8 months) as an adjunct to hormone replacement therapy.

 

MESTEROLONE

Mode of action

Same as Testosterone.
Indications

Same as Testosterone.
Contraindications

Same as Testosterone.
Specific considerations

Same as Testosterone.

Adverse effects

Same as Testosterone but spermatogenesis unimpaired.
Comparative information
All can cause virilisation in women and precocious sexual development in children (see
Adverse effects).
Testosterone should be used in preference to synthetic androgens in male hypogonadism due to either pituitary or testicular disease or following castration. Androgen replacement is important to prevent long term complications such as osteoporosis, in addition to maintaining sexual function.
Practice points

·         androgens are misused by some athletes and body builders in an attempt to increase muscle mass; such misuse exposes these people to an increased risk of serious adverse effects

Products

MESTEROLONE TABS 25 MG (PROVIRON®)

 

TESTOSTERONE

Mode of action
Stimulate and maintain sexual function and characteristics in men.
Indications
Male hypogonadism due to either pituitary or testicular disease or following castration; Delayed puberty in adolescent males.
Contraindications

Prostate or breast cancer (in men); Pregnancy and breastfeeding.
Specific considerations
Cardiovascular disorders, renal or hepatic impairment, epilepsy, migraine, diabetes: risk of fluid retention.
Women:Avoid use; risk of severe adverse effects, including suppression of ovarian activity and menstruation, virilisation.
Children:Use with extreme caution in boys; risk of inhibition of growth due to premature closure of epiphyses; do not use in girls except on specialist advise.
Adverse effects

Severe adverse effects result mainly from inappropriate use of androgens in women, children, athletes and body builders.
sodium and water retention, oedema, acne, gynaecomastia, impotence, testicular atrophy, priapism, inhibition of spermatogenesis, degenerative changes in seminiferous tubules, amenorrhoea, clitoral enlargement, impaired glucose tolerance, hypercalcaemia, polycythaemia, decreased clotting factors, increased LDL cholesterol, aggressive behaviour, psychotic symptoms, physical and psychological dependence, withdrawal symptoms, premature closure of epiphyses

Adverse effects of physiological doses of testosterone are mainly related to the route of administration.
GI adverse effects, eg oily stools, nausea (testosterone undecanoate); bleeding, infection, extrusion (implant).
Skin irritation: Very common with patches; pre-treatment with a topical corticosteroid may reduce incidence. Testosterone gel is less irritating than the patches.

Dosage
Dosage should be adjusted according to clinical response and formulation.
Male hypogonadism
Testosterone undecanoate, oral 120–160 mg daily in 2 divided doses for 2–3 weeks (if using an odd number of capsules daily, the morning dose should be bigger), then adjust, according to response, to 40–120 mg daily.
Testosterone implant, SC 100–600 mg every 4–5 months

Testosterone enanthate, initially, IM 250 mg every 2–3 weeks.  Maintenance, 250 mg every 3–6 weeks

Testosterone esters, IM 100–250 mg every 2–3 weeks
Testosterone patch, apply 1 patch (5 mg/24 hours) each night. Adjust the dose using 2.5 mg/24 hours patches (usual range 2.5–7.5 mg daily).
Testosterone gel , apply 5 g (equivalent to testosterone 50 mg) once daily. Adjust dose, according to response, in increments of 2.5 g (use half a 5 g sachet); maximum 10 g daily.
Delayed puberty
Testosterone undecanoate , initially 40 mg once daily; maintenance 80–120 mg once daily.
Testosterone enanthate , IM 50–100 mg each month.

Counselling
Capsules: This medicine is absorbed best when taken with a meal, Swallow whole without chewing.
Patches: Apply at night to clean, flat, dry, unbroken skin, eg back, abdomen, thigh or upper arm (not the scrotum). Avoid oily or hairy skin (very hairy skin may be clipped to enable the patch to stick) and bony areas such as the hip or shoulder. Remove the old patch each night and apply a new patch to a different area, to reduce skin irritation.
Gel: Spread thinly onto clean, dry, healthy skin of the shoulder, arm or abdomen (not genitals). You don't need to rub it in but allow the gel to dry before getting dressed. Wash your hands thoroughly after using the gel and cover the area with clothing once the gel has dried. Do not allow others to touch the application area as there is potential for transfer of testosterone; shower before situations where skin-to-skin contact is likely.

Practice points

·         testosterone undecanoate has variable oral bioavailability and short duration of action; it may be used when other routes of administration are poorly tolerated or not recommended

·         enough testosterone to cause virilisation can be absorbed by children from skin contact with people using transdermal testosterone products; emphasise to patients the importance of others avoiding contact with the application area

·         androgens are misused by some athletes and body builders in an attempt to increase muscle mass; such misuse exposes these people to an increased risk of serious adverse effects

Products
TESTOSTERONE AMPS 100 MG/AMP (AS ENANTATE)

TESTOSTERONE AMPS 250 MG/AMP (AS ENANTATE) (SUSTANON®, TESTOVIRON®)

06.06.05.02 Anti-Androgens

 

CYPROTERONE

Cyproterone acetate is an anti-androgen used in the treatment of severe hypersexuality and sexual deviation in the male. It inhibits spermatogenesis and produces reversible infertility (but is not a male contraceptive); abnormal sperm forms are produced. Fully informed consent is recommended and an initial spermatogram. As hepatic tumours have been produced in animal studies, careful consideration should be given to the risk/benefit ratio before treatment. Cyproterone acetate is also used as an adjunct in prostatic cancer and in the treatment of acne and hirsutism in women.

Mode of action
Competitive blockade at androgen receptors; inhibit androgen activity.
Indications
Advanced prostate cancer; Suppression of GnRH analogue-associated initial tumour flare; Hot flushes associated with orchidectomy or GnRH analogue; Reduction of sexual drive in men; Moderately severe-to-severe signs of androgenisation in women (hirsutism, alopecia, seborrhoea, acne).
Contraindications
History of hepatic impairment, except if due to metastases.
Specific considerations
Thromboembolic disease, sickle cell anaemia, diabetes with vascular disease: rare reports of thromboembolic events.
Severe chronic depression: cyproterone can cause depression.
Diabetes: altered carbohydrate metabolism; monitor blood glucose concentration.
Adverse effects
Common: nausea, vomiting, increased transaminase concentrations, impotence, reduced libido, hot flushes, body hair loss, sweating, gynaecomastia, breast pain, itch, weight changes, headache, mood changes, insomnia, lethargycognitive changes, fatigue, oedema, inhibition of spermatogenesis, reduced ejaculate volume.
Infrequent: jaundice, hepatitisAllergic reactions, shortness of breath, diarrhoea, reduced adrenal function, depression.
Rare: hepatic failure (sometimes fatal with cyproterone), thrombosis, pulmonary embolism, tachycardia, intra-abdominal haemorrhage, osteoporosis.
Dosage
Advanced prostate cancer, suppression of GnRH analogue-associated initial tumour flare: Initially 100 mg 3 times daily; can reduce to twice daily.
Hot flushes with GnRH therapy or after orchidectomy:100 mg daily, reducing to 50 mg daily or alternate days.
Reduction of sexual drive in men: 50 mg twice daily.
Counselling

Take this medicine after a meal.
This medicine may cause tiredness and difficulty concentrating; do not drive or operate machinery if this occurs. You may get shortness of breath; see your doctor if this is troublesome.
See your doctor immediately if you notice yellowing of the skin or eyes, dark urine or itch.
Practice points

·         monitor liver function tests at baseline, then every 6 months

·         due to the risk of hepatotoxicity, the UK Committee on Safety of Medicines recommends that cyproterone use in prostate cancer be restricted to short courses unless patients are unresponsive to, or intolerant of, other treatments

o    when used with GnRH analogue to suppress tumour flare, start antiandrogens 2 weeks before GnRH analogue and continue for 2–4 weeks

o    if there is a risk of spinal cord compression or ureteric obstruction it is important to start antiandrogens first; consider orchidectomy for rapid castrate levels of androgen

o    monitor liver function tests at baseline, then at regular intervals, see individual monographs

o    transaminases usually return to normal with continued treatment; stop antiandrogen treatment if transaminase concentrations exceed 3 times upper limit of normal range

o    withdrawal of nonsteroidal antiandrogen should precede the use of more toxic treatments for hormone-refractory prostate cancer as paradoxical disease regression may occur

Products

CYPROTERONE TABS 50 MG (AS ACETATE) (ANDROCUR®)

 

FINASTERIDE

Mode of action
Inhibits 5-alpha-reductase conversion of testosterone to dihydrotestosterone (a potent cellular androgen that stimulates prostate growth). Reduces prostate size, decreases urinary outflow resistance and reduces symptoms.
Indications
Mild-to-moderate symptoms of BPH with clinically demonstrated prostatomegaly (>40 cm3), and surgery is contraindicated or refused; Androgenetic alopecia in men.
Specific considerations
Pregnancy: Finasteride may cause abnormalities of the external genitalia of a male fetus. Drugs taken by men have not been proven to result in abnormalities in their children. ADEC category X..
Adverse effects
Common: These adverse effects are infrequent with dosage used for alopecia (1 mg daily).
impotence, decreased libido, decreased ejaculate volume.
Rare: breast tenderness and enlargement, allergic reaction.
Dosage
5 mg daily.
Practice points

Products

FINASTERIDE TABS 5 MG (FINASCAR®, PROSCAR®, PROSTACARE®, PROTESIDE®)

 

06.06.06 Drugs for Menopausal Symptomes (HRT)

CONJUGATED OESTROGENS
Mode of action
A drop in production of endogenous oestradiol can lead to symptoms such as hot flushes, night sweats and urogenital atrophy. These symptoms can be relieved by administration of oestrogen in HRT. Progestogen reduces risk of endometrial carcinoma associated with unopposed oestrogen.
Indications
Menopausal symptoms, eg hot flushes (includes combination products with medroxyprogesterone)
Prevention of osteoporosis, when non-oestrogen treatment is inappropriate (includes combination products with medroxyprogesterone); controversial, see Postmenopausal osteoporosis
Female hypogonadism, seek specialist advice
Contraindications
Previous or active thromboembolic disorder ; Unexplained uterine bleeding; Severe liver disease; Breast cancer or other oestrogen-dependent tumour; Cerebrovascular or coronary artery disease.
Specific considerations
Pregnancy: Avoid use; ADEC category D.
History of breast cancer: although HRT is associated with an increased risk of breast cancer, there is uncertainty about the risk in patients with treated breast cancer, seek specialist advice.
Hypertension: may be exacerbated.
Diabetes: conflicting data on effects on glucose metabolism but no increased incidence of clinical diabetes.
Migraine: may be exacerbated or relieved.
Gall bladder disease: may be exacerbated.
Endometriosis: may be activated or exacerbated.
Epilepsy: higher dose of oestrogen may be needed, as antiepileptics may increase clearance of oestrogen; re-titrate oestrogen dose according to symptoms if necessary when changing treatment for epilepsy.

Smoking: increases risk of thromboembolism.
Uterine fibroids: fibroids may increase in size.
Jaundice during pregnancy or previous oestrogen use: may recur.
Acute Porphyria: may cause an attack; avoid if possible; oestrogens may be safe in replacement doses.
Hepatic impairment: Avoid use in severe impairment.
Surgery: When possible, stop HRT 4 weeks before elective surgery that has a significant risk of postoperative thromboembolism, as HRT may increase this risk.
Adverse effects

Common: mastalgia, abnormal mammogram, headache, depression, change in libido, weight change, breakthrough bleeding, spotting, leg cramps, dry eye syndrome (oestrogen alone)
Infrequent: breast cancer, premenstrual-like syndrome, dementia, migraine, stroke, venous thromboembolism, pulmonary embolism, cardiovascular events, fluid retention, oedema, increased BP, endometrial hyperplasia, dry eye syndrome (combination HRT), acne, itch, nausea, increased triglycerides
Rare: gall stones, cholestatic jaundice, pancreatitis, glucose intolerance, galactorrhoea, visual changes, chloasma, hypersensitivity (angioedema, urticaria), ovarian cancer, endometrial cancer, enlargement of uterine fibroids, enlargement of hepatic haemangiomas
Breast cancer

Incidence of breast cancer increases with age. Type of HRT and duration of use further increase the risk.
Recent studies have found:

·         increase in breast cancer, seen within 3–4 years

·         that, in contrast to previous studies, breast cancer was diagnosed at a more advanced stage (and was more likely to be fatal) for HRT users than for those taking placebo

·         breast cancer risk was highest for those taking progestogen and oestrogen

·         there was no evidence of a difference in breast cancer risk between sequential and continuous regimes, various routes of administration or different oestrogens or progestogens (risk with tibolone appears to be higher than for oestrogen alone and less than that of oestrogen and progestogen regimens)

·         increased risk diminishes to that of never users after HRT has been stopped for 5 years.

Endometrial cancer
Oestrogen-only HRT is associated with an increased risk of endometrial hyperplasia and cancer. This risk is reduced by addition of a progestogen,

Venous thromboembolism (VTE)
Women using HRT are likely to have a 2- to 4-fold increased risk for idiopathic thromboembolism compared with non-users. In younger women without heart disease this small increase in incidence (from 1/10 000 to 3/10 000 per year) appears acceptable, but in older women, particularly with established cardiovascular disease, both risks (increased from 23/10 000 to 62/10 000 per year) and benefits need to be weighed more carefully.
Dosage
Combination regimens, give either continuously (with a progestogen for 10–14 days each month) or for cycles of 3 weeks with a 7 day break, with a progestogen for last 10 days of oestrogen.
Menopausal symptoms: Oral, 0.3–1.25 mg daily, use minimum dose to control symptoms.
Osteoporosis prevention: Oral, 0.625 mg daily.
Patient counselling
Tell your doctor immediately if you develop:

symptoms of a blood clot (red, swollen or painful leg, difficulty in breathing, or chest pain)

changes in your breasts (skin changes, lump, nipple changes)

changes in vaginal bleeding a few months after starting HRT (e.g. heavy or irregular bleeding, or bleeding after sex).

Practice points

·         review need for treatment regularly (at least annually)

·         withdraw HRT slowly, eg over 3–6 months, to minimise withdrawal symptoms

·         choose vaginal preparations for women who only have urogenital symptoms

·         irregular or atypical bleeding may indicate endometrial pathology and warrants further investigation

·         HRT is not associated with improvement in quality of life (unrelated to relief of menopausal symptoms) and it is not effective for prevention of:

o    cardiovascular disease

o    dementia

o    anxiety or depression

·         consider HRT for women without coronary heart disease (taking into account risks, eg VTE, cancer) to:

o    treat menopausal symptoms

o    prevent loss of bone mineral density and fractures in women at high risk of osteoporosis, when other treatments are inappropriate (however benefit does not appear to outweigh risks, even in these patients, unless vasomotor symptoms are very troublesome)

·         consider need for progestogen carefully in women who have not had a hysterectomy; balance prevention of endometrial hyperplasia and reduced risk of endometrial carcinoma against the increased risk of breast cancer.

·         women who dislike periods may benefit from:

o    reducing the oestrogen dose or

o    using continuous progestogen or

o    using a progestogen course once every 3 months (produces less frequent withdrawal bleeds)

Perimenopause

·         HRT does not provide contraceptive protection; conception can still occur in the perimenopause even though fertility is reduced, see also Contraception

·         consider low dose oral contraceptives (in preference to HRT products) until the menopause occurs, then if still needed, change to HRT

·         vasomotor symptoms may occur during the pill-free week for oral contraceptives; symptoms may be reduced by tricycling packs or using HRT doses of oestrogen during this time

Products
CONJUGATED ESTROGENS TABS 0.625 MCG (PREMARIN®
)

 

06.06.07 Drugs for Peripheral Vascular Disease

NICERGOLINE

Adverse Effects and Precautions

Adverse effects which may occur after nicergoline include gastrointestinal disturbances and, particularly after parenteral administration, hypotension.

Porphyria: Nicergoline is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems, although there is conflicting evidence of porphyrinogenicity.

Uses and Administration

Nicergoline is an ergot derivative. It has been used similarly to co-dergocrine mesilate to treat symptoms of mental deterioration associated with cerebrovascular insufficiency and has also been used in peripheral vascular disease. Nicergoline has been given in doses of up to 60 mg daily by mouth in divided doses, and by intramuscular injection in doses of 2 to 4 mg twice daily; 4 to 8 mg daily has been given by slow intravenous infusion. Nicergoline tartrate has been used in preparations for parenteral administration.

Products

NICERGOLINE TABS 5 MG (SERGOLIN®, SERMION®)

 

PENTOXIFYLLINE (OXYPENTIFYLLINE)

Xanthine derivative
Mode of action
Vasodilator; reduces blood viscosity.
Indications
Symptom relief of claudication in patients with peripheral vascular disease unsuitable for surgical treatment.
Specific considerations
Cerebral or retinal haemorrhage, peptic ulcer disease: may exacerbate bleeding; avoid use.
Acute MI: risk of arrhythmia; avoid use.
Renal impairment: Dosage reduction may be required in severe impairment.
Pregnancy: No data available; avoid use; ADEC category B1.
Breastfeeding: No data available; avoid use.
Adverse effects
Common: nausea, vomiting, dizziness, headache, flushing.
Infrequent: angina, palpitations.
Rare: hypersensitivity, itching, rash, urticaria, bleeding, hallucinations, arrhythmias, aseptic meningitis.
Dosage
400 mg 2–3 times daily.
Counselling
Swallow tablet whole; do not crush or chew. Take with food to reduce stomach upset.

Products

PENTOXIFYLLINE TABS 400 MG (CIRCULAID®, OXYPHYL®, PENTOXINE®, PENTYLLIN®, TRENTAL®)

PENTOXIFYLLINE TABS 600 MG

 


 

Table 06–01 Insulins: Comparative Information

Insulin type

Onset of action (hours)

Time to peak activity (hours)

Duration of action (hours)

ultra-short acting

insulin lispro, insulin aspart

0.25

1

4–5

short acting

 

 

 

neutral

0.5

2–3

6–8

intermediate acting

non-mixed

1–2.5

4–12

16–24

mixed with short acting insulin

0.5–1

2–12

16–24

mixed with ultra-short acting insulin

0.25

1

16–18

long acting

insulin glargine

1–2

 

24

non-mixed

2–4

10–20

24–36

 

 

Table 06–02 Sulfonylureas: Comparative Information

Sulfonylurea

Frequency of administration

Risk of hypoglycaemia

glibenclamide

once or twice daily

high

glimepiride

once daily

high/intermediate

glipizide

once or twice daily

low/intermediate

gliclazide

once or twice daily

intermediate