Captopril

Concomitant use of alpha blocking agents may increase the antihypertensive effects of captopril and increase the risk of orthostatic hypotension.

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored.

Since captopril is excreted primarily via the kidneys, dosage should be reduced or the dosage interval should be increased in patients with impaired renal function. When concomitant diuretic therapy is required, a loop diuretic (e.g. furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment.

In patients with impaired renal function, the following daily dose may be recommended to avoid accumulation of captopril.

ACE inhibitors may enhance the hypotensive effects of certain tricyclic antidepressants and antipsychotics. Postural hypotension may occur.

Pharmacological studies have shown that ACE inhibitors, including captopril, can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics such as sulphonylurea in diabetics. Should this very rare interaction occur, it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE inhibitors.

Concomitant use of captopril with nitroglycerine and other nitrates, or other vasodilators, should be used with caution.

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with captopril. The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of captopril. However, no clinically significant drug interactions have been found in specific studies with hydrochlorothiazide or furosemide.

ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.

Captopril has been safely co-administered with other commonly used anti-hypertensive agents (e.g. beta-blockers and long-acting calcium channel blockers). Concomitant use of these agents may increase the hypotensive effects of captopril.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

It has been described that non-steroidal anti-inflammatory medicinal products (NSAIDs) and ACE inhibitors exert an additive effect on the increase in serum potassium whereas renal function may decrease. These effects are, in principle, reversible. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated. Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor.

Concomitant administration of allopurinol, procainamide, cytostatic or immuno-suppressive agents with ACE inhibitors may lead to an increased risk for leucopenia especially when the latter are used at higher than currently recommended doses.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of captopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.

Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may be corrected by volume expansion.

ACE inhibitors should be used with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Limited pharmacokinetic data demonstrate very low concentrations in breast milk. Although these concentrations seem to be clinically irrelevant, the use of captopril in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In the case of an older infant, the use of captopril in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

As with other antihypertensives, the ability to drive and use machines may be reduced, namely at the start of the treatment, or when posology is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility.

Frequency is defined using the following convention: common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) and very rare (<1/10,000).

Undesirable effects reported for captopril and/or ACE inhibitor therapy include:

Blood and lymphatic disorders

Very rare: neutropenia/agranulocytosis, pancytopenia particularly in patients with renal dysfunction, anaemia (including aplastic and haemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, auto-immune disorder

Metabolism and nutrition disorders

Uncommon: decreased appetite

Very rare: hyperkalaemia, hyponatremia, hypoglycaemia

Psychiatric disorders

Common: insomnia

Very rare: confusional state, depression

Nervous system disorders

Common: dysgeusia, dizziness

Uncommon: headache, paraesthesia

Rare: somnolence

Very rare: cerebrovascular accident, cerebrovascular insufficiency, syncope

Eye disorders

Very rare: vision blurred

Cardiac disorders

Uncommon: tachycardia, arrhythmia, angina pectoris, palpitations.

Very rare: cardiac arrest, cardiogenic shock

Vascular disorders

Uncommon: hypotension, Raynaud’s phenomenon, flushing, pallor, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common: dry, irritating (non-productive) cough and dyspnoea

Very rare: bronchospasm, rhinitis, alveolitis allergic/eosinophilic pneumonia

Gastrointestinal disorders

Common: nausea, vomiting, epigastric discomfort, abdominal pain, diarrhoea, constipation, dry mouth, peptic ulcer, dyspepsia

Rare: stomatitis/aphthous stomatitis, small bowel angioedema

Very rare: glossitis, pancreatitis

Hepato-biliary disorders

Very rare: hepatic function abnormal, cholestasis, jaundice, hepatitis, hepatic necrosis, hepatic enzyme increased, blood bilirubin increased, transaminase increased, blood alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Common: pruritus with or without a rash, rash, and alopecia

Uncommon: angioedema

Very rare: urticaria, Stevens-Johnson syndrome, erythema multiforme, photosensitivity reaction, pemphigoid, dermatitis exfoliative

Musculoskeletal, connective tissue and bone disorders

Very rare: myalgia, arthralgia

Renal and urinary disorders

Rare: renal impairment, renal failure, polyuria, oliguria, pollakiuria

Very rare: nephrotic syndrome

Reproductive system and breast disorders

Very rare: erectile dysfunction, gynaecomastia

General disorders and administration site conditions

Uncommon: chest pain, fatigue, malaise, asthenia

Very rare: pyrexia

Investigations

Very rare: proteinuria, eosinophilia, blood potassium increased, blood sodium decreased, blood urea increased, blood creatinine increased, blood bilirubin increased, haemoglobin decreased, haematocrit decreased, white blood cell count decreased, platelet count decreased, antinuclear antibody positive, red blood cell sedimentation rate increased.