| Summary
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients or to any other ACE inhibitor or to any other sulphonamide-derived drug.
History of angioedema associated with previous ACE inhibitor therapy.
Hereditary/idiopathic angioneurotic oedema.
Severe renal impairment (creatinine clearance < 30 ml/min).
Severe hepatic impairment.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Lactation (see section 4.6).
4.4 Special warnings and precautions for use
CAPTOPRIL
Hypotension: rarely hypotension is observed in uncomplicated hypertensive patients.
Symptomatic hypotension is more likely to occur in hypertensive patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, vomiting, or haemodialysis. Volume and/or sodium depletion should be corrected before the administration of an ACE inhibitor and a lower starting dose should be considered.
As with any antihypertensive agent, excessive blood pressure lowering in patients with ischaemic cardiovascular or cerebrovascular disease may increase the risk of myocardial infarction or stroke. If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required.
Renovascular hypertension: there is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.
Angioedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Captopril. This may occur at any time during treatment. In such cases, Captopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioneurotic oedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see section 4.8).
Cough: cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy.
Hepatic failure: rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Hyperkalaemia: elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.
Aortic and mitral valve stenosis/Obstructive hypertrophic cardiomyopathy/Cardiogenic shock:
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 hemodynamically significant obstruction.
Neutropenia/Agranulocytosis: neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors, including captopril. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Captopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.
If captopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of captopril therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count should be performed.
Captopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1000/mm3) is detected or suspected.
In most patients neutrophil counts rapidly return to normal upon discontinuing captopril.
Proteinuria: proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
Total urinary proteins greater than 1 g per day were seen in about 0.7% of patients receiving captopril. The majority of patients had evidence of prior renal disease or had received relatively high doses of captopril (in excess of 150 mg/day), or both. Nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.
Patients with prior renal disease should have urinary protein estimations (dip-stick on first morning urine) prior to treatment, and periodically thereafter.
Anaphylactoid reactions during desensitisation: sustained life-threatening anaphylactoid reactions have been rarely reported for patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.
Anaphylactoid reactions during high-flux dialysis/lipoprotein apheresis membrane exposure: anaphylactoid reactions have been reported in patients haemodialysed with high-flux dialysis membranes or undergoing low-density lipoprotein apheresis with dextran sulphate absorption. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.
Surgery/Anaesthesia: 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.
Diabetic patients: the glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
As with other angiotensin converting enzyme inhibitors, <Capozide> is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.
HYDROCHLOROTHIAZIDE
Renal impairment: in patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy (see section 4.3).
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see section 4.3).
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with captopril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).
Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Anti-doping test: hydrochlorothiazide contained in this medication could produce a positive analytic result in an anti-doping test.
Other: sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
CAPTOPRIL/HYDROCHLOROTHIAZIDE COMBINATION
Pregnancy: <Capozide> is not recommended during the first trimester of pregnancy (see section 4.6). If treatment is discontinued due to pregnancy the prescriber should decide whether treatment of hypertension should be continued.
Pregnancy: ACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6).
Risk of hypokalaemia: the combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.
Combination with lithium: Capozide is not recommended in association with lithium due to the potentiation of lithium toxicity (see section 4.5).
Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.6 Pregnancy and lactation
Pregnancy:
Given the effects of the individual components in this combination product on pregnancy, the use of <Capozide> is not recommended during the first trimester of pregnancy (see section 4.4). The use of <Capozide> is contra-indicated during the 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4).
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). (See section 5.3.) 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 (see sections 4.3 and 4.4).
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Lactation:
Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of <Capozide> 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 <Capozide> 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.
<Capozide> is not recommended during the first trimester of pregnancy (see section 4.4.). When a pregnancy is planned or confirmed, an alternative treatment should be initiated as soon as possible. Controlled studies with ACE inhibitors have not been done in humans, but limited number of cases of first trimester exposures have not shown malformations.
<Capozide> is contraindicated (see section 4.3) during the second and third trimesters of pregnancy. Prolonged captopril exposure during the second and third trimesters is known to induce toxicity in foetuses (decreased renal function, oligohydramnios, skull ossification retardation) and in neonates (neonatal renal failure, hypotension, hyperkalaemia) (see also section 5.3).
Hydrochlorothiazide in case of prolonged exposure during the third trimester of pregnancy may cause a foeto-placental ischaemia and risk of growth retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported in case of exposure near the term.
Hydrochlorothiazide can reduce plasma volume as well as the uteroplacental blood flow.
Should exposure to <Capozide> have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
<Capozide> is contraindicated during breast-feeding (see section 4.3).
Both captopril and hydrochlorothiazide are excreted in human breast milk. Thiazides during breast feeding by lactating mothers have been associated with a decrease or even suppression of the milk lactation. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia and nuclear icterus might occur.
Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with <Capozide> should be made taking into account the benefit of breast-feeding to the child and the benefit of <Capozide> therapy to the woman.
5.2 Pharmacokinetic properties
Captopril is quickly absorbed after oral administration and maximum serum concentrations are obtained around one hour after administration. Minimum mean absorption is approximately 75%. Peak plasma concentrations are reached within 60-90 minutes. The presence of food in the gastrointestinal tract reduces absorption by about 30-40%. Approximately 25-30% of the circulating drug is bound to plasma proteins. The apparent elimination half-life of unchanged captopril in blood is about 2 hours.
Greater than 95% of the absorbed dose is eliminated in the urine within 24 hours; 40-50% is unchanged drug and the remainder are inactive disulphide metabolites (captopril disulphide and captopril cysteine disulphide). Impaired renal function could result in drug accumulation.
Studies in animals indicate that captopril does not cross the blood-brain barrier to any significant extent.
Oral absorption of hydrochlorothiazide is relatively rapid. The mean plasma half-life in fasted individuals has been reported to be 5 to 15 hours. Hydrochlorothiazide is eliminated rapidly by the kidney, and excreted unchanged (> 95%) in the urine.
Lactation:
In the report of twelve women taking oral captopril 100 mg 3 times daily, the average peak milk level was 4.7μg/L and occurred 3.8 hours after the dose. Based on these data, the maximum daily dosage that a nursing infant would receive is less than 0.002% of the maternal daily dosage.
10. DATE OF REVISION OF THE TEXT
8th October 2009April 2010
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