Capotril Tablets
Use in pregnancy:
When used in pregnancy, ACE inhibitors can cause injury and even death 10 the developing fetus. When pregnancy IS detected, Captoprii should be drsconnnued as soon as possible.
Composition :
Each scored tablet contains:
Captopril 25 mg or 50 mg
Inactive ingredients: Mtcrocrystalhne cellulose. colloidal silicon dioxide, talc purified, magnesium stearate, lactose D’C. anhydrous, sodium starch glycolate.
Therapeutic Indications :
Hypertension: Capotrtl is indicated for the treatment of hypertension.
Heart Failure: Capotril is indicated for the treatment of chronic heart failure with reducnon of systohc ventricular function, in combination with diuretics and, when appropnate, digitalis and beta-blockers.
Myocardial Intarcttcn:
Short-term 14 weeks) treatment: Capotril is indicated in any clinically stable patient within the first 24 hours of an mfarctlon.
long-term prevention of symptomatic heart failure: Capotril IS indicated in clinically stable patients with asymptomatic left ventricular dysfunction (ejection fraction s 40%).
type i diabetic nephropathy : capotril is indicated for the treatment of macroproteinuric diabetic nephropathy in patients with type i diabetes
Posology and Method of administration :
Dose should be individualised according 10 patient’s profile and blood pressure response. The recommended maximum daily dose is 150 mg.Capotril should be taken one hour before meals.
Hypertension: The recommended starting dose is 25 mg bid or tid. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg BID or TID. Capotrtt may be used alone or with other antihypertensive agents, especially thiazide diuretics. A once-daily dosing regimenmay be appropriate when concomitant antihypertensive medication such as truazroe diuretics is added. In patients with a strongly active renin angiotensin-aldosterone system {hypovolaemia, renovascular hypertension, cardiac decompensattonl, it is preferable to commence with a single dose of 6.25 mg or 12.5 mg. The inauguration of this treatment should preferably take place under close medical
supervision. These doses will then be administered at a rate of two per day. The dosage can be gradually increased to 50 mg/day in one or two doses and if necessary to ]00 mg/day in one or two doses.
Heart failure:
Treatment with Capotril for heart failure should be initiated under close medical supervision. The usual startmq dose is 6.25 mg – 12.5 mg BID or TID. Titration to the maintenance dose (75 – 150mg/day) should be carried out based on patient’s response, clinical status and tolerabtltry, up to a maximum of 150 mg/day in divided doses. The dose should be increased incrementally, with intervals of at least 2 weeks to evaluate patient’s response.
Myocardial infarction:
Short-term treatment: Capotrtl treatment should begin in hospital as soon as possible followmg the appearance of the Signs and/or symptoms in patients with stable haemodynarrucs. A 6.25 mg test dose should be administered, With a 12.5 mg dose being adrrumstered 2 hours afterwards and a 25 mg dose ]2 hours later
From the following day, CapotrU should be administered in a 100 mg/day dose, in two daily administrations, for 4 weeks, If warranted by the absence of adverse haemodynamic reactions. At the end of the 4 weeks of treatment, the penent’s state should be reassessed before a decrsron is taken concerning treatment for the post -myocardial infarction stage.
Chronic treatment: if Capotril treatment has not begun dunng the first 24 hours of the acute myocardial mfarcnon stage, it is suggested that treatment be instigated between the 3rd and 16th day post -infarction once the necessary treatment conditions have been attained (stable haemodynamics and management of any residual ischaemia). Treatment should be started in hospital under strict surveillance (panicularly of blood pressure) until the 75 mg dose isreached. The Irunal dose must be low. parucularty if the pauent exhibits normal or low blood pressure at the mmanon of therapy Treatment should be rmuated with a dose of 6.25 mg followed by 12.5 mg 3 limes dally for 2 days and then 25 mg 3 times daily if warranted by the absence of adverse haemodynamic reactionsThe recommended dose for effective cardtoprotecuon during long-term treatment is 75 to 150 mg daily in two or three doses. In cases of symptomatic hypotension, as in heart failure, the dosage of diurencs and/or other concomitant vasodllators may be reduced in order to attain the steady state dose of Capotril Where necessary, the dose of Capotril should be adjusted in accordance with thepatient’s clinical reactions. Capotril may be used in combination with other treatments for myocardial infarction such as thrombolytic agents, beta-blockers and acetylsalicylic acid.
Type I Diabetic nephropathy : in patients with type I diabetic nephropathy, the recommended daily dose of Capotril is 75 – 100 mg in divided doses. If additional lowering of blood pressure is desired, additional antihypertensive medications may be added.
Renal Impairment: since Capotril 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 patientswith severe renal impairment.
In patients wuh rmpalred renal function, the following daily dose may be recommended to avoid accumulation of Capotril
Elderly patients: as with other antthypertensrve agents, consrderanon should be given to mitiating therapy with a lower starting dose (6.25 mg BID) in elderly patients who may have reduced renal function and other organ dysfunctions. blood pressure response and kept as low as
Children and adolescents: the efficacy and safety of Capotril have not been fully established. The use of Capotrtl In children and adolescents should be initiated under close medical supervtston. The initial dose of Capotrll is about 0.3 mg/kg body weight. For patients requiring special precautions (children with renal dysfunction, premature infants, new-borns and infants, because their renal
function is not the same with older children and adults) the staning dose should be only 0.15 mg captoprtl/kg weight. Generally, Capotril is administered to children 3 times a day, but dose and interval of dose should be adapted Individually according to patient’s response.
Contraindications :
– History of bypersenstnvrry to captopril, to any of the exciptents or any other ACE inhibitor.
– History of angioedema associated with previous ACE inhibitor therapy.
– Hereditary / idiopathic angioneurotic oedema.
– During pregnancy.
– lactation.
– The concomitant use of Capotcil with alisktren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60ml/min/l.73m2).
Special warnings and precautions for use :
Dual blockade of the renin-angtotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin 11 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 11 receptor blockers or altskiren is therefore not recommended If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervtstcn and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin 11 receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
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.
Patients with heart failure are at higher risk of hypotension and a lower starnnq dose is recommended when initiating therapy with an ACE inhibitor. Caution should be used whenever the dose of Capotril or diuretic is Increased in patients with heart failure.As With any antthypeaensive 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 norrnalsaline 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 supervtstcn with low doses, careful titration and monitoring of renal function.
Renal impairment: in cases of renal impairment (creatinine clearance :so 40ml/min), the initial dosage of Capotrtl must be adjusted according to the patient’screatinine clearance, and then as a function of the patient’s response to treatment.Routine monitoring of potassium and creatinine are part of normal medicalpractice for these patients.
Angioedema: angioedema of the extremities, face, lips, mucous membranes,tongue, glonis or larynx may occur in patients treated with ACE inhibitorsparticularly during the first weeks of treatment. However, in rare cases, severeangioedema may develop after long-term treatment with an ACE inhibitor.Treatment should be discontinued promptly. Angioedema involving the tongue,glottis or larynx may be fatal. Emergency therapy should be instituted. The patientshould be hospitalised and observed for at least 12 to 24 hours and should not bedischarged until complete resolution of symptoms has occurred.
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 lsomenmesl 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 somepatients treated with ACE inhibitors, including captopril. Patients at risk for the development of hyperkalaemia include those With renal insuffidency, diabetes metlttus, or those using concomitant potassium-sparing diuretics, potassium
supplements or potasslurn-contatrunq 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, regularonitoring of serum potassium is recommended.
Lithium: the combination of lithium and captoprtl is not recommended. aortic and mitral valve stenosis/Obstructive hypertropic cardiomyopathy: 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
emodynamically 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. Captoprtl should be used with extreme caution in patients with collagen vascular disease, immunosuppressant
erapy, treatment with allopurinol or procatnarnlde, 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 Capotril 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 Capotril therapy, and periodically thereafter. During treatment,
all patients should be instructed to report any sign of infection (e.g. sore throat, even when a differential white blood cell count should be performed. Captopril and other concomitant medication should be withdrawn if neutropenia eutrophils less than 1000/mm ) is detected or suspected. In most patients neutrophil counts rapidly return to normal upon discontinuing captopril.
proteinuria : proteinuria may occur particularly in pattents with existing renal function impairment or on relatively high doses of ACE inhibitors. Oral urinary proteins greater than 1 g per day were seen In about 0.7% of patients eiving captopril. The majority of patients had evidence of prior renal disease or received relatively high doses of captoprtl (in excess of 150 mg/day), or both. nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most case
, 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 panents with protemurta.
nents with prior renal disease should have urinary protein estimations (dip-stick first morning urine) prior to treatment, and periodically thereafter.
Interaction with other medicinal products :
Potassium-sparing diuretics or potassium supplements: ACE inhibitorsattenuate diuretic induced potassium loss. Potassium-sparing diuretics [e.q, spironolactone, trtamterene or arrutortde], potassium supplements, or potassium- containing salt substitutes may lead to significant increases in serum potassturn. If
concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium. Diuretics (thiazide or loop diuretics): prior treatment with high dose diuretics may result in volume depletion and arisk 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 captoprtl. However, no clinically significant drug interactions have beenfound in specific studies with hydrochlorothiazide or furosemide.
Other antihypertensive agents: captoprtl has been safely co-admtnlstered withother 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. Treatment with nitroglycerine and other nitrates, or other vasodtlators, should be used with caution.
Treatments of acute myocardial infarction: caproprtl may be used concomitantly with acetylsalicylic acid fat cardiologic doses), thrombolytics, beta-btockers and/or nitrates in patients with myocardial infarction.
lithium: 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.
Tricyclic antidepressants / Antipsychotics: ACE inhibitors may enhance thehypotensive effects of certain trtcycltc antidepressants and antipsychotics. Postural hypotension may occur. Allopurinol, procainamide, cytostatic or immunosuppressive agents:
concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia especially when the latter are used at higher than currently recommended doses.
Non-steroidal antt-Inflamrnatory drugs: it has been described that non-steroidal anti-inflammatory drugs (NSAlDsl 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 NSAlDs may reduce the antihypertensive effect of an ACE inhibitor.
Sympathomimetics: may reduce the antihypertensive effects of ACE mhibilors; patients should be carefully monuored.
Antidiabetics: pharmacological studies have shown that ACE inhibitors. including captopnl, can potentiate the blood glucose-reducing effects of insulin and oral anndtabettcs such as sulphonylurea in dtebencs. Should this very rare interaction
occur, it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE inhibilors.
Clinical Chemistry: Captopril may cause a false-positive urine test for acetone.
Pregnancy and Lactation :
Pregnancy: Capotril should not to be used during pregnancy as it may cause injury or death of fetus.
Lactation: Capotcil is contraindicated in the lactation period.
Effects on ability to drive and to use machines :
As wilh other antthypertensives, the ability to drive and to use machines may be reduced, namely at the start of the treatment, or when posology is rnodffied., and, also when used in combination with alcohol, but these effects depend on the individual’s susceptibility.
Undesirable effects :
Undesirable effects reported for caproprtl and/or ACE inhibitor therapy mclude:
Blood and lymphatic disorders:
Very rare: neutropenia/agranulocytosis, pancytopenia particularly in panents with renal dysfunction, anaemia (including aplastic and haemolytic), thrombocytopenta, lymphadenopathy, eosmoptuha, auto-immune diseases and/or positive, ANA-titres.
Metabolism and nutrition disorders:
Rare: anorexia
Very rare: hyperkalaemia, hypoglycaemia.
Psychiatric disorders:
Common: sleep disorders.
Very rare: confusion, depression
Nervous system disorders:
Common: taste impairment, dizziness.
Rare: drowsiness, headache and paraesthesia.
Very rare: cerebrovascular incidents, including stroke, and syncope.
Eye disorders:
Very rare: blurred vision.
Cardiac disorders:
Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations.
Very rare: cardiac arrest, cardiogenic shock.
Vascular disorders:
Uncommon: hypotension, Raynaud’s syndrome, flush, pallor.
Respiratory, thoracic and mediastinal disorders:
Common: dry, irritating (non-productive) cough and dyspnoea.
Very rare: bronchospasm, rhinitis, allergic alveolitis / eosinophilic pneumonia.
Gastrointestinal disorders:
Common: nausea, vomiting, gastric irritations, abdominal pain, diarrhoea; constipation, dry mouth.
Rare: stomatitis/aphthous ulcerations.
Very rare: glossitis, peptic ulcer, pancreatitis.
Hepato-biliary disorders:
Very rare: impaired hepatic function and cholestasts (including jaundice), hepatitis including necrosis, elevated liver enzymes and bilirubin.
Skin and subcutaneous tissue disorders:
Common: pruritus with or without a-rash, rash, and alopecia.
Uncommon: angioedema.
Very rare: urticaria, Stevens-Johnson syndrome, erythema mulnforme, photosensi- tiviry, erythroderma, pemphigoid reactions and exfoliative dermatitis.
Musculoskeletal, connective tissue and bone disorders:
Very rare: myalgia, arthralgia.
Renal and urinary disorders:
Rare: renal function disorders induding renal failure, polyuria, oliguria, increased urine frequency.
Very rare: nephrotic syndrome.
Reproductive system and breast disorders:
Very rare: impotence, gynaecomaslia.
General disorders:
Uncommon: chest pain, fatigue, malaise.
Very rare: fever.
Investigations:
Very rare: proteinuria, eosinophilia, increase of serum potassium, decrease of serum sodium, elevation of BUN, serum creatinine and serum bilirubin, decreases in haemoglobin, haematocrit, leucocytes, thrombocytes, positive ANA-titre, elevated ESR.
Overdose :
Symptoms of overdosage are severe hypotension. shock, stupor, bradycardia, electrolyte disturbances and renal failure. Measures to prevent absorption (e.g. gastriC lavage, administration of adsorbents
and sodium sulphate within 30 minutes after intake) and hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementanons should be given rapidly. Treatment with angiotensin-ll should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. Captoprii may be removed from circulation by haemodialysis.
Pharmacological properties :
Pharmacodynamic properties:
Pharmacotherapeutic group: ACE inhibitors.
Captopril is a highly specific, competitive inhibitor of anqiotensin-l converting The beneficial effects of ACE inhibitors appear to result primarily from the suppression of the plasma renin-angiotensin-aldosterone system. Renin is an endogenous enzyme synthesised by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin-I, a relatively inactive decapeptide. Angiotensin-I is then converted by angiotensin converting enzyme, a
pepttdyldtpepndase, to angiotensin-B. Anqiotensin-Il is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in decreased plasma anqtotenstn-Il, which leads to decreased vasopressor
activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin-II on the renin secretion results in an increase of the plasma renin activity. Another function of the converting enzyme is to degrade the potent vasodepres- stve kinin peptide bradykinin to inactive rnerabolttes. Therefore, inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system which contributes to peripheral vasodilation by activating the prostaglandin system; it is possible that this mechanism is involved in the hypotensive effect of ACE inhibitors and is responsible for certain adverse reactions. Reductions of blood pressure are usually maximal 60 to 90 minutes after oral
administration of an individual dose of captopril. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captoprii and thiazide-type diuretics are additive.
In patients with hypertension, captoprii causes a reduction in supine and erect blood pressure, without inducing any compensatory increase in heart rate, nor water and sodium retention. i
In the recommended daily dose, t~e antihypertensive effect persists even during I long-term treatment. Temporary withdrawal of captoprii does not cause any rapid, excessive increase in blood pressure (rebound). The treatment of hypertension I with captopril leads also to a decrease in left ventricular hypertrophy.
Captopnl cardioprotection effects are observed regardless of the patient’s age or gender, location of the infarction and concomitant treatments with proven efficacy during the post-infarction period (thrombolytic agents, beta-blockers and acetylsalicylic acid).
The effects of treatment with captoprii on the preservation of renal function are in addition to any benefit that may have been derived from the reduction in blood pressure.
Pharmacokinetic properties:
Captopril is an orally active agent that does not require biotransformation for activity. The average minimal 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 captoprii 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 (captoprii disulphide and captopril cysteine disulphide). Impaired renal function could result in drug accumulation. Therefore, in patients with impaired renal function, the dose should be reduced and/or dosage interval
prolonged.
Special precautions for storage :
Store in a dry place et a temperature not exceedmg 30 “c.
Store in the original package to protect from moisture.
Packaging :
Capotril 25 mg scored Tablets: Carton~x containing (AI/PVC) blisters each of 10 scored tablets and insert leaflet
Capotril 50 mg scored Tablets: Carton box containing 1 or 2(Al/PVC} blisters each of 10 scored tablets and insert leaflet
produced by :
EGYPTIAN INT. PHARMACEUTICAL INDUSTRIES CO.
E.I. P.I. CO.
10th OF RAMADAN CITY , INDUSTRIAL AREA TENTH, EGYPT
