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Logo ZAPTO-CO TABLETS

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ZAPTO-CO TABLETS

COMPOSITION:
Each tablet contains:
Captopril 50 mg
Hydrochlorothiazide 25 mg

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Other hypotensives.

PHARMACOLOGICAL ACTION:
This combination of an angiotensin converting enzyme (ACE) inhibitor (captopril) and a diuretic (hydrochlorothiazide) lowers blood pressure by different, though complementary mechanisms. With diuretic treatment, blood pressure and blood volume fall resulting in a rise in angiotensin II levels which tend to blunt the hypotensive effect. Captopril blocks this rise in angiotensin II by, preventing the conversion of angiotensin to angiotensin II by inhibition of ACE. Because captopril reduces the production of aldosterone, its combination with hydrochlorothiazide may also minimise diuretic induced hypokalaemia.
Hydrochlorothiazide acts by reducing reabsorption of electrolytes from the renal tubules thereby increasin, the excretion of sodium and chloride ions and consequently of water.

INDICATIONS:
ZAPTO-CO tablets are indicated for the treatment of mild to moderate hypertension in adult patients who have been stabilized on the individual agents given in the same proportions.

CONTRA-INDICATIONS:
A history of previous hypersensitivity to captopril or hydrochlorothiazide.
Patients hypersensitive to bumetanide, furosemide, carbonic anhydrase inhibitors or other sulfonamide type medications.
Severe renal and/or hepatic insufficiency.
Patients with aortic stenosis or outflow tract obstruction.
Patients with Addison's disease.
Patients with anuria.
Patients with porphyria.
Safety in lactation has not been established. Thiazide diuretics are excreted in breast milk. Treatment with hydrochlorothiazide can inhibit lactation.
Safety in children less than 18 years of age has not been established.
Pregnancy (see warnings)

WARNINGS:
Should a woman become pregnant while receiving ZAPTO-CO, the treatment must be stopped promptly and an alternative medicine used. Should a woman contemplate pregnancy, the doctor should consider alternative medication.
ACE-inihibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inihibitors in the second and third trimester Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.
Angioedema:
Angioedema involving the extremities, face, eyes, lips, mucous membranes, tongue, glottis or larynx has been reported. Patients should be advised to immediately report to their doctor any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, tongue, larynx and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of adrenaline should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of therapy; some cases required medical therapy.
Haematological:
Neutropenia/Agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving captopril, usually within three months after treatment has started.
Captopril should not be used routinely in patients with pre-existing impaired renal function, collagen vascular disease or who are receiving immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, because the occurrence of neutropenia has been almost exclusively limited to this group. Thus for patients in this group on therapy, white blood cell and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months, and periodically thereafter. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.
During treatment all patients should be instructed to report any sign of infection (eg persistent sore throat, fever), when a differential blood cell count should be performed. Captopril and hydrochlorothiazide and other concomitant medication should be withdrawn if neutropenia (neutrophils less than 1000/mm³) is detected or suspected. In most patients neutrophil counts rapidly returned to normal upon discontinuing the medication.
Proteinuriahas been reported in patients receiving captopril, but this has been predominantly in those who had prior renal disease. Although membranous glomerulopathy was found in biopsies taken from proteinuric patients, a causal relationship to captopril has not been established. For patients with renal disease, patients with prior renal disease urinary protein estimations (dipstick) should be done prior to treatment and periodically thereafter. Some patients with renal disease, particularly those with bilateral renal artery stenosis may develop increases in blood urea and serum creatinine after reduction of blood pressure with captopril and hydrochlorothiazide.
Azotemia may be induced by thiazide in patients with impaired renal function.
Captopril and hydrochlorothiazide therefore would not be appropriate for patients with renal impairment since loop diuretics rather than a thiazide are preferred for such patients. In patients with impaired renal function cumulative effects of thiazide may develop.
Renal impairment: ZAPTO-CO is not recommended for use in renal impairment.

DOSAGE AND DIRECTIONS FOR USE:
ADULTS:
Dosage must be individualized.
  ZAPTO-CO should be taken one hour before food intake.
In the treatment of hypertension, captopril and hydrochlorothiazide may be used for patients requiring individual doses of captopril and a diuretic. The usual dosage is one tablet once a day. If a satisfactory reduction of blood pressure has not been achieved after four weeks, the dose of captopril may be increased to not more than 150 mg per day, in divided daily doses. The dose of captopril must be increased by the addition of captopril on its own.
  A significant number of patients may achieve long-term control of their blood pressure on half a tablet (captopril 25 mg/hydrochlorothiazide 12,5 mg) per day, particularly in the elderly patients.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
CAPTOPRIL:
Adverse effects tend to be dose-related and more frequent in patients with impaired renal function.
The most common adverse effects are skin rashes which may be accompanied by pruritus, fever, and eosinophilia, a persistent dry cough; and taste disturbances, which may sometimes be associated with weight loss. The skin rash is usually pruritic and maculopapular and generally occurs during the first 4 weeks of treatment.
Proteinuria has occurred mainly in patients with existing renal disease and some of these patients develop the nephrotic syndrome. Evidence of deterioration in renal function, including increasing blood concentrations of urea and creatinine, and reversible acute renal failure have been reported in patients with existing renal or renovascular dysfunction and may be aggravated by hypovolemia. Captopril administration has also been associated with increases in blood-potassium concentrations.
Transient hypotension may occur at the start of therapy particularly in patients with congestive heart failure and in sodium- or volume-depleted patients. This can be minimized by starting with a low dose of captopril and giving the initial dose at night.
Other adverse effects reported with captopril include angioedema (see warnings), tachycardia, headache, paraesthesias, lymphadenopathy, photosensitivity, stomatitis, gastro-intestinal irritation, abdominal pain and, less frequently, cases of hepatocellular injury and jaundice.
Renal function should be assessed in all patients prior to administration of captopril. Regular white blood cell counts should be made during the initial stages of therapy.
Since raised serum-potassium concentrations may develop, potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes should be used with caution. The hypotensive effect of captopril is enhanced by diuretics and other antihypertensive agents. Indomethacin has been shown to reduce or abolish the hypotensive action of captopril, and salicylates appear to produce a similar effect. Captopril may cause false positive results in tests for acetone in urine.
HYDROCHLOROTHIAZIDE
Hydrochlorothiazide may cause a number of metabolic disturbances. It may provoke hyperglycaemia and glycosuria in diabetic and other susceptible patients. It may cause hyperuricaemia and precipitate attacks of gout in some patients. Administration of hydrochlorothiazide may be associated with electrolyte imbalances including hypochloraemic alkalosis, hyponatraemia, and hypokalaemia. Hypokalaemia intensities the effect of digitalis on cardiac muscle and administration of digitalis or its glycosides may have to be temporarily suspended. Patients with cirrhosis of the liver are particularly at risk from hypokalaemia. Hyponatraemia may occur in patients with severe congestive heart failure who are very oedematous, particularly with large doses in conjunction with restricted salt in the diet. The urinary excretion of calcium is reduced. Hypomagnesaemia has also occurred. Adverse changes in plasma lipids have also been noted but their clinical significance is unclear.
Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps, seizures, oliguria, and gastro-intestinal disturbances.
Other side-effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhoea, headache, dizziness, photosensitivity reactions, postural hypotension, paraesthesia, impotence, and yellow vision. Hypersensitivity reactions include skin rashes, pulmonary oedema, and pneumonitis. Cholestatic jaundice, pancreatitis, and blood dyscrasias including thrombocytopenia and, less frequently, granulocytopenia, leucopenia, and aplastic and haemolytic anaemia have been reported.
Hydrochlorothiazide should be used with caution in patients with impaired hepatic function since it may increase the risk of hepatic encephalopathy. It should also be given with caution in renal impairment since it can further reduce renal function.
Blood-glucose concentrations should be monitored in patients taking antidiabetic agents, since requirements may change.
All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in presence of vomiting or during parenteral fluid therapy. Elderly patients are particularly susceptible to electrolyte imbalance.
There is a possibility that hydrochlorothiazide may exacerbate or activate systemic lupus erythematosus in susceptible patients.
Hydrochlorothiazide may enhance the toxicity of digitalis glycosides by depleting serum-potassium concentrations. It may enhance the neuromuscular blocking action of competitive muscle relaxants, such as tubocurarine.
It may enhance the effect of antihypertensive agents, while postural hypotension associated with hydrochlorothiazide therapy may be enhanced by concomitant ingestion of alcohol, barbiturates, or opioids. The potassium-depleting effect of hydrochlorothiazide may be enhanced by corticosteroids, corticotrophin, or carbenoxolone. Concomitant administration of hydrochlorothiazide and lithium is not generally recommended since the association may lead to toxic blood concentrations of lithium.
Hydrochlorothiazide crosses the placenta and there have been reports of neonatal jaundice, thrombocytopenia, and electrolyte imbalances following maternal treatment. Reductions in maternal blood volume could also adversely affect placental perfusion.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage will lead to hypotension and electrolyte depletion.
Volume expansion with an intravenous infusion of sodium chloride injection is recommended to normalize the blood pressure. Captopril can be removed by haemodialysis.
Further treatment is symptomatic and supportive.

IDENTIFICATION:
An orange biconvex, bisected tablet engraved with a mortar and pestle.

PRESENTATION:
Blister packs of 28 tablets each.

STORAGE INSTRUCTIONS:
Store below 25°C in well-closed containers.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
28/7.1.3/0603

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacare Limited
7 Fairclough Road
Korsten
PORT ELIZABETH
6001

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
10 June 1994

                        G991
        KOHLER C&P PE.

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