COMPOSITION MONOZIDE 20/12,5 is a combination of fosinopril sodium 20 mg and hydrochlorothiazide 12,5 mg.
PHARMACOLOGICAL CLASSIFICATION Category A.7.1.3. Other hypotensives
PHARMACOLOGICAL ACTION Fosinopril is hydrolysed primarily in the liver to fosinoprilat, the pharmacologically active angiotensin converting enzyme (ACE) inhibitor. ACE-inhibitors regulate the renin-angiotensin-aldosterone system.
The mechanism of antihypertensive effect of thiazide diuretics such as hydrochlorothiazide is unknown. Thiazides increase excretion of sodium and chloride in approximately equal amounts from the renal tubules. This natriuresis causes a secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion and decreases serum potassium.
Following oral administration of MONOZIDE, the extent of absorption is 30 - 40% for fosinopril and 50-80% for hydrochlorothiazide. The extent of absorption of fosinopril is essentially unaffected by the presence of food in the gastrointestinal tract, however, the rate of absorption may be slowed. The absorption of hydrochlorothiazide is increased by agents that decrease gastrointestinal motility.
Fosinoprilat is highly protein-bound (>95%), but has negligible binding to cellular components of the blood. Hydrochlorothiazide crosses the placenta freely.
Hydrochlorothiazide is not metabolized and is eliminated rapidly by the kidney. Its plasma protein binding is 68%. Its mean plasma half-life is 5-15 hours.
Fosinoprilat is eliminated approximately equally by the liver and kidneys. In elderly (male) subjects (65-75 years old) the area under the plasma concentration time curve (AUC) for HCTZ was elevated in the elderly group following multiple dosing.
With HCTZ, onset of diuresis occurs in 2 hours, and peak effect at about 4 hours, and the action persists for approximately 6-12 hours.
INDICATIONS MONOZIDE is indicated for the treatment of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions.
CONTRA-INDICATIONS Hypersensitivity to the product or its components, other ACE-inhibitors, or other sulphonamide-derived drugs (e.g. thiazides). Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Lactating mothers, as following oral administration, fosinoprilat was detected in human milk.
Safety and effectiveness in individuals less than 18 years of age have not been established.
Patients who are anuric.
Patients with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor, (see SPECIAL PRECAUTIONS)
Should a woman become pregnant while receiving an ACE-inhibitor the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication.
ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oligria, and anuria in new-borns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective scull ossification have been observed. Prematurity and low birth mass can occur. Hypotension: Fosinopril can cause symptomatic hypotension in patients who are volume and/or salt depleted. In patients with congestive heart failure, with or without associated renal insufficiency, fosinopril may cause excessive hypotension, which may be associated with oliguria, azotemia and acute renal failure. In addition, the antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient (see SPECIAL PRECAUTIONS).
DOSAGE AND DIRECTIONS FOR USE Dosage must be individualized. Adults and Elderly: The dose is one 20 mg fosinopril sodium/12,5 mg hydrochlorothiazide tablet once daily. Renal impairment: In patients with creatinine clearance >30 and <80 mL/min, MONOZIDE therapy should be initiated only after titration of the individual components. MONOZIDE is not recommended for patients with severe dysfunction (creatinine clearance <30 mL/min), (see SPECIAL PRECAUTIONS).
In hypertensive patients with normal renal and hepatic function who received repeated doses of fosinopril, the effective t½ for accumulation of fosinoprilat averaged 11.5 hours.
Fosinopril is not well dialyzed. Clearance of fosinoprilat by haemodialysis and peritoneal dialysis averages 2% and 7% of urea clearance, respectively.
In patients with creatinine clearances of 10-80 mL/min/1.73m², the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function, while absorption, bioavailability, and protein-binding are not appreciably altered.
An increase in plasma AUC levels was observed in patients with renal insufficiency. In patients with severe renal impairment (creatinine clearance <20 mL/min/1.73m²), the elimination half-life of HCTZ was reported to increase to 21 hours.
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis): The apparent total body clearance of fosinoprilat ia approximately one half of that in patients, with noraml hepatic function.
Rarely ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. A patient receiving Monozide who develops jaundice or marked elevation of hepatic enzymes should discontinue Monozide and receive appropriate medical follow-up. Monozide 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. Also, since the metabolism of fosinopril to fosinoprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop elevated plasma levels of fosinopril.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
FOSINOPRIL: Cardiovascular: Cardiac arrest, angina/myocardial infarction, stroke, hypertensive crisis, tachycardia, flushing, peripheral vascular disease, orthostatic hypotension, syncope. General: Palpitations/chest pain. Fatigue, oedema, excessive sweating, weakness, ecchymosis, fever. Gastrointestinal: Gastric bleeding, abdominal distension and/ or pain, constipation flatulence, pancreatitis, hepatitis, oral lesions, dry mouth, appetite/weight change. Dermatologic: Pruritis/rash urticaria, photosensitivity. Endocrine/metabolic: Gout. Haemotologic: Lymphadenopathy, leukocytosis, serositis, neutropenia. Musculoskeletal: Arthritis, arthralgia, myalgia, musculoskeletal pain/paresthesias. Respiratory: Hoarseness, pharyngitis, laryngitis, pneumonia, pulmonary congestion, epistaxis. A symptom-complex of cough, bronchospasm and eosinophilia. Special senses: Tinnitus, ear pain, taste disturbances. Nervous/psychiatric: Equilibrium disturbance, headache, memory disturbances, drowsiness, confusion, dizziness. Urogenital: Renal insufficiency, prostate disorder. Angioedema: Angioedema involving the extremities, face, lips, mucous membranes tongue, glottis or larynx has been seen in patients treated with fosinopril. If angioedema involves the tongue, glottis or larynx airway obstruction may occur and can be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of adrenalin should be promptly instituted Swelling confined to the face, mucus membranes of the mouth lips and extremities has usually resolved with discontinuation of fosinopril; some cases required medical therapy, (see SIDE EFFECTS AND SPECIAL PRECAUTIONS). Anaphylactoid reactions during densitization: Life-threatening anaphylactoid reactions have been reported while desensitizing with hymenoptera venom in patients receiving ACE-inhibitors.
Therefore, patients on ACE-inhibitors undergoing such densensitization procedures should be treated with caution. Anaphylactoid reactions during high flux dialysis/lipoprotein apheresis membrane exposure: Anaphylactoid reactions have been reported in patients haemolyzed with high flux dialysis membranes and in those undergoing low-density lipoprotein apheresis with dextran sulphate absorption, while on ACE-inhibitor therapy. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. Neutropenia/Angranulocytosis: Angiotensin coverting enzyme inhibitors have been known to rarely cause agranulocytosis and bone marrow depression; these occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitoring of white blood cell counts should be considered in such patients. Hypotension: Fosinopril can cause symptomatic hypotension, this occurs rarely, and is most likely to occur in patients who are volume and/or salt-depleted as a result of prolonged diuretic therapy, salt restriction, dialysis, diarrhoea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with MONOZIDE.
In patients with congestive heart failure, with or without associated renal insufficiency, MONOZIDE therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and rarely with acute renal failure. In such patients, MONOZIDE therapy should be initiated under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose is increased. Foetal/Neonatal Morbidity and Mortality: When used in pregnancy during the second and third trimesters, fosinopril can cause injury and even death to the developing foetus. When pregnancy is detected, MONOZIDE should be discontinued as soon as possible. Hepatic Failure: Fosinopril has been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis. The mechanism of this syndrome is not understood. Patients receiving fosinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue the fosinopril and receive appropriate medical follow-up. Impaired renal function: MONOZIDE should be used with caution in patients with severe renal disease (creatinine clearance <30 mL/ min/1,73 m² ) as changes in renal function can occur as a consequence of fosinopril's inhibiting the renin-angiotensin-aldosterone system. In hypertensive patients with renal artery stenosis in one or both kidneys, increases in blood urea nitrogen and serum creatinine may occur during treatment with fosinopril.
These increases are usually reversible upon discontinuation in therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease developed increases in blood urea nitrogen and serum creatinine, when fosinopril was given concomitantly with a diuretic. This effect is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of MONOZIDE may be required. Impaired Hepatic Function: MONOZIDE 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. Patients with impaired liver function could develop elevated plasma levels of fosinopril. In a study in patients with alcoholic or biliary cirrhosis, the apparent total body clearance of fosinoprilat was decreased and the plasma AUC approximately doubled. Cough: Cough has been reported with the use of fosinopril. Characteristically the cough is non-productive, persistent and resolves after discontinuation of therapy. Surgery/Anesthesia: In patients undergoing surgery during anesthesia with agents that produce hypotension, fosinopril may augment the hypotensive response. HYDROCHLOROTHIAZIDE Skin: Stevens-Johnson Syndrome and other hypersensitivity reactions such as skin rashes. Haematologic: Leukopenia, agranulacytosis, thrombocytopenia, aplastic anaemia and haemolytic anaemia, bone marrow depression. Other: Dizziness, vertigo, nausea and vomiting, headache, xanthopsia, hyperglycaemia, glycosuria, hyperuricaemia, muscle spasm, weakness, restlessness, gastric irritation, constipation and diarrhoea, jaundice, pancreatitis, fever, respiratory distress, interstitial nephritis, electrolyte imbalance including hyponatraemia, hypochloraemic alkylosis, glycosurea, transient blurred vision, photosensitivity, postural hypotension, paresthesias, impotence and anorexia have been reported in patients receiving thiazides. Impaired renal function: MONOZIDE should be used with caution in patients with severe renal disease (creatinine clearance <30 mL/ min/1.73m²). Cumulative effects of hydrochlorothiazide and hydrochlorothiazide - associated precipitation of azotemia may occur in these patients. Electrolyte Imbalance: Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
HCTZ can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Patients should be periodically observed for clinical signs or symptoms of fluid and electrolyte imbalance such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea or vomiting. Although hypokalaemia may develop when HCTZ is used, especially with brisk diuresis or in the presence of severe cirrhosis. concurrent therapy with fosinopril reduces diuretic-induced hypokalemia. The net effect of MONOZIDE may be to elevate, reduce or leave serum potassium unchanged. Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is decreased by HCTZ. Pathological changes in the parathyroid gland with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged HCTZ therapy. The common complications of hyperparathyroid-ism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. HCTZ should be discontinued before carring out tests for parathyroid function. HCTZ has been shown to increase the urinary excretion of magnesium which may result in hypomagnesaemia. Metabolic Disorders: Hyperuricaemia may occur, and an acute attack of gout may be precipitated in certain patients receiving HCTZ therapy. Insulin requirements in diabetic patients may be altered and latent diabetes mellitus may become manifest during HCTZ administration. Increases in cholesterol and triglyceride levels have been associated with HCTZ therapy. Systemic Lupus Erythematosus: HCTZ-has been reported to cause exacerbation or activation of systemic lupus erythematosus, (see also WARNINGS - Neutropenia/Agranulocytosis).
HCTZ should not be given to patients with Addisons Disease.
During clinical trials with MONOZIDE, the incidence of adverse events in the elderly (>65 years) was similar to that seen in younger patients. FOSINOPRIL/HYDROCHLOROTHIAZIDE The following side effects have occurred with use of the combination product: rhythm disturbance, change in libido, dyspepsia/heartburn, oesophagitis, somnolence, depression, sinus congestion, rhinitis, urinary frequency. Interactions: Alcohol, barbiturates, or narcotics: Potentiation of HCTZ induced orthostatic hypotension may occur. Antacids: Antacids (aluminium hydroxide, magnesium hydroxide, and simethicone) may impair absorption of MONOZIDE. Therefore, if concomitant administration of these agents is indicated, dosing should be separated by 2 hours. Antidiabetic drugs (oral agents and insulin): HCTZ may elevate blood glucose levels, thus, dosage adjustments of antidiabetic agents may be necessary. Antigout medications: Dosage adjustments of antigout medication may be necessary, since HCTZ may raise the level of blood uric acid. Increase in dosage of probenecid or sulphinpyrazone may be necessary. Calcium Salts: HCTZ may increase serum calcium levels due to decreased excretion. If calcium must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly. Cholestryramine resin and colestipol HCl: May delay or decrease absorption of HCTZ. HCTZ should be taken at least one hour before or four to six hours after these medications. Lithium: Increased serum lithium levels and risk of lithium toxicity have been reported in patients receiving fosinopril and/or diuretic agents concomitantly with lithium. MONOZIDE and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. Inhibitors of Endogenous Prostaglandin Synthesis: In some patients, these agents can reduce the effects of diuretics. Also, indomethacin has been reported to reduce the antihypertensive effect of other ACE-inhibitors, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (e.g. aspirin) may have a similar effect. Other diuretics and antihypertensive medications: The thiazide component of MONOZIDE may potentiate the actions of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. HCTZ may interact with diazoxide; blood glucose, serum uric acid levels, and blood pressure should be monitored. Potassium supplements and potassium-sparing diuretics: Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of MONOZIDE and such agents is indicated, they should be given with caution and the patient's serum potassium monitored frequently. Drugs used during surgery: The effects of nondepolarizing muscle relaxants, preanaesthetics and anaesthetics used in surgery (e.g. tubocurarine chloride and gallamine triethiodide) may be potentiated by HCTZ; dosage adjustments may be required. Fluid and electrolyte imbalances should be monitored and corrected prior to surgery if feasible. Caution should be used in patients taking MONOZIDE and pressor agents (e.g., nor adrenalin), who undergo surgery. Preanaesthetic and anaesthetic agents should be given in reduced dosage, and if possible, HCTZ therapy discontinued one week prior to surgery. Other agents: The bioavailability of unbound fosinopril is not altered by coadministration with aspirin, chlorthalidone, cimetidine, digoxin, metoclopramide, nifedipine, propranolol, propantheline, or warfarin. Laboratory Test Interactions: Fosinopril may cause a false low measurement of serum digoxin levels with assays utilizing the charcoal absorption method. Other kits, which utilize the antibody coated-tube method, may be used instead. Therapy with MONOZIDE should be interrupted for a few days before carrying out tests of parathyroid function.
Laboratory test abnormalities occuring in patients taking MONOZIDE: Serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides calcium, neutropaenia. Laboratory test abnormalities reported in patients taking fosinopril or hydrochlorothiazide separately: Increased serum levels of liver function tests (transaminases, LDH, alkaline phosphatase and bilirubin). Pregnancy: The use of fosinopril during the second and third trimesters of pregnancy has been associated with foetal an neonatal injury, and death. When pregnancy is detected, MONOZIDE should be discontinued as soon as possible. (see WARNINGS). Nursing Mothers: Both fosinopril and HCTZ are detectable in breast milk. Because of the potential for serious adverse reactions in nursing infants from MONOZIDE, the agent should be discontinued in nursing mothers. Geriatic Use: Overall differences in effectiveness or safey were not observed between younger and elderly (>65 years) patients; however, greater sensitivity of some older individuals cannot be ruled out. Paediatric Use: Safety and effectiveness in children have not been estalished.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Treatment should be symptomatic and supportive. Therapy with MONOZIDE should be discontinued and the patients closely monitored. Suggested measures include induction of emesis and/ or gastric lavage and correction of dehydration electrolyte imbalance and hypotension. Fosinopril is poorly removed from the body by haemodialysis or peritoneal dialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.
IDENTIFICATION: MONOZIDE 20/12,5: A peach coloured, round, biconvex tablet with "1493" on one side and a bisect bar on the other side.
PRESENTATION HDPE bottles, glass bottles, blister packs, or aluminium foil packs of 30 tablets.
STORAGE INSTRUCTIONS Store at temperatures not exceeding 25°C. Keep tightly closed (protect from moisture).
Keep out of reach of children.
REGISTRATION NUMBER: 31/7.1.3/0416
NAME AND BUSINESS ADDRESS OF APPLICANT Bristol-Myers Squibb (Pty) Ltd
47 Van Buuren Road
DATE OF PUBLICATION OF THIS PACKAGE INSERT September 1997