INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
MONOPRIL 10 mg TABLETS
MONOPRIL 20 mg TABLETS

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form)

MONOPRIL 10 mg TABLETS
MONOPRIL 20 mg TABLETS

COMPOSITION
Each MONOPRIL 10 mg tablet contains 10 mg of fosinopril sodium.
Each MONOPRIL 20 mg tablet contains 20 mg of fosinopril sodium.

PHARMACOLOGICAL CLASSIFICATION
A7.1.3 Vascular medicines, other hypotensives.

PHARMACOLOGICAL ACTION
Following oral administration, fosinopril sodium an ester prodrug, is hydrolysed to the pharmacologically active fosinoprilat, and inhibitor of angiotensin converting enzyme (ACE).
ACE inhibitors regulate the renin-angiotensin-aldosterone sytem.
Following oral administration, the extent of fosinopril absorption is 30-40%. While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption is essentially unaffected. Rapid and complete hydrolysis to active fosinoprilat is believed to be in the gastrointestinal mucosa and liver. The rate of conversion of fosinopril to fosinoprilat may be slowed in patients with hepatic dysfunction.
Peak plasma concentrations are proportional to the dose and are achieved approximately three hours after administration.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia may occur in patients who are salt and/or volume-depleted. The reduction in blood pressure may be progressive, so that several weeks of therapy may be required to achieve maximal therapeutic effect. The blood pressure lowering effects of fosinopril and thiazide-type diuretics are additive.
The effective elimination half life of fosinoprilat in young healthy volunteers averages 11,5 hours after intravenous administration. Fosinoprilat is highly protein bound (>95%), has a relatively small volume of distribution, and negligible binding to cellular components in the blood. Elimination of fosinoprilat occurs approximately equally from hepatic and renal routes, allowing compensatory excretion by the alternative route in patients with either renal or hepatic insufficiency.
In patients with heart failure, the beneficial effects of MONOPRIL are thought to result primarily from suppression of the renin-angiotensin-aldosterone system: inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload.
In patients with heart failure, the effective half-life is 14 hours.
In patients with heart failure treated with diuretics and with or without digoxin, the initial dose of MONOPRIL resulted in a decrease in preload and afterload. Single daily doses of MONOPRIL maintain the haemodynamic effects throughout the 24 hour dosing interval. In addition, heart rate has been shown to decrease from baseline and stroke volume index to increase despite reduced left ventricular filling pressure. No tachyphylaxis has been seen.

INDICATIONS

1.	Mild to moderate hypertension, alone as initial therapy, or in combination with other antihypertensive agents.
2.	Heart failure, and when indicated, in combination with a diuretic and/or digitalis.

CONTRA-INDICATIONS
Hypersensitivity to the product or its components, or other angiotensin-converting enzyme inhibitors.
Lactating mothers: 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 with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor. (See SPECIAL PRECAUTIONS).

WARNINGS

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, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.
Hypotension: A hypotensive response, sometimes associated with deterioration of renal function, has been seen in patients with congestive heart failure, renovascular hypertension, renal dialysis, or volume and/or salt depletion. (See SPECIAL PRECAUTIONS).

DOSAGE AND DIRECTIONS FOR USE
Monotherapy: The recommended initial dose of MONOPRIL is 10 mg once a day, both as monotherapy and when added to a diuretic. The usual dosage range needed to maintain a response at trough is 20-40 mg. Dosage should be adjusted according to blood pressure response at peak (2-6 hours) and trough (24 hours) blood pressure. In some patients treated with once daily dosage, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate dividing the daily dose should be considered. If blood pressure is not adequately controlled with MONOPRIL alone, a diuretic may be added.
Use With a Diuretic: Initially the diuretic should be discontinued for 2 to 3 days to avoid a symptomatic hypotensive response. Monotherapy (as above) may then be initiated. If diuretic therapy cannot be discontinued, it may be resumed with an initial dose of MONOPRIL 10 mg, under careful medical supervision for several hours until blood pressure has stabilized. Concomitant use with potassium sparing diuretics or potassium supplements may lead to hyperkalemia. (See SPECIAL PRECAUTIONS).
Dosage in Renal Impairment: Because of the dual excretion pathway for fosinoprilat, a dosage reduction is normally unnecessary in patients with impaired renal function (creatinine clearance 10 to 80 mL/min/1,75 m²), including end-stage renal failure (creatinine clearance <10 mL/min/1,75 m²). It is advisable to initiate treatment with 10 mg Monopril.
Clearance of fosinoprilat by haemodialysis and peritoneal dialysis averages 2% and 7%, respectively of urea clearances.
Use in hepatic insufficiency (alcoholic or biliary cirrhosis): It is advisable to initiate treatment at a dose of 10 mg. Although the rate of hydrolysis may be slowed, the extent of hydrolysis is not appreciably reduced in patients with hepatic impairment. In this group of patients, there is evidence of reduced hepatic clearance of fosinoprilat with compensatory increase in renal excretion.
Heart Failure: The recommended initial dose of MONOPRIL is 10 mg once daily. Therapy should be initiated under close medical supervision. If the initial dose of MONOPRIL is well tolerated, the dose may be titrated at weekly intervals according to clinical response up to 40 mg once daily The appearance of hypotension after the initial dose should not preclude careful dose titration with MONOPRIL following effective management of hypotension. MONOPRIL should be used in conjunction with a diuretic. Because of the dual excretion pathway for fosinoprilat a dosage reduction is normally unnecessary in patients with impaired renal or hepatic function.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The most commonly reported side effects which may occur:headache, dizziness, cough.
The most commonly reported side effects in Placebo-Controlled Hypertension trials (occurring in 1% or more of patients). None of these adverse experiences was observed significantly more frequently in fosinopril treated patients than placebo-treated patients.
General: Fatigue, chest pain, edema, viral infection, pain.
Cardiovascular: Rhythm disturbances/Palpitations
Dermatological: Rash
Gastrointestinal: Nausea, vomiting, diarrhoea, abdominal pain, heartburn
Musculoskeletal/Connective tissue: Musculoskeletal pain, myalgia.
Nervous system: Headache, dizziness, mood change (including stress reaction and nervousness), paresthesia, sleep disturbances.
Respiratory: cough, sinus abnormality, upper respiratory infection, rhinitis, pharyngitis.
Special senses: Eye disturbances other, taste alterations , vision disturbances.
Urogenital: Abnormal urination (including changes in urinary frequency, polyuria and olguria), sexual dysfunction.
Other clinical adverse experiences reported with fosinopril:
General: Weakness, fever, hyperhidrosis, ecchymosis.
Cardiovascular: Cardiac arrest, angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, tachycardia, flushing, peripheral vascular disease, sudden death, shock, syncope, conduction disorders.
Hypotension, orthostatic hypotension and syncope occurred in 0.1, 1.5, and 0.2% respectively, of patients treated with fosinopril. Hypotension or syncope was a cause for discontinuation of therapy in 0,3% of patients.
Dermatologic: Pruritus, dermatitis, urticaria.
Endocrine/Metabolic: Gout
Gastrointestinal: Bleeding, pancreatitis, hepatitis, tongue swelling, dysphagia, oral lesions, abdominal distention, appetite/weight change, constipation, flatulence, dry mouth.
Hematologic: Lymphadenopathy
Musculoskeletal: Arthritis
Nervous/Psychiatric: Equilibrium disturbances, memory disturbances, drowsiness, confusion, cerebral infarction, depression, tremor.
Respiratory: Dyspnea, bronchospasm, pneumonia, pulmonary congestion, laryngitis/hoarseness, epistaxis, tracheobronchitis, pleuritic chest pain.
A symptom-complex of cough, bronchospasm and eosinophilia has been observed in two patients treated with fosinopril.
Special senses: Tinnitus, ear pain
Urogenital: Renal insufficiency, prostate disorder.
Head and Neck Angioneurotic oedema: Swelling of the face, tongue, glottis, larynx, lips and extremities with difficulty in swallowing or breathing has been seen in patients treated with angiotensin-converting enzyme inhibitors. Treatment with MONOPRIL should be discontinued promptly and medical attention sought after to ensure complete resolution of symptoms.
In those instances where swelling has been confined to the face and lips the condition may resolve without treatment, although antihistamines may be useful in relieving symptoms. Angioneurotic odema associated with laryngeal oedema may be fatal. Where the involvement of the tongue, glottis or larynx, is likely to cause airway obstruction, appropriate therapy such as subcutaneous adrenalin 1:1000 (0,3 mL to 0,5 mL) should be administered promptly. Patients with a history of agioedema unrelated to ACE-inhibitor therapy may be at an increased risk of angioedema while receiving an ACE-inhibitor.
Intestinal Angioedema: 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 esterasae 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 different diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Laboratory Test Abnormalities: Hyperkalemia, hyponatremia, renal insufficiency, leukopenia and neutropenia. Modest transient decreases in haemoglobin and haematocrit values.
Liver function: elevation of transaminases, LDH, alkaline phosphatase and serum bilirubin.
Hepatic failure: ACE-inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis. The mechanism of this syndrome is unknown. Patients receiving ACE-inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Periodic monitoring is advisable in patients on long-term ACE inhibitor therapy.
Impaired Renal Function:
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 an ACE inhibitor. These increases are usually reversible upon discontinuation of 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 develop increases in blood urea nitrogen and serum creatinine, usually minor or transient when fosinopril is given concomitantly with a diuretic. This effect is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of MONOPRIL may be required.
In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with an ACE inhibitor may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
Agranulocytosis and bone marrow depression:
Have been reported, mostly in patients with renal impairment, especially if they have associated collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Monitor white blood cell counts in these patients.
Hepatic insufficiency:
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the mean Area Under the Curve, (blood plasma concentration) of fosinoprilat was approximately twice that of healthy volunteers.
Hyperkalemia:
Patients with renal insufficiency, diabetes mellitus, or using potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes or other drugs associated with increases in serum potassium (e.g. heparin) are at risk of developing hyperkalemia.
Hypotension:
A hypotensive response may be observed, usually associated with the first dose. A transient, hypotensive episode is not a contra-indication to continuing therapy once the patient’s blood pressure has been stabilised. Patients at risk of an excessive hypotensive response, sometimes associated with renal dysfunction, include especially those with congestive heart failure, renovascular hypertension, renal dialysis, or volume and/or salt depletion of any aetiology. In these patients it may be prudent to discontinue or reduce the dose of diuretic therapy or take other measures to ensure adequate hydration prior to initiating MONOPRIL therapy. Initiation, or increase in dose for those hypotensive risk patients should be under medical supervision. (See DOSAGE AND DIRECTIONS FOR USE).
Cough:
Cough has been reported with the use of ACE inhibitors, including fosinopril. Characteristically , the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Geriatric use:
Among patients who received fosinopril in clinical studies, overall differences in efficacy or safety were not observed between older patients (65 years or older) and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.
Surgery/Anaesthesia:
The hypotensive effect of anaesthesia and analgesics may be augmented by MONOPRIL. This may be corrected by intravenous administration of fluid.
Anaphylactoid Reactions:
Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during haemodialysis with high-flux dialysis membranes (e.g. AN69) in patients receiving ACE-inhibitors as medication. Anaphylactoid reactions have also been reported in patients 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. Therefore, special attention should be given to these patients; and in particular, to those having already shown similar reactions.
Analphylactoid reactions during desensitization:
Life-threatening anaphylactoid reactions have been reported while desensitizing with hymenoptera venom in patients receiving ACE inhibitors. Therefore, patients on ACE inhibitors undergoing such desensitization procedures, should be treated with caution.

Drug Interactions:
Diuretics: An exaggerated hypotensive response may be expected when MONOPRIL is administered concomitantly with diuretics.
Since increases in serum potassium have been observed with MONOPRIL, the potassium wasting effect of most diuretics may be blunted by concomitant MONOPRIL therapy.
Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients receiving concomitant diuretics than in those treated with MONOPRIL alone especially in patients with cardiac failure. Concomitant administration with potassium sparing diuretics may lead to hyperkalaemia.
Antacids: Co-administration of antacids with MONOPRIL has been shown to reduce serum levels and urinary excretion of fosinoprilat as compared with MONOPRIL administered alone, suggesting that antacids may impair absorption of fosinopril.
Non-steroidal Anti-inflammatory Drugs: Indomethacin may reduce the antihypertensive effect of ACE inhibitors, especially in cases of low renin hypertension. Aspirin may have a similar effect.
Lithium: Concomitant therapy with lithium may increase the serum lithium concentration.
Other anti-hypertensive Agents: Combination with other anti-hypertensive agents such as beta blockers, methyldopa, calcium antagonists, and diuretics may increase the anti-hypertensive efficacy.
Other Agents: The bioavailability of unbound fosinopril is not altered by co-administration of fosinopril with aspirin, chlorthalidone, cimetidine, digoxin, hydrochlorothiazide, metoclopramide, nifedipine, propranolol, propantheline or warfarin.
Laboratory Test Interactions: Fosinopril may cause a false low measurement of serum digoxin levels with assays using the charcoal absorption method. Other kits which use the antibody coated-tube method may be used instead. Therapy with MONOPRIL should be interrupted for a few days before carrying out test of parathyroid function.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The primary manifestations of overdosage would be hypotension which can usually be corrected by the intravenous administration of fluid. Also, induction of emesis and/or gastric lavage are suggested measures. Fosinopril is poorly removed from the body by haemodialysis or peritoneal dialysis.

IDENTIFICATION

MONOPRIL 10 mg:	A white to off-white, flat end diamond shaped tablet, 9,4 mm x 6,6 mm with a partial bisect bar on both sides engraved with the word ‘SQUIBB’and the number ‘158’on one side and ‘m’on the other side.
MONOPRIL 20 mg:	Oval, white, biconvex tablet. One side engraved with “Monopril 20”and “BMS”on the other side.

PRESENTATION
Blister packs of 30 tablets.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C. Protect from moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER

MONOPRIL 10 mg	X/7.1.3/284
MONOPRIL 20 mg	X/7.1.3/285

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road
Bedfordview, 2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
February 1996

* Authorised user of the TM Monopril

Updated on this site: July 2005
Source: Pharmaceutical Industry
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