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Logo RAN-RAMIPRIL 10 CAPSULES

SCHEDULING STATUS:
Schedule 3

PROPRIETARY NAME
(and dosage form):

RAN-RAMIPRIL 10 CAPSULES

COMPOSITION
Each capsule contains
ramipril 10 mg.
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A.        7.1.3 Other hypotensives

PHARMACOLOGICAL ACTION
Ramipril inhibits angiotensin I-converting enzyme (ACE) activity. It inhibits the conversion of the relatively inactive angiotensin I to the active angiotensin II. Angiotensin II is a potent vasoconstrictor and stimulates the release of aldosterone. Decreased angiotensin II levels result in a decrease in vasopressor activity and a reduction in aldosterone secretion, which may result in small increases in serum potassium.
It is also thought that ACE inhibition may inhibit degradation of bradykinin, leading to increased bradykinin levels.
Pharmacokinetics
Following oral administration, ramipril is rapidly absorbed from the gastro-intestinal tract, and peak plasma concentrations of ramipril are reached within one hour. Ramipril is converted in the liver to its diacid metabolite, ramiprilat, by cleavage of an ester group. Peak plasma concentrations of ramiprilat are reached two to four hours after drug intake. Based on the urinary recovery of ramipril and its metabolites the extent of absorption is estimated to be 30% to 60%.
Food intake has no relevant influence on the extent of absorption.
The protein binding of ramipril is about 73% and of ramiprilat about 56%.
Ramipril is almost completely metabolised and the metabolites are excreted mainly via the kidneys. Besides the bioactive metabolite ramiprilat, further inactive metabolites have been identified, i.e. diketopiperazine ester, diketopiperazine acid, and conjugates.
Plasma concentrations of ramiprilat decline in a polyphasic manner. The effective half-life of ramiprilat after multiple once daily administration of ramipril is 13 to 17 hours for 5 to 10 mg ramipril and several times longer for lower doses such as 1,25 to 2,5 mg ramipril. The prolonged half-life at low dosages is due to a high fraction of the metabolite being bound to the angiotensin converting enzyme at low plasma concentrations and thus a slow dissociation of this enzyme inhibitor complex. However, with high dosages a shorter half-life due to a higher free fraction leading to easier dissociation is observed. Steady-state plasma concentrations of ramiprilat after once daily dosing of the usual doses of ramipril are reached at about treatment day four.
Patients with renal impairment
In patients with impaired renal function the elimination of ramipril and ramiprilat from plasma is delayed and the urinary excretion reduced.

INDICATIONS
Ran-Ramipril 10 Capsules
are indicated for the treatment of:
Mild to moderate hypertension.
Cardiac failure following myocardial infarction.
To reduce proteinuria and the decline in glomerular filtration rate in patients with diabetic nephropathy and hypertension.
To reduce the risk of myocardial infarction, stroke or cardiovascular death and to reduce the need for revascularization procedures in patients with an increased cardiovascular risk [such as manifest coronary heart disease (with or without a history of myocardial infarction), a history of stroke or a history of peripheral vascular disease].
To reduce the risk of myocardial infarction stroke or cardiovascular death in diabetic patients.

CONTRA-INDICATIONS
Sensitivity to any of the components of Ran-Ramipril 10 Capsules.
Patients with a history of angioedema related to previous ACE-inhibitor therapy or angiotensin receptor blocker.
Hereditary or idiopathic angioedema.
Aortic stenosis.
Hypertrophic obstructive cardiomyopathy.
Severe renal function impairment (creatinine clearance below 30 mL/min).
Renal artery stenosis in patients with a single kidney.
Concomitant therapy with potassium sparing diuretics such as spironolactone, triamtrene, amiloride.
Porphyria

WARNINGS
Should a woman become pregnant while receiving an ACE inhibitor, the treatment must be stopped promptly and changed to a different medicine. (See Pregnancy and Lactation).
If a woman is contemplating pregnancy, a different class of medicine should be used. (See Pregnancy and Lactation).
Ran-Ramipril 10 Capsules should be used with caution in the following conditions:
Cerebrovascular disease or ischaemic heart disease –Reduction in blood pressure could aggravate these conditions and may result in myocardial infarction and cerebrovascular accidents.
Volume depleted patients (e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting) – Although it may occur in normo volumic patients, hypotension is more likely in volume depleted patients. A sudden reduction in angiotensin II may result in sudden and severe hypotension. There is also an increased risk of Ran-Ramipril 10 Capsules induced renal failure, especially in those with congestive heart failure.
Patients at a high risk of symptomatic hypotension e.g. patients with salt or volume depletion with or without hyponatremia should have these conditions corrected before therapy with Ran-Ramipril 10 Capsules. Monitoring is required after initiating therapy.
Severe autoimmune disease, especially systemic lupus erythematosus, other collagen vascular disease or scleroderma: Increase the risk for development of neutropenia or agranulocytosis.
In acute myocardial infarction, treatment with Ran-Ramipril 10 Capsules should not be initiated in patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 micromol/L or proteinuria exceeding 500 mg/24 hours). If renal dysfunction develops during treatment (serum creatinine concentrations exceeding 177 micromol/L or doubling of the pre-treatment value) then Ran-Ramipril 10 Capsules may need to be withdrawn (see alsoContra-indications).
In acute myocardial infarction, patients may develop persistent hypotension and/or impaired renal function.
Hypotension in acute myocardial infarction –Treatment with Ran-Ramipril 10 Capsules must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These include patients with systolic blood pressure of 13,33 KPa or lower or cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 15,99 KPa or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 13,33 KPa or lower. If hypotension persists (systolic blood pressure less than 11,99 KPa for more than 1 hour) then Ran-Ramipril 10 Capsules should be withdrawn.
Bone marrow depression –Increased risk of agranulocytosis and neutropenia.
Diabetes mellitus – Increased risk of hyperkalaemia, as well as hypoglycaemia may occur.
Hyperkalaemia –Ran-Ramipril 10 Capsules may cause an increase in serum potassium levels.
Renovascular disease –Ran-Ramipril 10 Capsules should not be used in patients with renovascular disease or suspected renovascular disease, but it may be used cautiously in severe resistant hypertension in such patients. In this instance Ran-Ramipril 10 Capsules should only be used under specialist supervision. The elderly, patients with peripheral vascular diseases or generalised atherosclerosis may have asymptomatic renovascular disease. (See Dosage and Directions).
Renal artery stenosis, bilateral or in one kidney or renal transplant – Increased risk of renal function impairment may increase in blood urea and serum creatinine concentrations, which may be reversible upon discontinuation of therapy. There is also an increased risk of agranulocytosis and neutropenia when immunosuppressants are concurrently administered.
Renal function impairment –Decreased elimination of Ran-Ramipril 10 Capsules resulting in an increased risk of hyperkalaemia. These patients may require lower doses.
Anaphylactoid reactions have occurred in patients using ACE inhibitors during desensitising protocols involving for example, hymenoptera venom.
Anaphylactoid reactions have been reported in patients exposed to either high-flux membrane dialysis or low-density lipoprotein apheresis with dextran sulphate absorption.
Hypersensitivity/Angioedema –If Angioedema of the face, extremities, lips, tongue, glottis and/or larynx is observed in patients treated with Ran-Ramipril 10 Capsules, Ran-Ramipril 10 Capsules should be discontinued promptly. These patients should be monitored to ensure complete resolution of symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. These patients should never receive any Ran-Ramipril 10 Capsules again.
Ran-Ramipril 10 Capsules causes a higher rate of angioedema in black patients than in non-black patients.
Safety and efficacy in children has not been established.
Concomitant therapy with potassium sparing diuretics such as spironolatone, triamtrene, and amiloride may lead to hyperkalaemia which may be severe and lead to cardiac conduction abnormalities, dysarrythmias and cardiac arrest.

INTERACTIONS
Concomitant use of Ran-Ramipril 10 Capsules with:
Diuretics, alcohol and hypotension-producing medications – The antihypertensive effect is additive. Dosage adjustments may be necessary during concurrent use or when one medicine is discontinued.
Loop, thiazide or related diuretics –‘First dose hypotension’may occur (See Dosage and Directions for Use).
Indomethacin and nonsteroidal anti-inflammatory medicines (NSAIDs) –reduce the antihypertensive effects of Ran-Ramipril 10 Capsules. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with Ran-Ramipril 10 Capsules.
Potassium supplements or potassium sparing diuretics such as spironolactone, triamterene or amiloride –Concurrent administration may result in hyperkalaemia.
Lithium –Increases in lithium concentrations have been reported. Frequent monitoring of serum lithium concentrations is recommended.

PREGNANCY AND LACTATION
Use of Ran-Ramipril 10 Capsules limited to the first trimester does not appear to present a significant risk to the foetus, but foetal exposure after this time has been associated with teratogenicity and severe toxicity in the foetus and newborn, including death. Ran-Ramipril 10 Capsules crosses the placenta. Foetal exposure to ACE inhibitors during the second and third trimester can cause hypotension, renal failure, skull hypoplasia, hyperkalaemia and oliguria. Oligohydramnios may occur resulting in pulmonary hypoplasia, limb contractures and craniofacial deformation.
Infants who have been exposed in utero to Ran-Ramipril 10 Capsules should be closely monitored.
Peritoneal dialysis may be of some benefit in the clearance of Ran-Ramipril 10 Capsules from the neonatal circulation. Safety in lactation has not been established.

DOSAGE AND DIRECTIONS FOR USE
Adults
Ran-Ramipril 10 Capsules
may be taken with/without meals preferably at the same time every day. The capsules should be taken with half a glass of liquid during or after meals.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of Ran-Ramipril 10 Capsules. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with Ran-Ramipril 10 Capsules to reduce the likelihood of hypotension. In case the diuretic therapy cannot be discontinued, the initial dose should be with ramipril 1,25 mg.
Hypertension
Administration of Ran-Ramipril 10 Capsules to hypertensive patients results in a reduction of both supine and erect blood pressure. The antihypertensive effect is evident within one to two hours after intake of the medicine, peak effect occurs three to six hours after intake and has been shown to be maintained for at least 24 hours at recommended doses. The dose range is of ramipril is 2,5 mg to 10 mg as a single daily dose.
The recommended initial dosage in patients not on diuretics is 2,5 mg ramipril once a day. The dosage should be increased to ramipril 5 mg and up to a maximum of 10 mg Ran-Ramipril 10 Capsules once a day at intervals of one to two weeks based on patient response.
A maximum dose of 10 mg should not be exceeded.
Post-Myocardial Infarction
Treatment with ramipril should be initiated in hospital between day 3 and day 10 following an acute myocardial infarction if the patient manifests with evidence of heart failure and is haemodynamically stable.
The recommended dosage is ramipril 2,5 mg twice daily for two days. If well tolerated increase the dose to ramipril 5 mg twice daily.
If patients are unable to tolerate ramipril 2,5 mg initially, ramipril 1,25 mg twice daily may be given initially and later increased to 2,5 mg twice daily.
Non-diabetic and diabetic nephropathy
The recommended initial dose is ramipril 1,25 mg once daily. Depending on how the patient tolerates the medicine, the dose should be increased. It is recommended that the dose, if increased, be doubled at intervals of 2 to 3 weeks. Maximum permitted daily dose is 10 mg Ran-Ramipril 10 Capsules.
In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic for at least 2 to 3 days or depending on the duration of action of the diuretic, longer, before starting treatment with ramipril, or at least, to reducing the diuretic dose.
To reduce the risk of myocardial infarction, stroke or cardiovascular death
The recommended initial dose is ramipril 2,5 mg once daily. Depending on the tolerability, the dose is gradually increased. The increase should be implemented by doubling the dose after one week of treatment. Three weeks later, it should be doubled again to the usual maintenance dose of 10 mg Ran-Ramipril 10 Capsules once daily.
Dosage Adjustment in Renal Impairment
Ran-Ramipril 10 Capsules
are not recommended for use in dialysis patients.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Haematological:
Less frequent: Decrease in white blood cell count, haemoglobin and haemocrit, bone marrow depression, anaemia, thrombocytopenia, agranulocytosis, haemolytic anaemia.
Cardiovascular:
Less frequent: Orthostatic effects including hypotension, myocardial infarction, cerebrovascular accident, palpitations and tachycardia.
Neurological:
More frequent: Dizziness, headache, fatigue.
Less frequent: Mood alterations, mental confusion, paraesthesia, vertigo, sleep disturbances.
Endocrine/Metabolic:
Less frequent: Hyperkalaemia, hyponatraemia, increases in blood urea, increases in serum creatinine.
Gastro-intestinal:
More frequent: Diarrhoea, nausea.
Less frequent: Abdominal pain, indigestion, dry mouth, pancreatitis, vomiting and taste disturbances.
Kidney/Genito-urinary:
Less frequent: Uraemia, oligouria, anuria, renal dysfunction, acute renal failure, impotence.
Liver/Hepatic:
Less frequent: Hepatitis (hepatocellular or cholestatic) jaundice, increase in liver enzymes, increase in serum bilirubin.
Musculoskeletal:
Less frequent: Asthenia.
Respiratory:
More frequent: Cough.
Less frequent: Bronchospasm, rhinitis, sinusitis.
Skin:
Less frequent: Rash, urticaria, diaphoresis, alopecia, pruritus psoriasis, severe skin disorders including pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme.
Other:
Less frequent: Hypersensitivity/angioedema reactions: Angioedema of the face, which may be fatal, extremities, lips, tongue, glottis and/or larynx and intestinal angioedema. A symptom complex has been reported which may include fever, vasculitis, myalgia, arthritis/arthralgia, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leucocytosis. Rash, photosensitivity or other dermatological manifestations may occur.
Special Precautions
Myocardial infarction and cerebrovascular accidents may be due to severe falls in blood pressure in high-risk patients e.g. those with ischaemic heart disease or cerebrovascular disease.
In volume depleted patients or patients with ischaemic heart disease or cerebrovascular disease, therapy should be monitored especially when the dose of Ran-Ramipril 10 Capsules or diuretic is adjusted.
If hypotension occurs, the patient should be placed in the supine position and if necessary receive an intravenous infusion of 0,9% saline.
Increases in blood urea and serum creatinine have been seen in patients with no apparent pre-existing vascular disease, especially when Ran-Ramipril 10 Capsules has been given concomitantly with a diuretic. Dosage reduction or discontinuation of Ran-Ramipril 10 Capsules or the diuretic may be required.
Signs of facial or extremity swelling or difficulty in swallowing or breathing require immediate medical attention because of the risk of angioedema.
Caution when driving or performing tasks requiring alertness because of possible dizziness.
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Ran-Ramipril 10 Capsules may block angiotensin II formation secondary to compensatory rennin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See Side-effects and Special Precautions.
Symptoms of overdose
Severe hypotension, electrolyte disturbances and renal failure.
Treatment of overdose
Treatment is symptomatic and supportive. Treatment should include volume expanders.

IDENTIFICATION
Blue cap, white body, self-lock hard gelatin capsules of size '4' imprinted with ‘R’on cap and ‘10’on body in black edible ink, containing a white to off-white granular powder.

PRESENTATION
Carton containing 30 capsules packed in aluminium strips of 10 capsules each.

STORAGE INSTRUCTIONS
Store below 25°C, protected from moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
38/7.1.3/0471

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THE PACKAGE INSERT
July 2005

New addition to this site: January 2006
Source: Pharmaceutical Industry

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