INSTRUCTION 

for medical use of the preparation 

CАRDIPRIL 1,25, CАRDIPRIL 2,5, CАRDIPRIL 5, CАRDIPRIL 10

General characteristics: 

International and chemical names: ramipril; (2S, - [1 - [R * (R *), 2 alpha, 3а beta, 6а beta]] -1 - [2 - [[1 - (etoxicarbonil)-3- phenylpropyl] amino]-1-oxopropyl] octahydrocyclopenate [b] pyrrole -2- carboxylic acid;

Main physical and chemical properties: 

(1.25 mg): hard gelatin capsules, size 2, of yellow and orange color, content of the capsule: white or almost white powder;

(2.5 mg): hard gelatin capsules, size 2, of blue and white color, content of the capsule: white or almost white powder;

(5 mg): hard gelatin capsules, size 4, of reddish-brown and white color, content of the capsule: white or almost white powder;

(10 mg): hard gelatin capsules, size 4, of blue and white color, content of the capsule: white or almost white powder.

Composition: 1 capsule contains ramipril 1.25 mg or 2.5 mg, or 5 mg, or 10 mg; auxiliary substances: pregelatinised starch (Unigel - 270).

Medicinal form. Capsules.

Pharmacotherapeutical group. Inhibitor of angiotensin converting enzyme. АТС code С09АА05.

Pharmacological properties

Pharmacodynamics. Ramipril is an inhibitor of angiotensin converting enzyme. It inhibits angiotensin ІІ formation and prevents its vasoconstrictive action, block bradykinin disintegration which promotes formation of nitric oxide and prostaglandins. Decreases general peripheric resistance, cardiac afterload, pressure in pulmonary circuit. Decreases aldosterone secretion. Decreases resistance in renal vessels, improves renal blood supply.

Pharmacokinetics. In case of oral intake, its absorption is about 50-60% (food intake does not influence the degree of absorption, but decreases its rate. Its concentration increases disproportionately with the dose increase. Ramiprilate is released in the liver, its activity exceeds that of ramipril 6-folds, and there form inactive metabolites (in case of disturbed liver function, metabolism is slowed). Maximal plasma concentration of ramipril is achieved in 1-2 hours, the one of ramiprilate – in 2-4 hours; binding with plasma proteins is 73% and 56%; half-life is – 5.1 hours and 13-17 hours, respectively. It is excreted with urine (60%, 2% of which – in unchanged state) and with faces – 40%. In case of renal insufficiency, the half-life (may exceed 50 hours) and AUC increase (3-4-folds), and its excretion decreases. In elderly patients there is noted the change of maximal concentration and AUC without influence on clinical indexes.

Indications. 
- arterial hypertension.- congestive heart failure (as a part of combined therapy).

- cardiac insufficiency after acute myocardial infarction in patients with stable geodynamics.

- expressed diabetic or non-diabetic nephropathy, as well as its initial stages.  

- prophylaxis of myocardial infarction, stroke or risk of death from cardio-vascular disorders.

 
Way of introduction and doses.  

Arterial hypertension: recommended initial dose – 2.5 mg once a day (1 capsule 2.5 mg). According to the state of the patient daily dose may be doubled every 2 – 3 weeks. Usual supportive dose is 2.5 – 5 mg a day. Maximal daily dose is 10 mg.

If treatment of the patient requires doses higher than 5 mg, instead of further Cardipril dose increase it is necessary to consider the possibility of its combination with other antihypertensive preparations, e.g., diuretics or calcium channel-blocking agents.

Congestive heart failure: recommended initial dose – 1.25 mg once a day (1 capsule 1.25 mg). According to the therapeutic effect daily dose may be increased by doubling it every 2 – 3 weeks. Maximal daily dose should not exceed 10 mg.

Cardiac insufficiency after acute myocardial infarction: the initiation of using the preparation is recommended on day 2 – 9 after myocardial infraction. The initial dose is 1.25 mg – 2.5 mg twice a day. According to the therapeutic effect daily dose may be increased up to 2.5 mg – 5 mg twice a day. Maximal daily dose should not exceed 10 mg.

Expressed diabetic or non-diabetic nephropathy, as well as its initial stages:recommended initial dose – 1.25 mg once a day (1 capsule 1.25 mg). According to the therapeutic effect daily dose may be increased by doubling it every 2 – 3 weeks. Recommended maximal daily dose is 5 mg.

Prophylaxis of myocardial infarction, stroke or risk of death from cardio-vascular disorders. Initial dose – 2.5 mg once a day (1 capsule 2.5 mg). According to the tolerance of the preparation in one week of administration daily dose should be increased twice (5 mg a day). This dose should be doubled again after 3 weeks of administration. Supportive recommended dose is 10 mg once a day.

Capsules should be swallowed as a whole, without chewing, with big amount of water (approximately 1 glass). Capsules can be taken irrespectively from times of meal.

Side effects. 
From the side of cardiovascular system and blood: arterial hypotension, stenocardia, cardiac insufficiency, chest pain; very seldom – arrhythmia, tachycardia.

From the side of nervous system and sense organs: dizziness, headache, asthenia, very seldom – cerebrovascular disorders, amnesia, sleepiness, cramps, depression, sleep disturbance, neuralgia, neuropathy, paresthesia, tremor, decreased hearing, sight disorder.

From the side of urinary system: renal disfunction, proteinuria, oliguria, edemas.

From the side of blood-forming system: hemolytic anemia, myelodepression, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis.

From the side of organs of gastro-intestinal tract: nausea, vomiting, diarrhea, very seldom – dry mouth or excessive salivation, anorexia, dyspepsia, dysphagia, constipation, abdominal pain, gastroenteritis, pancreatitis, hepatitis, hepatic disfunction, transaminase level alteration.

From the side of respiratory system: dry cough, infectious diseases of the upper air ways, very seldom – dyspnoea, pharyngitis, sinusitis, rhinitis, tracheobronchitis, laryngitis, bronchiospasm.

Allergic reactions: urticaria, rash, erythema multiforme, photosensitization, angioneurotic edema.

Other: loss of body weight, anaphylactoid reactions, increased level urea nitrogen and creatinine, angioneurotic edema, arthralgia/arthritis, myalgia, fever, hyperkaliemia, alteration of enzyme activity, bilirubin concentration, uric acid, glucose. 

Contraindications. 

Hypersensitivity (Quincke's edema in anamnesis associated with previous therapy with angiotensin-converting enzyme inhibitors, hereditary or idiopathic Quincke's edema); systemic lichen ruber, scleroderma (increased risk of development of neutropenia or agranulocytosis); inhibition of bone-marrow blood-formation; hyperkaliemia, double-sided renal artery stenosis, renal artery stenosis of only kidney, kidney transplantation, renal insufficiency, hyponatremia (risk of dehydratation, arterial hypotension, renal insufficiency), hepatic insufficiency, primary aldosteronism, pregnancy, lactation, children under 18 years old.

Overdose. 

Symptoms: severe arterial hypotension, shock, electrolytic disorders, renal insufficiency. Treatment of overdose depends on the way and time of introduction of the preparation, as well as on the type and severity of symptoms.

Treatment: gastric lavage, activated charcoal. It is necessary to monitor and support all essential functions of the patient’s organism in conditions of intensive therapy; in case of hypotension it is possible to introduce catecholamines and angiotensin ІІ, introduce additional fluid and sodium. Hemodialysis is ineffective.

Precautions at use. 

In patients with cardiac insufficiency intake of the preparation may lead to the development of expressed arterial hypotension, accompanied with oliguria or azotemia and sometimes – development of acute renal insufficiency.

Patients with malignant arterial hypertension or with concomitant severe cardiac insufficiency should start the treatment in hospital conditions. 

Before initiation and during therapy with angiotensin-converting enzyme inhibitors it is necessary to calculate total leukocyte number and determine leukocytic form (up to once a month during first 3-6 months of treatment in patients with increased risk of neutropenia – in case of renal disfunction, collagenosis or in those who receive high doses, as well as at first signs of the development of infection). If neutropenia has been confirmed therapy with angiotensin-converting enzyme inhibitors should be discontinued.

After first dose intake and at increasing of the diuretic dose and/or Cardipril the patients should stay under doctor’s supervision for 8 h to avoid the development of uncontrolled hypotensive reaction. 

Before and during treatment it is necessary to monitor the arterial pressure, renal function, К+ content in plasma, haemoglobin content in peripheral blood, вмісту К+ content, creatinine, urea, concentrations of electrolytes and liver enzymes in blood.

It is necessary to indicate the preparation with care to the patients who are on low-salt or salt-free diet (increased risk of development of arterial hypotension). 

Transitory hypotension is not a contraindication to continue the treatment after stabilization of arterial pressure. In case of recurring expressed hypotension it is necessary to decrease the dose or withdraw the preparation.

It is not recommended to use dialysis membranes with polyacrylonitritemetalylsylphate (e.g., AN 69) with angiotensin-converting enzyme inhibitors (possible development of anaphylactoid reactions in the patients).

It is necessary to inform the surgeon about use of Cardipril before surgery.

Use of Cardipril in elderly patients receiving diuretics and/or those with cardiac insufficiency, as well as with hepatic or renal disfunction, requires special attention. 

In early stages of treatment with Cardipril patients with hepatic disfunction require thorough medical observation. 

Alcohol use is not recommended during treatment with Cardipril.

During treatment it is necessary to abstain from driving or other activities requiring high concentration of attention and rate of psychomotor reactions, as there is a possibility of dizziness, especially after initial dose of angiotensin-converting enzyme inhibitor in patients receiving diuretics. It is necessary to be careful when doing physical exercises or at hot temperature due to the risk of dehydratation and arterial hypotension caused by the decrease of liquid volume in the body.

Interaction with other drugs. 

Antihypertensive preparations, diuretics, opium analgetics, preparations for narcosis enhance hypotensive action. Non-steroid anti-inflammatory agents (especially indometacin), table salt weaken the effect. Indometacin and other non-steroid anti-inflammatory agents may counteract atihypertensive action via inhibition of prostaglandin synthesis in kidneys and/or due to sodium and liquid retention. These patients require thorough supervision.

Cyclosporine, potassium-sparing diuretics (amylorid, spironolactone, triamterene), milk, potassium preparations, potassium admixtures, salt-substitutes enhance the risk of development of hyperkaliemia.

Preparations inhibiting bone marrow enhance the risk of development of neutropenia and/or lethal agranulocytosis.

At concomitant use with lithium preparations their concentration in blood increase.

Enhances hypoglycemic effect of the derivatives of sulphonylurea, insulin.Enhanced risk of development of leucopenia at concomitant use with allopurinol, cytostatic preparations, immunosuppressants, procaineamide hydrochloride.

Enhances inhibiting action on the central nervous system of ethanol.

Oestrogens decrease hypotensive effect (retain liquid).

Storage conditions and shelf life. Keep out of the reach of children in dry place at temperature below 30єC. Shelf life is 3 years.  

Packing. 10 capsules in a blister; 1 or 3 blisters in a carton.  

Terms of dispensing. On prescription.  

Applicant. Flamingo Pharmaceuticals Ltd. E-28, MIDS, Taloja, Mumbai – 410208, or 7/1, Corporate Park, Sion-Trombai Road, Chembur, Mumbai – 400071, India.