APPROVED BY

The Order of Ministry of Health of Ukraine

21.09.2016 № 989

Registration Certificate

№ UA/5200/01/02

№ UA/5200/01/03

№ UA/5200/01/04

 

INSTRUCTION

for medical use of medicinal product

  

CАRDIPRIL 2,5

CАRDIPRIL 5

CАRDIPRIL 10

 

Composition:

Active substance: ramipril;

1 capsule contains ramipril 2,5 mg or 5 mg, or 10 mg;

Excipient: pregelatinized starch.

Dosage form. Capsules.

Basic physical and chemical properties:

Cardipril 2,5: 2 size, blue/white, hard gelatine capsules. The capsule contains white or almost white powder;

Cardipril 5: 4 size, red and brown/white, hard gelatine capsules. The capsule contains white or almost white powder;

Cardipril 10: 4 size, blue/white, hard gelatine capsules. The capsule contains white or almost white powder.

Pharmacotherapeutic group. Inhibitors of angiotensin converting enzyme (ACE). Monocomponent of ACE inhibitors. Ramipril.

ATC code C09AA05.

Pharmacological properties.

Ramipril, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.Since angiotensin II also stimulates the release of aldosterone, ramipril causes a reduction in aldosterone secretion. 

ACE inhibitors are effective even in patients with hypertension, in which renin concentration in plasma is low. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamics.

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

In patients with pronounced non-diabetic or diabetic nephropathy ramipril reduces the rate of progression of renal failure and the onset of end-stage of renal failure, as the result – the necessity in dialysis or kidney transplantation. Ramipril reduces the albumin excretion in patients with first manifestations of non-diabetic or diabetic nephropathy.

Studies have shown that ramipril with high statistical significance reduces the frequency of onset of myocardial infarction (20%), stroke (32%) or cardiovascular mortality (26%). In addition, ramipril reduces overall mortality and the necessity for revascularization, as well as delays the occurrence and progression of congestive heart failure. Ramipril reduces the risk of nephropathy in the general population and patients with diabetes. Also, ramipril significantly reduces the incidence of microalbuminuria. These effects were observed in patients with both hypertension and normotension.

Pharmacokinetics.

There is presystemic metabolism of prodrugs in the liver. As a result, an active metabolite ramiprilat is formed (by hydrolysis that occurs mainly in the liver). In addition to such activation of ramiprilat, ramipril is glucuronidized and transformed into ramipril diketopiperasine (ether). Ramiprilat is also glucuronidized and transformed into ramiprilat diketopiperasine (acid).

As a result of this activation/metabolization of prodrugs, about 20% of received oral ramipril is bioavailable. After oral administration of ramipril 2.5 mg and 5 mg the bioavailability of ramiprilat is about 45% compared with its availability after intravenous introduction of the same dose.

After oral administration of ramipril 10 mg marked with a radioactive mark, approximately 40% of the mark is excreted with faeces and approximately 60% - with urine. After oral administration of ramipril 5 mg to the patients with drainage of the bile ducts approximately the same amount of ramipril and its metabolites is excreted with urine and bile in the first 24 hours.

Approximately 80-90% of the metabolites in urine and bile are ramiprilat or ramiprilat metabolites. Ramipril glucoronid and ramipril diketopiperasine make approximately 10-20% of the total, and non-metabolized ramipril makes about 2%.

In the animal studies there was revealed that ramipril is excreted in milk.

Ramipril is rapidly absorbed after oral administration. By measuring the amount of radioactivity in the urine, which represents only one way of elimination, there was established that absorption of ramipril is at least 56%. Administration of ramipril with food showed no significant effect on absorption.

Peak plasma concentration of ramipril is achieved in 1 hour after oral administration. The half-life of ramipril is about 1 hour. Peak concentration of ramiprilat in blood plasma was between 2 and 4 hours after oral administration of ramipril.

Decrease in concentration of ramiprilat in blood plasma has several phases. The half-life of the initial phase of distribution and elimination makes about 3 hours. Then comes the transition phase (half-life makes about 15 hours), and - the final phase, where plasma ramiprilat concentrations are very low, and a half-life is approximately 4-5 days.

The presence of final phase is caused by the slow dissociation of ramiprilat of close but saturated connection with ACE.

Despite the prolonged final phase of excretion, after reception of ramipril in a single dose of 2.5 mg a higher steady state - when ramiprilat plasma concentrations remain constant - is achieved in about 4 days. After taking multiple doses, depending on the dose, the "effective" half-life is 13-17 hours.

Studies in-vitro have shown that inhibition constant of ramiprilat makes 7 mmol / L, and the half-dissociation time of ramiprilat with ACE makes 10.7 hours that indicates about its high activity. The binding of Ramipril and ramiprilat with serum proteins are approximately 73% and 56% respectively.

In healthy people 65 to 76 years old ramipril and ramiprilat kinetics are similar to kinetics of young healthy people.

When renal function is impaired then the kidneys’ excretion of ramiprilat is decreased and the renal clearance of ramiprilat is decreased in proportion to creatinine clearance. This leads to increase of ramiprilat plasma concentrations that are decreased more slowly than in patients with normal renal function.

On the background of impaired hepatic function when you administrate high doses (10 mg) the transformation of ramipril into ramiprilat occurs later and plasma concentrations of ramipril are increased and ramiprilat excretion becomes slow.

No significant accumulation of ramipril and ramiprilat were observed in both healthy people and hypertensive patients after oral administration of ramipril 5 mg once a day for 2 weeks as well as in patients with congestive heart failure.

Clinical particulars.

Indications.

• Treatment of hypertension.
• Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:
  - Manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease);
  - Diabetes with at least one cardiovascular risk factor.
• Treatment of renal disease:
  - Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria;
  - Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor;
  - Manifest glomerular non-diabetic nephropathy as defined by macroproteinuria ≥ 3 g/day.
• Treatment of symptomatic heart failure.
• Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

Contraindications.

The drug is not recommended for children (under 18 years).

Hypersensitivity to ramipril or any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section «Composition»); History of angioneurotic oedema(hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs); Significant renal artery stenosis (bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney); hypotensive or haemodynamically unstable states, systemic lupus erythematosus, sclerosis (increased risk of neutropenia or agranulocytosis); suppression of bone marrow hematopoiesis; hyperkalemia, kidney transplantation, renal failure, hyponatremia (risk of dehydration, hypotension, renal failure), liver failure, primary hyperaldosteronism.

Pregnant women or women who plan to become pregnant (see section «Pregnancy and lactation»).

Do not use it along with preparations containing aliskiren, for patients with diabetes mellitus or moderate or severe renal failure (GFR <60 ml / min).

Do not use of ramipril or other ACE inhibitors in combination with extracorporeal therapy methods that can cause contact of blood with negatively charged surfaces, as there is a risk of severe anaphylactoid reactions that sometimes lead to severe anaphylactic shock. Thus, when you take ramipril you can not undergo a dialysis or hemofiltration using polyacrylic, sodium-2-methylsulfonate membranes with high ultrafiltration activity (for instance, «AN 69») and LDL apheresis procedure (LDL) using dextran sulphate.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section «Contraindications»). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Combined use of ramipril with medicinal products containing aliskiren, is contraindicated in patients with diabetes mellitus or moderate severe renal impairment and is not recommended for other categories of patients (see section «Contraindications» and «Precautions for use»).

Combinations requiring precautions.

Not recommended combinations.

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur. During concomitant treatment with ramipril and potassium-sparing diuretics (eg, spironolactone) or potassium salts, close monitoring of serum potassium is required.

Use with caution.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated. It is recommended the regular monitoring of serum sodium concentration in patients receiving concomitant therapy with diuretics (see section "Precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions in concomitant therapy with ramipril.

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents (e.g. insulin and sulfonylureas derivatives).

ACE inhibitors may increase the effect of insulin. In some cases, this may lead to the development of hypoglycaemic reactions in patients using anti-diabetic agents at the same time. Close blood glucose monitoring is recommended.

Food.

Food does not significantly change the absorption of ramipril.

Take into account.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalemia.

Heparin. Increase of calcium concentrations in serum is to be anticipated.

Alcohol.  Increased vasodilation. Ramipril may increase the alcohol effect.

Salt. Increased salt intake may diminish the antihypertensive effect of Cardipril.  

Specific hyposensitization. As a result of ACE inhibition the probabilities of occurrence of sever anaphylactic and anaphylactoid reactions in relation to insect venom are increased. It is believed that such effects may also occur in relation to other allergens.

Precautions for use.

Ramipril should be used under constant medical control.

Special population.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) using medicines containing aliskiren.

Dual blockade of the renin-angiotensin-aldosterone system through the combined use of ramipril and aliskiren is not recommended because there is an increased risk of hypotension, hyperkalemia and changes in renal function.

Combined therapy of ramipril and aliskiren is contraindicated for patients with diabetes mellitus or renal impairment (GFR ˂60 ml/min) (see section «Contraindications»).

There were cases of angioedema face, extremities, lips, tongue, glottis, or throat In patients treated with ACE inhibitors.

Urgent treatment of angioedema, which is a threat to life, involves immediate introduction of epinephrine (subcutaneously or slow intravenously) and at the same time ECG monitoring and blood pressure should be done. In case of angioedema, Ramipril must be discontinued. Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of Ramipril should be considered prior to desensitization.

There were cases of intestinal angioedema in patients treated with ACE inhibitors. These patients complained about abdominal pain (with or without nausea or vomiting); in some cases facial angioedema is occurred. Symptoms of intestinal angioedema disappeared after discontinuation of ACE inhibitor.

There is no sufficient appropriate therapeutic experience use in patients with severe renal impairment (creatinine clearance below 20 mL / min per 1.73 m² of body surface area).

Patients with increased activity of renin-angiotensin system.

Special care should be taken in the treatment of patients with increased active renin-angiotensin system. Such patients have a risk of sudden and significant reduction of blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is prescribed for the first time or for the first time in a higher dose. When you start to intake drug for the first time or when a dosage was increased, close blood pressure control should be monitored due to possibility of its sharp decline.

Significant activation of the renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example:

- in patients with severe and particularly malignant hypertension. In the initial phase of treatment a special medical observation is required;

- in patients with heart failure, especially in those who were treated with other medicines that may lower blood pressure. In the case of severe heart failure in the initial phase of treatment a special medical observation is required;

- in patients with hemodynamically significant difficulties of left ventricle blood inflow or outflow (e.g. due to aorta stenosis or mitral valve stenosis or hypertrophic cardiomyopathy). In the initial phase of treatment a special medical observation is required;

- in patients with hemodynamically significant renal artery stenosis. In the initial phase of treatment a close medical observation is required. The initiated diuretics therapy may be discontinued;

- in patients previously treated with diuretics. If discontinue or dose reduction of diuretic is not possible, in the initial phase of treatment a special medical observation is required;

- in patients who have or may develop a lack of fluid or salt (as a result of insufficient fluid or salt intake, or, for example, due to diarrhea, vomiting or excessive sweating in cases where the compensation for a lack of fluid and salts is insufficient);

- in patients undergoing extensive surgery or during anaesthesia with the use of drugs that cause arterial hypotension.

Generally it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload). In clinically significant conditions the treatment may be started or continued only when all specific measures have been taken to prevent excessive reduction in blood pressure and deterioration of renal function.

Patients with liver disease.

In patients with impaired liver function response to treatment may be either increased or reduced. In addition, in patients with severe liver cirrhosis with oedema and / or ascites activity of the renin-angiotensin system may be significantly increased; therefore these patients must be treated with caution.

Patients with a significant reduction of blood pressure have a particular risk. For the patients who have a particular risk due to their significant reduction of blood pressure (e.g. patients with hemodynamically significant stenosis of coronary arteries or blood vessels that supply blood to the brain), on the initial phase of treatment a special medical observation is required.

Elderly.

In elderly patients the response to ACE inhibitors may be more pronounced. At the beginning of treatment the evaluation of renal function is recommended.

Surgery. If it is possible, the treatment of angiotensin converting enzyme inhibitors such as ramipril should be discontinued 1 day before the surgery.

Monitoring of renal function.

It is recommended to monitor renal function before and during the treatment and to adjust the dose, especially in the first weeks of treatment with an ACE inhibitor. Special close monitoring is required for patients with:

- heart failure;

- vasorenal disease, including patients with hemodynamically significant unilateral renal artery stenosis. In the last patient group, even insignificant increase of creatinine level in blood serum may be indicative of unilateral deterioration of renal function;

- deterioration of renal function;

- kidney transplant.

Monitoring of electrolytes balance.

It is recommended to carry out regular monitoring of concentration of potassium in the blood serum. Closer control of serum potassium level is required for patients with reduced renal function.

Hyperkalemia. Hyperkalaemia has been observed in some patients treated with ACE inhibitors including Ramipril. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, and metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section «Interaction with other medicinal products and other forms of interaction»).

Control of electrolyte balance. Hyponatremia. Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatremia.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see section «Interaction with other medicinal products and other forms of interaction» and «Adverse reactions»).

Hematology monitoring.

It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (such as lupus or scleroderma) or those treated with other medicines that may cause changes in the blood picture. Cases of neutropenia/agranulocytosis, thrombocytopenia and anemia and have been observed rarely. There was also reported suppression of bone marrow function.

Ethnic differences. ACE inhibitors cause higher rate of angioedema in black patients than in non black patients. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough. Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Pregnancy and lactation.

Pregnancy.

The drug is contraindicated for pregnant women or women who plan to become pregnant. If pregnancy is established during therapy, the drug should be discontinued immediately and, if necessary it could be replaced by other drug approved for use in pregnant women (see section «Contraindications»).

Lactation.

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Effects on ability to drive and use machines.

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

Method of administration and dosage.

Oral use.

It is recommended that capsules are taken each day at the same time of the day. The medication may be taken before, with or after meals, because food intake does not modify its bioavailability. Capsules have to be swallowed with liquid. They should not be chewed or crushed.

Adults.

Diuretic-Treated Patients. Hypotension may occur following initiation of treatment; this is more likely in patients who are being treated concomitantly with diuretics.  In such cases, caution is recommended, since CBV and/or electrolytes quantity may be reduced in these patients.

If possible, the diuretic should be discontinued 2 to 3 days before beginning treatment with ramipril (see section «Precautions for use»).

In hypertensive patients in whom the diuretic is not discontinued, therapy with the drug should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of the drug should be adjusted according to blood pressure target.

Hypertension.

The dose should be individualized according to the profile of the patient (see section «Precautions for use») and blood pressure control. Ramipril may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose. Treatment should be started gradually with an initial recommended dose of 2.5 mg a day.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of the treatment should takes place under medical supervision (see section «Precautions for use»).

Titration and maintenance dose. The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of ramipril is 10 mg once a day. Usually the dose is administered once daily.

(See also dosage on diuretic treated patients above)

Cardiovascular prevention.

Starting Dose. The recommended initial dose is 2.5 mg once a day.

Titration and maintenance dose. Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks- to increase it up to the target maintenance dose of 10 mg once a day.

(See also dosage on diuretic treated patients above)

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg once a day.

 (use in an appropriate dosage).

Titration and maintenance dose. Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

(See also dosage on diuretic treated patients above)

In patients with diabetes and at least one cardiovascular risk

Starting Dose:

The recommended initial dose is 2.5 mg once a day.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg after one or two weeks and then to 10 mg after another two or three weeks is recommended. The target daily dose is 10 mg.

(See also dosage on diuretic treated patients above)

In patients with non-diabetic nephropathy is characterized by macroproteinuria ≥ 3 g / day

Starting Dose:

The recommended initial dose is 1.25 mg once a day.

 (use in an appropriate dosage).

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure.

Starting Dose:

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

 (use in an appropriate dosage).

Titration and maintenance dose

Ramipril should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

(See also dosage on diuretic treated patients above)

Secondary prevention after acute myocardial infarction and heart failure.

Starting Dose. After 48 hours, following myocardial infarction in a clinically and haemo dynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

(See also dosage on diuretic treated patients above)

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance:

- if creatinine clearance is ≥ 60 ml/min, it is not necessary to adjust the initial dose (2.5 mg / day), the maximum daily dose is 10 mg;

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg / day); the maximum daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg /day and the maximum daily dose is 5 mg;

- in haemodialysed hypertensive patients: Ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment. In patients with hepatic impairment, treatment with Ramipril must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg.

Elderly. Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg should be considered. (use in an appropriate dosage).

Children.

The drug is not recommended for children (under 18) because the safety and efficacy of ramipril in children has not been established.

Overdose.

Symptoms .  Overdosage mau cause an excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure..

Treatment. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

 

Adverse reactions.

Since ramipril is an antihypertensive agent a lot of its side effects are secondary relative to its ability to lower blood pressure, as the result there is an adrenergic reversible regulation or hypoperfusion of bodies. The numerous other effects (e.g. effect on electrolyte balance, certain anaphylactoid reactions or inflammatory reactions of mucous membranes) are caused by inhibition of ACE or by other pharmacological effects of this class of drugs. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Cardiac disorders: Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations; oedema peripheral.

Blood and lymphatic system disorders: Eosinophilia; white blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased , hemoglobin decreased, platelets count decreased; bone marrow failure, pancytopenia, haemolytic anaemia.

Nervous system disorders: Headache, dizziness; paraesthesia, vertigo, ageusia, dysgeusia; tremor, balance disorder; cerebral ischaemia, including ischaemic stroke TIA (transient ischaemic attack), impaired psychomotor skills, burning sensation, parosmia.

Eye disorders: Visual disturbance including blurred vision; conjunctivitis.

Ear and labyrinth disorders: Hearing impaired, tinnitus.

Respiratory, thoracic and mediastinal disorders: Non-productive tickling cough, bronchitis, sinusitis, dyspnoea; bronchospasm including asthma aggravated, nasal congestion.

Gastrointestinal disorders: Gastro-intestinal inflammation, digestive distrubances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting; pancreatitis (cases of with fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel  angioedema, upper abdominal pain, including gastritis, constipation, dry mouth; glossitis; aphthous stomatitis.

Renal and urinary disorders: Renal impairment including renal failure acute, urine output increased, worsening of pre-existing proteinuria, blood urea increased, blood creatinine increased.

Skin and subcutaneous tissue disorders: Rash in particular maculo-papular; angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis; exfoliative dermatitis, urticaria, onycholysis,; photosensitivity reactions; toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders: Muscle spasms, myalgia; arthralgia.

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: Blood potassium increased; anorexia, decreased appetite; blood sodium decreased.

Vascular disorders: Hypotension, orthostatic blood pressure decreased, syncope; flushing; vascular stenosis, hypoperfusion, vasculitis; Raynaud's phenomenon.

General disorders and administration site conditions: Chest pain, fatigue; pyrexia; asthenia.

Immune system disorders: Anaphylactic or anaphylactoid reactions, antinuclear antibody increased.

Hepatobiliary disorders: Hepatic enzymes and/or bilirubin conjugated increased; jaundice cholestatic, hepatocellular damage; acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).).

Reproductive system and breast disorders: Transient erectile impotence, libido decreased; gynaecomastia.

Psychiatric disorders: Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence; confusional state; disturbance in attention.

Paediatric Population. Although e nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

Tachycardia, nasal congestion and rhinitis, and conjunctivitis "common" (ie, ≥ 1/100 to < 1/10) in paediatric, and "uncommon" (ie, ≥ 1/1,000 to < 1/100) in adult population.

Conjunctivitis "common" (ie, ≥ 1/100 to < 1/10) in paediatric and "rare” (i.e. ≥ 1/10,000 to < 1/1,000) in adult population.

Tremor and urticaria "uncommon" (ie, ≥ 1/1,000 to < 1/100) in paediatric population while "rare" (ie, ≥ 1/10,000 to < 1/1,000) in adult population.

The overall safety profile for ramipril in paediatric patients does not differ significantly from the safety profile in adults.

Shelf-life. 3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original package at temperature not exceeding 30 °С.

Package.

Cardipril 2,5: 10 capsules in a blister, 1 or 3 blister in a pack.

Cardipril 5 or Cardipril 10: 10 capsules in a blister; 3 blister in a pack.

Terms of dispensing. On prescription.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer’s registered address

Е-28, Opp. Fire Brigade, M.I.D.C., Taloja, Dist. Raigad, Maharashtra, IN-410208, India

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London,

United Kingdom.

Date of last update.

21.09.2016.