Patient information leaflet

STATINAM

Trade name: Statinam

International nonproprietary name: none.

Description: white to almost white, round, biconvex,film-coated tablets

Composition: each film-coated tablet contains:

active ingredient – amlodipine (as amlodipine besilate) 5mg; atorvastatin (as atorvastatin calcium) 10 mg;

Excipients: pregelatinised starch, calcium carbonate, croscarmellose sodium, hypromellose 2910, anhydrous colloidal silicon dioxide, calcium stearate, microcrystalline cellulose, opadry II white (85F).

Ingredients of opadry II white (85F): partially hydrolyzed polyvinyl alcohol,macrogol/polyethyleneglycol; talc (E553b), titanium dioxide (E171).

Pharmaceutical form: film-coated tablets

Pharmacotherapeutic group: HMG-CoA reductase ingibitors (statins), different combinations, atorvastatin and amlodipine.

Pharmacological characteristics

Combination product, which is applied for combine cardiovascular disease treatment such as: arterial hypertension/stenocardia and dislipidemy).The pharmacological action of the drug product is conditioned by properties of its components. Amlodipine has hypotensive and antianginal action. The mechanism of hypotensive action of amlodipine is conditioned by direct relaxing action on unstriated vessel muscles. Antianginal action is due to widening of coronary and peripheral arteries and arteriolas: in case of breast-pang it reduces the intensity of myocardial ischemia; widening the peripheral arteriolas it decreases peripheral resistance of vessels, lowers heart after loading, it reduces myocardium oxygen demand. Atorvastatin is the hypolipidemic agent that belongs to the group of statins. It lowers the level of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B and triglycerides; causes the increase of high density lipoprotein cholesterol and apoliprotein A. It dose-dependently lowers the level of low-density lipoprotein in patients with homozygous hereditary hypercholesterolemia which is tolerant to the therapy by other hypolipidemic medical products. It reduces the risk of ischemia complications development (including the development of death by myocardial infarction), the risk of rehospitalization because of stenocardia accompanied by myocardial ischemia symptoms. It does not have any cancerigenic and mutagenic effects. The therapeutic effect is reached in two weeks after the beginning of the therapy, reaches it maximum effect in four weeks and preserves within the whole period of treatment.

Indications for use

Statinam is prescribed to the patients to whom the simultaneous treatment with amlodipine and atorvastatin is recommended.

Amlodipine.

Arterial hypertension: Amlodipine is indicated for treatment of arterial hypertension. The drug product is administered both as the monotherapy and in combination with the other antianginal or hypotensive drug products.

Ischaemic heart disease (IHD)

Chronic stable stenocardia: Amlodipine is indicated for treatment of chronic stable stenocardia. The drug product is administered both as the monotherapy and in combination with the other antianginal or hypotensive drug products.

Vasospastic stenocardia(Prinzmetal's angina or variant stenocardia): amlodipine is indicated for treatment of confirmed or in case of suspected vasospastic stenocardia. The drug product is administered both as the monotherapy and in combination with the other antianginal drug products.

Coronary artery disease confirmed by angiographic study (CAD): amlodipine is indicated for patients with coronary artery disease that has been recently confirmed by angiographic study and with no cardiac distress or with indicant ejection fraction <40% in order to reduce the risk of hospitalization because of stenocardia and to lower the risk of revascularization procedure.

Atorvastatin

Associated with a high-risk of atherosclerotic vascular disease development at hypercholesteremia it is recommended to administer atorvastatin in patients with multiple risk factors. It is recommended to provide treatment with drug products if the response to therapeutic diet is lowering that is referred to saturated fat and cholesterin reduction and also in case of insufficiency of other drug-free methods. In patients with coronary artery insufficiency or multiple risk factors coronary artery insufficiency development the treatment of Statinam component of atorvastatin may be started together with therapeutic diet.

Atorvastatin is recommended to be taken for cardiovascular disease prevention to:

-                     reduce risk of myocardial infarction;

-                     reduce risk of apoplectic attack;

-                     reduce risk of revascularization and stenocardia

In patients with type 2 diabetes with no clinical evidence of coronary artery insufficiency with the several risk factors of coronary artery insufficiency (for instance: retinopathy, albuminuria, smoking or hypertension) atorvastatin is indicated to:

-                     reduce risk of myocardial infarction;

-                     reduce risk of apoplectic attack;

In patients with clinical evidence of coronary artery insufficiency atorvastatin is indicated to:

-                     reduce risk of nonfatal myocardial infarction;

-                     reduce risk of fatal and nonfatal apoplectic attack;

-                     reduce risk of revascularization;

-                     reduce risk of hospitalization with backward heart failure;

-                     reduce risk of stenocardia development

Heterozygous heritable and nonheritable hypercholesterolemia:

Atorvastatin is indicated as supplement to the diet in order to reduce higher level of total cholesterol, LDL, apoB and triglycerides and also to increase HDL in patients with primary hypercholesteremia (heterozygous heritable and nonheritable) with mixed dislipidemy (type IIa and IIb according to Fredricson’s classification);

Increased level of triglycerides in blood serum: Atorvastatin is indicated in combination with the diet in order to lower the higher level of triglycerides in blood serum (type IV according to Fredricson’s classification);

Primary dysbetalipoproteinemia: Atorvastatin is indicated for treatment of patients with primary dysbetalipoproteinemia if the diet does not have any appropriate effect;

Homozygous heritable hypercholesterolemia: Atorvastatin is indicated in order to reduce the higher level of total cholesterol and LDL in patients with homozygous heritable hypercholesterolemia in combination with other drug products which reduce the level of lipids (for example: apheresis of LDL) or if such treatment is impossible;

Drug use in children

Statinam drug product is not administered to children under 18 years old.

Restriction on drug administration

The research of antidyslipidemic component of Statinam with chylomicron surplus (type I and V according to Fredricson’s classification) was not performed.

Posology and administration

For treatment of hypertension/ stenocardia and hyperlipidemia the dose of Statinam is selected individually taking into consideration the effectiveness and acceptability of each component of the drug product. Statinam tablets are indivisible and cannot be administered in the period of amlodipine dose titration, starting with 2.5 mg. If amlodipine dose titration, starting with 2.5 mg, or atorvastatin administration in dose that exceeds 10 mg is necessary, it is recommended to administer monocomponent drug products such as: amlodipine and atorvastatin in the corresponding dose.

Amlodipine (arterial hypertension or stenocardia).

In case of hypertension treatment the recommended initial dose of amlodipine is 5 mg once a day. Maximal dose - 10 mg once a day. In patients of low stature, delicate constitution, elderly age as well as in patients with hepatic failure the initial dose is 2.5 mg once a day. The same dose may be administered when using amlodipine in combination with the other antihypertensive agents.

The dose is corrected depending on the patient's condition. On the average the processes of adjustment of drug dosage takes 7-14 days for a doctor to have a possibility to estimate the patient’s response to every dose-rate to the full extent. The adjustment can be carried out even within the shorter period of time under conditions of frequent health assessment of the patient.

For treatment of chronically stabile or vasospastic stenocardia the recommended dose of amlodipine is 5-10 mg. Lower dose is administered to elderly people and patients with hepatic failure. In order to reach an appropriate effect for most patients the required dose is 10 mg.

In patients with atherosclerotic heart disease the recommended dosage range is 5-10 mg once a day. During clinical test most of the patients were administered 10 mg.

Atorvastatin (hyperlipidemia)

Hyperlipidemia (heterozygous heritable and nonheritable) and mixed dyslipidemia (types IIa and IIb according to Fredricson’s classification)

The recommended initial dose of atorvastatin is 10-20 mg once a day. When it is necessary to reduce LDL significantly (more than 45%) the treatment may be started with the dose of 40 mg once a day. Atorvastatin is administered within the dosage range – 10-80 mg once a day. Atorvastatin may be administered at any time of the day,the food intake does not have any effect on drug product. Initial and maintenance dose of atorvastatin is selected individually depending on the therapy task and patient’s response. After the beginning of treatment and/or atorvastatin titration the lipid level must be analyzed every 2-4 weeks, and then the dose should be corrected.

Homozygous heritable hypercholesterolemia

The dose of atorvastatin in patients with homozygous heritable hypercholesterolemia is 10-80 mg/day. Atorvastatin is used as supplement to the other treatment courses, which allows to reduce the lipids level (for instance, LDL apheresis) and also in cases when it is impossible to use such treatment courses.

Associated treatment which reduces the level of lipids

Atorvastatin may be used in combination with bile acid sequestrant. It is necessary to monitor myopathy symptoms in patients who are treated with statins and fibrates.

Use by patients with kidney failure

Kidney diseases do not have any effect on atorvastatin concentration in blood plasma, and have no effect on LDL reduction by atorvastatin. Therefore, the correction of dose in patients with kidney failures is not carried out.

Administration in combination with other drug products (with cyclosporine, clarithromycin, ritonavir in combination with sacvinavir and with lopinavir in combination with ritonavir).

During administration in combination with cyclosporine the day dose of atorvastatin must be 10 mg. In patients who are administered clarithromycin, itraconasole and HIV positive patients who receive medical treatment with ritonavir and sacvinavir or lopinavir in combination with ritonavir, if the dose of atorvastatin exceeds 20 mg, it is necessary to make clinical judgement of patient's condition, which will help to provide a safe dose.

Statinam

Statinam may be replaced with certain drug products (amlodipine and atorvastatin). Patients may be prescribed the equivalent dose of Statinam and in order to reach an additional antianginal action, reduction of arterial tension and lowering of lipids level the increased amounts of amlodipine, atorvastatin or of the both components may be applied.

Statinam  may be administered as an add-on therapy in patients who have already been treated with one of the drug product’s component. As an initial therapy in terms of one index and to continue the treatment in terms of another index, the initial dose of Statinam is selected to continue the administration of component that has already been used, and for the second component the recommended initial dose is administered.

Statinam is used for initial treatment of patients with hyperlipidemia and hypertension or stenocardia. The basis for recommended initial dose of Statinam is the corresponding combination of recommendations for monotherapy.

Maximum daily dose for Statinam components is 10 mg of amlodipine and 80 mg of atorvastatin.

Side effect

Side effect of the drug product is conditioned by pharmacological properties of its components. The adverse reactions, known at the present time, which are conditioned by each active component of the drug product are given below. The frequency of side reactions means:

frequent (>1%), infrequent (< 1%), rare (<0.1), very rare (0.01%).

Amlodipine

Heart-vascular system: frequent ‑ peripheral oedema (of malleolus and feet), heartbeats; infrequent ‑ steep decline of arterial tension, postural hypotension, vasculitis; rare ‑ heart failure development or worsening; very rare ‑ rhythm disturbance (bradycardia, ventricular tachycardia, auricular fluttering), myocardial infarction, thoracalgia, bilious headache.

Nervous system: frequent ‑ headache, faintness, undue fatiguability, drowsiness; infrequent –cacesthesia, syncope, asthenia, hypesthesia, paresthesia, peripheral neuropathy, shivering, insomnia, mood swings, abnormal dreams, nervosism, acedia, psychic tension; rare – convulsions, apathy, agitation; very rare – ataxia, amnesia.

Digestive system: frequent – nausea, transabdominal pain; infrequent – bdelygmla, cacation regime change (including lock and flatulency), dyspepsia, diarrhoea, abepithymia, dryness of the mouth, thirst; rare ‑ gum hyperplasia, increased appetite; very rare – gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholesteric), hepatic transaminitis, hepatite.

Blood-forming organs: very rare ‑ thrombocytopenic purpura,leucopenia, thrombocytopenia.

Genitourinary system: infrequent – pollakiuria, micturition, nocturia, impotence; very rare ‑ dysuria, polyuria.

L ocomotor system: infrequent – arthralgia, myotonia,myodynia, dorsodynia, arthrosis; rare – myasthenia.

Respiratory system: infrequent ‑ labored breathing, rhinitis; very rare: cough.

Hypersensitivity reaction: infrequent ‑ skin itch, hives; very rare ‑ circumscribed edema, erythema multiforme, urticaria fever.

Others: infrequent – calvities, ringing of the ears, gynecomastia, weight gain/loss, vision disorders, diplopia, accommodation disorder, ophthalmoxerosis, conjunctivitis, ophthalmalgia, food faddism, shivers, nasal hemorrhage, diaphoresis; rare ‑ dermatitis; very rare – cold clammy sweat, parosmia, dermatodyschromia, hyperglycosemia.

Atorvastatin

Nervous system:frequent ‑insomnia, headache, asthenic feeling; infrequent – cacesthesia, faintness, amnesia, paresthesia, peripheral neuropathy, hypesthesia.

Digestive system: frequent – nausea, diarrhoea, abdominal pain, dyspepsia, lock, flatulency; infrequent – vomit, anorexia, hepatite, pancreatitis, cholestatic jaundice.

L ocomotor system: frequent ‑myodynia, infrequent and rare – backache, myotonia, myitis, myopathy, arthralgia, rhabdomyolysis.

Hypersensitivity reaction: infrequent ‑urticaria fever, pruritus, skin rash, anaphylaxis, bullous eruption, multiform erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), magliant erythema multoforme (Stevens-Johnson syndrome).

Metabolism: infrequent – hypoglycemia, hyperglycemia, increase activity of serumalcreatinine phosphokinase.

Blood-forming organs: infrequent – thrombocytopenia.

Others: infrequent – impotence, peripheral oedema, weight gain, chest pain, secondary kidney failure, calvities, ringing of the ears, lassitude.

Contraindications

Hypersensitivity, active liver disease or lasting activity increase of liver enzymes (more than thrice) of unknown cause, expressed arterial hypotension (systolic blood pressure less than 90 millimeters of mercury), administration in women at childbearing age who do not use valid methods of contraception; pregnancy, lactation period, age under 18 years old.

With care: arterial hypotension, aortic stenosis, chronic heart failure of nonischemic ethiology (III-IV class according to NYHA classification), acute myocardial infarction (and one month after that), hypertrophic obstructive cardiomyopathy, sick sinus syndrome, alcohol addiction and/or hepatic disorder (inanamnesis), elderly age.

Overdose

Symptoms: hypernormal peripheral vasodilatation leading to reflex tachycardia; expressed and persistent diminution of arterial tension, which includes shock development and fatality. Additionally, the possible symptoms may also be a complaint of the liver, acute renal failure; in case of long-term administration it leads to myopathy and rhabdomyolysis.

Treatment:

Activated carbon immediately or two hours after the administration, gastric lavage, elevated limb position, control of circulating blood volume, diuresis, indices of heart and lungs, heart-vascular system function support, vasoconstrictor drugs, gluconate Ca2+ intravenously (to remove the sequences of Ca2+ channels blocking). Atorvastatin binds to plasma proteins to a considerable extent and as a result haemodialysis is noneffective. In case of myopathy development followed by rhabdomyolysis and acute renal failure (rare) – immediate stopping of drug product administration and immediate administration of diuretic and sodium hydrocarbonate solution. Rhabdomyolysis can lead to hyperkalemia development; in order to remove that it is necessary to administer calcium chloride or calcium gluconate intravenously, glucose infusion with insulin, the use of ion exchanger of potassium ion, haemodialysis in bad cases.

Interaction with other drug products

Amlodipine pharmacokinetics in case of combined therapy with atorvastatin does not change.

Inhibitors of microsomal hepatic enzymes may raise the concentration of amlodipine in plasma increasing the risk of side effects development and inductors of microsomal hepatic enzymes may decrease the concentration of amlodipine in plasma.

In contrast with the other blockers of slow calcium channel, the clinically significant interaction of amlodipine and nonsteroidal antiinflammatory drug products especially with indomethacin is not indicated. Thiazide and loop diuretics, beta-adrenergic blocking agents, finoptin, ACE inhibitors and nitrate strengthen antianginal or hypotensive effect of amlodipine. Ca2+ drug products can reduce the effectof blockers of slow calcium channels. Antiviral agents (ritonavir) increase plasma concentration blockers of slow calcium channels, including amlodipine. Neuroleptics and isoflurane– strengthening of hypotensive action of dihydropyridine derivatives.

In case of simultaneous prescription of cyclosporine, fibrate, erythromycin, clarithromycin, immunodepressive, antifungal drug products (belonging to azols) and nicotinamide the concentration of atorvastatin in plasma (and the risk of myopathy) increases.

In case of simultaneous administration with erythromycin (500 mg 4 times per day) or clarithromycin (500 mg twice a day) it the increase of concentration of atorvastatin in blood plasma is reported.

Antacids reduce the concentration of atorvastatin over 35% (the effect on LDL cholesterolis not changed).

In case of simultaneous administration of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day) the atorvastatin concentration in plasma is not changed.

Clinically significant interaction was not mentioned in case of simultaneous administration with warfarin, cimetidine, phenazone.

Simultaneous administration of atorvastatin and protease inhibitor known as cytochromes inhibitors CYP3A4 is accompanied by increased concentration of atorvastatin in plasma (during the simultanious administration with erythromycin Cmax of atorvastatin is up by 40 %).

In case of digoxin administration in combination with atorvastatin in a dose of 80 mg/day, the concentration of digoxin is approximately up by 20 %.

It increases the concentration (in case of being prescribed together with atorvastatin in a dose of 80 mg/day) of oral contraceptives, which contain no rethisterone over 30% of and ethinyl estradiol over 20%. Hypolipidemic effect of the combination with colestipol surpasses that of each drug product apart, despite the atorvastatin concentration is down by 25% in case of its simultaneous administration with colestipol.

Simultaneous administration with drug products, which decrease the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) raise the risk of endogenous steroid hormones reduction (special care should be taken).

In case of digoxin administration together with atorvastatin in a dose of 80 mg/day the concentration of digoxin is up by 20 %.

Precautions

Skeletal muscles. When administering the tablets which contain atorvastatin and amlodipine rare cases of rhabdomyolysis with acute renal failure and following myoglobinuria, which was affected by atorvastatin are known. The risk factor for rhabdomyolysis development is nephatony. Such patients need much more careful monitoring of their skeletal muscles.

Atorvastatin like other statins can very rare lead to myopathy development that is shown as myoneuralgia or muscle weakness in association with increase of creatin phosphokinase (CFK) level by more than 10 times from high threshold value. The simultaneous administration of higher doses of atorvastatin with drug products such as cyclosporine and strong cytochrome inhibitors CYP3A4 (for instance clarithromycin, itraconasole, and HIV protease inhibitor) raise the risk of myopathy/ rhabdomyolysis development.

Every patient with diffuse myodynia, muscular aches, asthenia or significant increase of CFK needs to be examined for the presence of myopathy. Because of danger of myopathy development in case of statins administration to whichatorvastatin belongs (the ingredient of Statinam), the patients are recommended to report immediately on muscular aches, sickliness or asthenia, especially if it is accompanied by ailment or febriculosity.

Patients with acute myopathy and risk factors, who predispose to nephatony development followed by rhabdomyolysis (for instance bad acute infection, arterial hypotension, major operations, traumas, bad metabolic, endocrineand, electrolyte disorders and out-of-control convulsions) must suspend or stop the administration of the drug product.

Liver failure. Statins including atorvastatin and other drug products which decrease the level of lipids, can precipitate biochemical disturbance of hepatic function. It is recommended to measure the indices of hepatic function before and 12 week after the beginning of treatment with any increase of the dose of the drug product and also from time to time (for example every six months). The change in the level of liver enzymes usually takes place within the first 3 months after the beginning of atorvastatin administration, which is the component of Statinam. Patients with higher level of transaminase must be monitored until the disorders disappear.

If the higher level of GPT or AST remains unchanged (more than three times of high threshold value) it is recommended to decrease the dose or stop the administration.

Active hepatopathy or unexplained constant raised transaminase activity level are contraindication to Statinam administration.

Stenocardia progression and/or myocardial infarction. Stenocardia progression and acute myocardial infarction can develop after the beginning of amlodipine dosage increase especially in patients with serious obstructive coronary artery disease.

Hypotension. The development of endeictic hypotension is possible, especially in patients with frank stenosis of aorta. Because of the dose adjustment starting with the minimal one the development of acute hypotension is hardly probable.

Beta-blockers withdrawal effect. Amlodipine being a component of Statinam is not a beta-blocker and that is why it can not prevent the development of beta-blocker withdrawal effect; in case of such withdrawal effect it is necessary to reduce the dose of beta-blocker.

Endocrine function. Atorvastatin, like other statins influences the cholesterol synthesis and theoretically can reduce the level of adrenal hormones and/or sex steroids. Clinical research studies showed that atorvastatin does not reduce the basic level of cortisol in plasma and has no negative effect on adrenalin body reserve. The effect on male fertility was not studied with sufficient number of patients. Effects, if any, on pituitary-gonadal system in women during the menopause is unknown. It is necessary to take care when prescribing statins with drug products which may reduce the level or endogenic steroid hormones activity, such as ketoconazole, spironolactone and cimetidine.

Effects on the ability to drive and control potential hazardous machines: in the period of treatment one should take care when driving and practicing the hazardous types of activities that need boosting attention span and quickness of psychomotor action.

Storage conditions

Store in protected from light and moisture place at temperature below 25 °C.

Keep out of reach of children.

Shelf life

2 years. Do not use after the expiration of shelf life specified on the package.

Package

10 tablets in a blister. Three blisters together with a leaflet are put into a cardboard pack.

Prescription status

On prescription.

 

Manufacturer:

Belmedpreparaty RUE

30 Fabritsius Str., 220007 Minsk, Republic of Belarus,

Tel./fax: (+375 17) 220 37 16,

e-mail: medic@belmedpreparaty.com,

http://www.belmedpreparaty.com