Simvastatin - instructions for use, doses, side effects, contraindications

Excipients - ascorbic acid 2,000 mg, 4,000 mg, 8,000 mg, 16,000 mg, lactose monohydrate 69,970 mg, 139,940 mg, 279,880 mg, 559,760 mg, microcrystalline cellulose 5,750 mg, 11,500 mg, 23,000 mg, 46,000 mg of pregelatinized starch 10,000 mg, 20,000 mg , 40,000 mg, 80,000 mg, citric acid monohydrate 1,250 mg, 2,500 mg, 5,000 mg, 10,000 mg, butyl hydroxy anisole 0.030 mg, 0.060 mg, 0.120 mg, 0.240 mg, magnesium stearate 1,000 mg, 2,000 mg, 4,000 mg, 8,000 mg; , composition of the shell:

opadray pink 20A54239 * - 4,000 mg, 8,000 mg (for tablets 10 mg, 20 mg)

opadrai pink 20A54211 ** -16,000 mg, 32,000 mg (for tablets 40 mg, 80 mg)

giprolose 1,200 mg, 2,400 mg, hypromellose-6 cp 1,200 mg, 2,400 mg, titanium dioxide 1,154 mg, 2,308 mg, talc 0,440 mg, 0,880 mg, iron oxide red oxide 0.00456 mg, 0.00912 mg, iron oxide dye yellow 0.00144 mg, 0.00288 mg.

*. * giprolose 4,800 mg, 9,600 mg, hypromellose-6 cp 4,800 mg, 9,600 mg, titanium dioxide 4,479 mg, 8,958 mg, talc 1,760 mg, 3,520 mg, iron oxide red oxide 0.01609 mg, 0.3219 mg.

Description:

Dosage of 10 mg: round biconvex tablets, covered with a film shell of light pink color, with engraving "A" on one side and engraving "01" on the other side. On the cross-section, two layers are visible: the nucleus is almost white, surrounded by a shell of light pink color.

Dosage of 20 mg: round biconvex tablets covered with a film 'shell, light pink color, engraved "A" on one side and engraved "02" on the other side. On the cross-section, two layers are visible: the core is almost white, surrounded by a light pink color shell. , - '

Dosage of 40 mg: round biconvex tablets covered with a pink film shell, with engraving "A" on one side and engraving "03" on the other side. On the cross-section, two layers are visible: the core is "almost white, surrounded by a pink shell.

Dosage of 80 mg: oblong-shaped, biconvex tablets covered with a film 'shell of pink color, engraved "A" on one side and engraved "04" on the other side. On. transverse, cut, two layers are visible: the nucleus is almost white, surrounded by a pink shell.

Pharmacotherapeutic group:lipid-lowering agent - HMG-CoA reductase inhibitor

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.01 Simvastatin

Pharmacodynamics:

A hypolipidemic drug obtained synthetically from_: product fermentation Aspergillus terreus, is an inactive lactone in the body undergoes hydrolysis with the formation of a hydroxy-acid derivative. The active, metabolite suppresses HMG-CoA reductase, an enzyme that catalyzes the initial reaction of cholesterol synthesis - the formation of mevalonic acid from HMG-CoA. Since the transformation

HMG-CoA in mevalonic acid is an early stage in the synthesis of cholesterol, then the use of simvastatin does not cause accumulation in the body potentially toxic styrene. HMG-CoA is lightly metabolized to acetyl-CoA, which participates in many synthesis processes in the body.

Reduces the concentration of triglycerides, low density lipoproteins (LDL), very low density lipoproteins and total cholesterol in the blood plasma (in cases of heterozygous, familial and non-family forms, hypercholesterolemia, mixed hyperlipidemia, when increasing cholesterol concentration is a risk factor) due to inhibition of synthesis cholesterol in the liver and an increase in the number of LDL receptors on the surface of cells, which leads to increased capture and catabolism of LDL. Increases the concentration of high density lipoproteins (HDL) and reduces the ratio of LDL / HDL and total cholesterol / HDL.

HThe beginning of the action - 2 weeks after the beginning of the admission, the maximum therapeutic effect - after 4-6 weeks / Action persists with the continuation of treatment; When the therapy is stopped, the cholesterol concentration returns to the initial value (before the start of treatment).

Pharmacokinetics:

Absorption is high; bioavailability is less than 5%. After oral administration, the average period of time until the maximum concentration of the drug in the blood plasma (TS_max) - 1,3-2,4 hours and decreases by 90 % after 12 hours. Communication with blood plasma proteins - 95%.

Simvastatin hydrolyzes in tissues into an active form, beta-hydroxy acid and inactive metabolites. Metabolised in the liver by gi, has the effect of "primary" passage through the liver. In the metabolism of the drug, isozymes participate CYP3A4, CYP3A5 and CYP3A7. The half-life (T1/2) of active metabolites is 1.9 hours.

It is output, basically; through the intestine (60%) in the form of metabolites. About 10-15% is excreted by the kidneys in an inactive form.

Indications:

Ischemic heart disease (CHD) (including asymptomatic ischemic heart disease) - secondary prevention, with the aim of reducing the "overall mortality, in order to reduce the risk of coronary death and prevent myocardial infarction, in order to reduce the risk, the development of stroke and transient cerebral circulatory disorders, with a view to slowing the progression of coronary atherosclerosis. Hypercholesterolemia

as an addition to the diet, when the application of only diet and other non-medicinal methods of treatment is not enough, for:

- decrease in elevated, total cholesterol, LDL cholesterol, triglycerides, apolipoprotein B (apo B);

- for increase_; HDL cholesterol in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fahrenkson's type-II hyperlipidemia), or mixed hypercholesterolemia (hyperlipidemia IIb type according to Fredrickson's classification);

- decrease in the ratio of LDL cholesterol to HDL cholesterol and - total Cholesterol to HDL cholesterol;
hypertriglyceridemia (type IV hyperlipidemia according to Fredrickson classification);
supplement to the diet and other ways of treating patients with homozygous familial, hypercholesterolemia to reduce the increased concentration of total cholesterol, LDL cholesterol and apolipoprotein B;
primary dysbetalapoproteinemia, (type III hyperlipidemia, according to classification Fredrickson).

Contraindications:

increased susceptibility to simvastatin or other components of the drug, as well as other drugs of the statin series, (inhibitors of HMG-CoA reductase) in history; '
liver disease in the active phase or persistent increase in the activity of "hepatic" transaminases of unclear etiology;
diseases of skeletal muscles (myopathy);
pregnancy and lactation period, as well as. application in women; planning pregnancy;
age under 18 years (safety and efficacy not established); .
deficiency of lactase, lactose intolerance, syndrome, glucose-galactose - malabsorption. .

Carefully:

Patients with alcoholism, patients with liver diseases in the anamnesis, patients after organ transplantation who undergo immunosuppressant therapy (due to an increased risk of rhabdomyolysis and kidney failure, insufficiency); at - conditions that can lead to the development of severe renal function deficiency, such as arterial hypotension, acute infectious diseases of severe course, expressed metabolic and endocrine disruptions, disturbances of water-electrolyte balance, surgical interventions (including dental), or trauma; patients with reduced or. increased tonus of skeletal muscles of unclear etiology; patients with epilepsy, uncontrolled seizures; with simultaneous; admission with fibrates, cyclosporine, nicotinic acid, in lipid-lowering doses (more than 1 g / day), amiodarone, verapamil, diltiazem,grapefruit juice; with severe renal failure (creatinine clearance less than 30ml / min).

Pregnancy and lactation:

Simvastatin is contraindicated in pregnancy. Women of reproductive age who receive Simvastatin, should carefully follow the measures for contraception. If a pregnancy occurs during the treatment, Simvastatin should be canceled, and a woman warned of a possible danger to the the fetus.

Data on the isolation of simvastatin in Breast milk is not, but since a small number of others medicines of this class is excreted in female milk, to women, host Simvastatin, not it is recommended to breast-feed in connection with the possibility of developing serious adverse reactions in children.

Dosing and Administration:

Before starting treatment with the drug Simvastatin the patient should be prescribed a standard hypocholesterol diet, which must be observed throughout the course of treatment.

Recommended doses are from 5 to 80 mg. The drug is taken orally 1 time per day, at night (2-3 hours after eating). The dose should be selected at intervals of not less than 4 weeks.The maximum daily dose is 80 mg. Patients with IHD or a high risk of CHD

The standard starting dose for patients at high risk of developing coronary artery disease (in combination with or without hyperlipidemia, patients with diabetes mellitus, patients with a history of stroke or other cerebrovascular diseases, patients with peripheral vascular disease) is 20 mg / day. Therapy should be started simultaneously with the use of diet and exercise therapy.

Patients with hypercholesterolemia The initial dose is 10-20 mg / day. For patients who need

significant (more than 45%) decline inthe concentration of LDL, the initial dose can be 20-40 mg / day. If the drug is ineffective at a dose of 40 mg per day, it is recommended to switch to another type of lipid-lowering therapy. The use of the drug in a dose of more than 40 mg significantly increases the risk of myopathy. If the LDL concentration is less than 75 mg / dl (1.94 mmol / L), the total cholesterol concentration is less than 140 mg / dL (3.6 mmol / L), the dose of the drug should be reduced. Patients with homozygous familial hypercholesterolemia Simvastatin is recommended at a dose of 40 mg, once a night, or 80 mg in 3 divided doses: 20 mg in the morning, 20 mg in the afternoon and 40 mg in the evening. In this group of patients Simvastatin should be used as an adjunct to other treatment that reduces

the concentration of cholesterol (eg, LDL plasmapheresis) or as monotherapy if other treatment is not available. Concomitant therapy Simvastatin can be used both in the form of monotherapy, and in combination with bile acid sequestrants. The drug is taken no less than 2 hours before the reception of sequestrants or not earlier than 4 hours after their admission.

In patients taking cytotoxic drugs, nicotinic acid in lipid-lowering doses (more than 1 g / day), immunosuppressants, ciclosporin, danazol, gemfibrozil or d Other fibrates (except fenofibrate) concomitantly with the drug Simvastatin, the maximum dose is 10 mg / day. Daily dose of the drug Simvastatin should not exceed 20 mg for patients concomitantly taking amiodarone, verapamil and 40 mg for patients taking diltiazem (see section "Interaction with other medicinal products ").

With renal insufficiency Because the Simvastatin is allocated by the kidneys in a small amount, there is no need for dose adjustment in patients with moderate renal insufficiency.In severe renal failure (creatinine clearance less than 30 ml / min), it is necessary to assess the risk-benefit ratio of the drug in doses exceeding 10 mg / day. If such dosages are considered necessary, they should be administered with caution.

Side effects:

From the digestive system: dyspepsia (nausea, vomiting, abdominal pain, constipation, or diarrhea, flatulence), gastralgia, hepatitis; Cholestatic jaundice, hepatic insufficiency, increased activity of "liver" transaminases, alkaline phosphatase, creatine phosphokinase (CK), acute pancreatitis. ,

From the nervous system and sensory organs: asthenia, dizziness, headache, insomnia, paresthesia, peripheral neuropathy, blurred vision,

a violation of taste sensations, memory impairment, depression, nightmares.

From the musculoskeletal system: Myopathy (including myositis), myalgia, myasthenia gravis, muscle spasms, rhabdomyolysis,

Allergic and immunopathological reactions: skin rash, hives, itching, alopecia, angioedema,lupus-like syndrome, rheumatic polymyalgia, dermatomyositis, vasculitis,thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate: (ESR), arthritis / arthralgia, photosensitivity, fever, skin hyperemia, "blood flushes" to the face, dyspnea, erythema multiforme, toxic epidermal necrolysis, including Stevens-Johnson syndrome.,

From the respiratory system: bronchitis, sinusitis, interstitial lung diseases. ^

Other: anemia, palpitations, acute renal failure (due to rhabdomyolysis), decreased potency, swelling, urinary tract infection.

Overdose:

In none of the known few cases of overdose (the maximum dose of 450 mg) specific symptoms were identified.

Treatment: cause vomiting, take Activated carbon, symptomatic therapy. It is necessary to monitor the liver and kidney function, the activity of CKK in the blood serum.

With the development of myopathy with rhabdomyolysis and acute renal failure (a rare but severe side effect), the drug should be stopped immediately and the diuretic and the sodium bicarbonate solution (intravenous infusion) should be administered to the patient. If necessary, hemodialysis is indicated. .

Rhabdomyolysis can cause hyperkalemia, which can be eliminated by intravenous calcium chloride or calcium gluconate, by infusing 5% dextrose (glucose) solution with insulin of short action.

Interaction:

Cytostatics, a nicotinic acid in lipid-lowering doses (more than 1 g / day), fibrates, immunosuppressants, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors increase the risk of myopathy, rhabdomyolysis and acute renal insufficiency (see section "Method of administration and dose").

Indirect anticoagulants

Simvastatin enhances the effect of indirect anticoagulants and increases the risk of bleeding (prothrombin time or INR (international normalized ratio) should be monitored).

Digoxin

Simvastatin increases the concentration of digoxin in the blood serum.

Isozyme CYP3A4

Simvastatin is metabolized by isoenzyme CYP3A4, but does not inhibit it, therefore, its inhibitory effect on plasma concentrations of drugs metabolized by isoenzyme is not expected CYP3A4.

When using the drug Simvastatin simultaneously with inhibitors of isoenzyme CYP3A4 increased risk of myopathy / rhabdomyolysis. Simultaneous use of the drug Simvastatin with the following preparations is not recommended: itraconazole, ketoconazole, fluconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone). In that case, if the use of these drugs necessary, therapy with simvastatin should be carried out with extreme caution (careful control of the function is necessary liver).

Ciclosporin, danazol

Risk of myopathy / rhabdomyolysis increases with the simultaneous use of cyclosporine or danazol with high doses of the drug Simvastatin (see section "Method of administration and dose").

Gemfibrozil

Gemfibrozil increases the area under the concentration-time curve (AUC) simvastatin 1,9 times (see section "Method of administration and dose").

Amlodipine

With simultaneous application Amlodipine and simvastatin are noted magnification AUC and maximum the concentration of simvastatin in blood plasma (Stach) in 1,3 and 1,4 times, respectively, without changing the hypolipidemic effect of simvastatin. The clinical significance of this effect is unknown.

With simultaneous application Amloldipine and simvastatin at a dose of 80 mg have a slightly increased risk of developing myopathy.

Amiodarone, verapamil or diltiazem

With the simultaneous use of amiodarone, verapamil or diltiazem with simvastatin increases the risk of rhabdomyolysis / myopathy (see section "Dosing and Administration"),

Fusidic acid

The risk of myopathy may increase with simultaneous application of fusidic

acids with inhibitors of HMG-CoA-

reductase, including Simvastatin. Some cases of development of rhabdomyolysis with the use of simvastatin are known. In case of simultaneous use of the drug Simvastatin and fusidic

acid should carefully monitor the patient. In addition, the possibility of temporary suspension of drug therapy Simvastatin .

Kolestyramine and colestipol

Kolestyramin and colestipol reduce bioavailability (the use of simvastatin is possible in 2-4 hours after taking these drugs, with an additive effect noted).

Grapefruit juice

Grapefruit juice in large quantities increases Cmax and AUC simvastatin and the risk of myopathy (their simultaneous use is not recommended).

olhicine

Limited information is available on cases

development of myopathy with simultaneous

the use of simvastatin and colchicine.

Rifampicin

Rifampicin is an inducer

isoenzyme CYP3A4. At simultaneous

use of rifampicin and simvastatin

there was a decrease AUC simvastatin on

93 %.

Nicotinic acid in lipid-lowering

doses (more than 1 g / day)

There have been cases of development

Myopathy / rhabdomyolysis with simultaneous

use of simvastatin and nicotine

acids in lipid-lowering doses (more than 1

g / day)

Special instructions:

In case of missing the current dose, the drug must be accepted as soon as possible. If it's time for the next dose, do not double the dose.

Simvastatin, like other HMG inhibitors-CoA reductase, can cause myopathy, which manifests itself in the form of muscle pain, weakness and increased CKD ten times higher than normal. Also, myopathy can manifest itself in the form of Rabdomyolysis sometimes in combination with acute

renal insufficiency, caused by myoglobulinuria, in rare cases leading to a lethal outcome.Among predisposing factors of myopathy development, the elderly age (over 65 years), females, uncontrolled hypothyroidism and renal insufficiency are distinguished. Do not use Simvastatin at an increased risk of rhabdomyolysis and renal failure.

The risk of developing myopathy with the drug Simvastatin, as well as other inhibitors of HMG-CoA reductase, is dose-dependent (the risk increases with increasing dose).

Patients are encouraged to immediately report unexplained muscle pain, lethargy, or weakness, especially if accompanied by malaise or fever.

In the development of myopathy with rhabdomyolysis and acute renal failure should immediately stop taking the drug and inject the patient with a diuretic and a solution of sodium bicarbonate (intravenous infusion).

If necessary, hemodialysis is indicated. Rhabdomyolysis can cause hyperkalemia, which can be eliminated by intravenous calcium chloride or calcium gluconate, by infusing 5% dextrose (glucose) solution with short-acting insulin.

When treating the drug Simvastatin it is possible to increase the activity of CK in the serum, which should be taken into account in the differential diagnosis of chest pain. The criterion for the discontinuation of the drug is an increase in the activity of CK in the blood serum of more than 10 times the upper limit of the norm. In patients with myalgia, myasthenia gravis and / or with a marked increase in the activity of CPK, the drug is stopped on the background of treatment.

Risk of myopathy and rhabdomyolysis significantly increases with simultaneous application of the drug Simvastatin and potent inhibitors of isoenzyme CYP3A4. Application of the drug Simvastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors and nefazodone is not recommended, but if this combination is necessary, care should be taken (careful monitoring of liver function is necessary). Simvastatin should be combined with caution with the following drugs: ciclosporin, verapamil, diltiazem, fibrates, a nicotinic acid in lipid-lowering doses (more than 1 g / day), amiodarone, verapamil, diltiazem.

There is a risk of myopathy with separate use of fenofibrate and the drug Simvastatin, so you need to be careful when taking this combination at the same time. It is necessary to avoid simultaneous reception of the drug Simvastatin and grapefruit juice.

Before starting treatment, it is necessary to conduct a study of liver function (monitor the activity of "liver" transaminases every 6 weeks for the first 3 months, then every 8 weeks for the remaining first year and then 1 time in six months). In those cases, when the activity of "hepatic" transaminases increases (exceeding the upper limit of the norm by 3 times), treatment is canceled.

Abolition of lipid-lowering drugs during pregnancy does not significantly affect the results of long-term treatment of primary

hypercholesterolemia.

In patients with reduced thyroid function (hypothyroidism) or in the presence of certain kidney diseases (nephrotic syndrome) with increasing cholesterol concentration, first therapy of the underlying disease should be performed. Simultaneous use of the drug Simvastatin and gemfibrozil is possible only in those cases when the expected benefit significantly exceeds potential risk of such a drug combination.The possibility of simultaneous application of the drug Simvastatin and other fibrates (except fenofibrate), nicotinic acid in lipid-lowering doses (more than 1 g / day) or cyclosporine should be carefully weighed taking into account the potential risk of such combinations. With the simultaneous use of the drug Simvastatin and rifampicin should monitor the concentration of cholesterol in the blood plasma in order to adequately correct the dose of simvastatin. Well-controlled studies on use in children are not available.

Simvastatin is not indicated in cases where there is hypertriglyceridemia I, V types. Patients with severe renal failure receive treatment under the control of kidney function.

The data of modern long-term clinical studies do not contain information on the adverse effects of simvastatin on the lens of the human eye.

Effect on the ability to drive transp. cf. and fur:It is necessary to take into account the danger of developing dizziness on the background of taking the drug Simvastatin when driving vehicles and performing activities that require increased concentration of attention and quick motor reaction.

Form release / dosage:

Thefilm coated film 10 mg, 20 mg, 40 mg, 80 mg.

10 tablets in a blister of three-layer PVC / PE / PVDC / film and aluminum foil.

1, 3, 5 or 10 blisters together with instructions for use are placed in a cardboard box.

Packaging:

10 tablets in a blister of three-layer PVC / PE / PVDC / film and aluminum foil.

1, 3, 5 or 10 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000693

Date of registration:28.09.2011

The owner of the registration certificate:Aurobindo Pharma Co., Ltd.Aurobindo Pharma Co., Ltd. India

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp03.09.2013

Illustrated instructions

Instructions

Simvastatin (Simvastatin)