ATORVASTATIN

Active material: Atorvastatin
When ATH: C10AA05
CCF: Lipid-lowering drugs
ICD-10 codes (testimony): E78.0, E78.1, E78.2
When CSF: 16.01.01
Manufacturer: ALSI Pharma Company Inc. (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated white, lenticular.

Excipients: calcium carbonate, microcrystalline cellulose, lactose, starch 1500, colloidal silicon dioxide (aэrosyl), magnesium stearate, Oradraj II (polyvinyl alcohol, macrogol (polyethylene glycol), talc, Titanium dioxide).

10 PC. – packings Valium planimetric (1) – packs cardboard.
10 PC. – packings Valium planimetric (2) – packs cardboard.
10 PC. – packings Valium planimetric (3) – packs cardboard.
10 PC. – packings Valium planimetric (4) – packs cardboard.
10 PC. – packings Valium planimetric (5) – packs cardboard.

Pills, Film-coated white, lenticular.

Excipients: calcium carbonate, microcrystalline cellulose, lactose, starch 1500, colloidal silicon dioxide (aэrosyl), magnesium stearate, Opadry II (polyvinyl alcohol, macrogol (polyethylene glycol), talc, Titanium dioxide).

10 PC. – packings Valium planimetric (1) – packs cardboard.
10 PC. – packings Valium planimetric (2) – packs cardboard.
10 PC. – packings Valium planimetric (3) – packs cardboard.
10 PC. – packings Valium planimetric (4) – packs cardboard.
10 PC. – packings Valium planimetric (5) – packs cardboard.

Pharmacological action

Lipid-lowering drugs. Selective competitive inhibitor of HMG-CoA reductase inhibitors – enzyme, converting 3-Hydroxy-3- metilglutaril Coenzyme a in mevalonovuju acid, that is the precursor of sterols, including cholesterol. TG and cholesterol in the liver are included in the composition of VLDL, arrive in blood plasma and transported in peripheral tissues. LDL is formed of VLDL in the course of interacting with LDL receptor. Atorvastatin reduces LDL cholesterol levels in the blood plasma, inhibiting HMG-KOA-reduktazu, cholesterol synthesis in the liver and by increasing the number of LDL receptors on the surface of cells in the liver, that leads to increased grip and catabolism of LDL. Reduces the formation of LDL, calls and persistent increase in LDL receptor activity.

Reduces the level of LDL in patients with homozygous Familial Hypercholesterolemia, that is typically not amenable to therapy lipid means. Reduces the total cholesterol to 30-46%, LDL – on 41-61%, apolipoprotein B – on 34-50% and TG – on 14-33%; cause high cholesterol-HDL and apolipoprotein (a). Dozozawisimo reduces the level of LDL in patients with homozygous hypercholesterolemia is hereditary, resistant to therapy with other lipid means.

Pharmacokinetics

Absorption

After taking the drug inside high absorption. C_max plasma levels achieved after 1-2 no.

Food reduces the speed and duration of drug absorption (on 25% and 9% respectively), However lowering cholesterol LDL is similar to that in the application of atorvastatin without food. Concentrations of atorvastatin when applied in the evening below, than in the morning (approximately 30%). Revealed a linear relationship between the degree of suction and dose of medication.

Bioavailability – 12%, System bioavailability inhibiting activity against HMG-CoA reductase inhibitors – 30%. Low system bioavailability due to presistemnym metabolism in GASTROINTESTINAL mucosa and when “first pass” through the liver.

Distribution

The binding to plasma proteins – 98%. Average V_d – 381 l.

Metabolism

Metabolised mainly in the liver under the influence of CYP3A4 Isoenzymes, CYP3A7 and CYP3A5 with formation of pharmacologically active metabolites (ortho- paragidroksilirovannyh and derivatives, beta-oxidation products). In vitro Ortho- and paragidroksilirovannye metabolites have an inhibitory effect on the g-KOA-reduktazu, comparable to that of atorvastatin. Ingibiruty effect of the drug in respect of the HMG-CoA reductase inhibitors by approximately 70% is determined by the activity of circulating metabolites.

Deduction

T_1/2 – 14 no. Inhibiting activity against g-KOA-reduktaza about 20-30 h thanks to active metabolites.

Return to jelchew after liver and/or vnepechenochnogo metabolism (It does not undergo pronounced enterohepatic recirculation). Less 2% from the inside of the dosage is determined in the urine.

Pharmacokinetics in special clinical situations

C_max women up 20%, AUC – below on the 10%; C_max in patients with alcoholic cirrhosis of the liver in 16 time, AUC- 11 times higher compared to patients with normal liver function.

Not displayed during hemodialysis.

Testimony

— combined with a diet to reduce elevated total cholesterol levels, cholesterol/LDL, Apolipoprotein b, and TG and increase the level of HDL cholesterol in patients with primary hypercholesterolemia, heterozygous Familial Hypercholesterolemia and precluded from accompanying and combination (mixed) hyperlipidaemia (types IIa and IIb on Fredriksonu);

— in combination with diet for the treatment of patients with elevated serum TG levels (Type IV by Fredriksonu) and patients with disbetalipoproteinemiej (Type III by Fredriksonu), whose diet does not give adequate effect;

-to reduce the levels of total cholesterol and cholesterol/LDL in patients with homozygous Familial Hypercholesterolemia, When diet and other non-pharmacological therapies are insufficient.

Dosage regimen

Before the appointment of atorvastatin patients should recommend a standard such as hypolipidemic diet, He must observe during the treatment period.

The drug can be taken at any time of the day with food or regardless of the time of the meal. Dose picked on the basis of baseline cholesterol/LDL, the goal of therapy and individual effect. At the beginning of treatment and/or during the rise of the dose of atorvastatin should be every 2-4 weeks to monitor levels of lipids in the blood plasma and appropriately correct dose.

Initial dose is averaged 10 mg 1 times/day and thereafter varies from 10 mg 80 mg 1 time / day.

With primary hypercholesterolemia and mixed Hyperlipidemia, with increasing serum TG level (Type IV by Fredriksonu), and also at disbetalipoproteinemii (Type III by Fredriksonu) in most cases the appointment of drug dose 10 mg 1 time / day. A significant therapeutic effect is observed, usually, through 2 of the week, the maximum therapeutic effect was usually observed through 4 of the week. In long-term care, this effect is.

When homozygous Familial Hypercholesterolemia the drug is prescribed in a dose 80 mg (4 tab. by 20 mg) 1 time / day.

In patients with renal insufficiency and renal diseases Atorvastatin concentration in plasma is not changing, LDL cholesterol reduction saves, therefore change the dose is not required.

At hepatic insufficiency dose should be reduced.

In applying the drug in elderly patients differences in security, performance or achievement of the objectives of the cholesterol-lowering treatment in comparison with the general population not noted.

Side effect

From the nervous system: > 2% – insomnia, dizziness; < 2% – headache, asthenia, malaise, drowsiness, nightmares, paresthesia, perifericheskaya neuropathy, amnesia, emotional lability, ataxia, Bell's paralysis, hyperkinesis, migraine, depression, gipesteziya, loss of consciousness.

From the senses: < 2% – amblyopia, tinnitus, dryness of the conjunctiva, ccomodation, hemorrhage in eyeball eyes, deafness, glaucoma, parosmija, loss of taste, dysgeusia.

Cardio-vascular system: > 2% – chest pain; < 2% – heartbeat, symptoms of vasodilation, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina.

From the hematopoietic system: < 2% – anemia, lymphadenopathy, thrombocytopenia.

The respiratory system: > 2% – bronchitis, rhinitis; < 2% – pneumonia, dyspnoea, exacerbation of asthma, nose bleed.

From the digestive system: > 2% – nausea; < 2% – heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, decreased or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, želčnaâ how, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, abnormal liver function, rectal bleeding, ground, krovotochivosty right, tenesmus.

On the part of the musculoskeletal system: > 2% – arthritis; < 2% – cramping of the leg muscles, ʙursit, tendosynovyt, myositis, myopathy, artralgii, myalgia, raʙdomioliz, Kryvosheya, Muscle hypertonicity, joint contractures.

With the genitourinary system: > 2% – urogenital infections, peripheral edema; < 2% – dizurija (incl. thamuria, nocturia, urinary incontinence or urinary retention, urgent need to urinate), jade, hematuria, vaginal bleeding, nefrourolitiaz, metrorragija, epididymitis, decreased libido, impotence, abnormal ejaculation.

Dermatological reactions: > 2% – alopecia, dermatoxerasia, increased perspiration, eczema, seborrhea, ecchymosis, petechiae.

On the part of the endocrine system: < 2% – gynecomastia, mastodinija.

Metabolism: < 2% – weight gain, worsening of gout.

Allergic reactions: < 2% – itching, skin rash, contact dermatitis, rarely – hives, angioedema, swelling of the face, photosensitivity, anaphylaxis, erythema multiforme exudative (incl. Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Laboratory findings: < 2% – giperglikemiâ, gipoglikemiâ, Increase serum CPK, albuminuria.

Contraindications

— active liver disease;

-increase in liver enzymes, ambiguous Genesis (more than 3 fold compared with CAH);

- Liver failure (Classes A and B in Child-Pugh);

- Pregnancy;

- Lactation;

- Up to 18 years (efficacy and safety have not been established);

- Hypersensitivity to the drug.

FROM caution the drug should be used in patients with chronic alcoholism, with a history of liver disease, heavy violations elektrolitnogo balance, endocrine and metabolic irregularities, hypotension, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgery, injuries, diseases of skeletal muscle.

Pregnancy and lactation

Atorvastatin is contraindicated for use in pregnancy and lactation (breast-feeding).

Unknown, is allocated whether atorvastatin with breast milk. In view of the possibility of adverse events in infants, If necessary, use during lactation should decide the issue of termination of breastfeeding.

Women of reproductive age at the time of treatment must use adequate contraception methods. Atorvastatin can be assigned to women of reproductive age only, if the probability of pregnancy have a very low, and the patient informed of possible risks of treatment for fetus.

Cautions

Atorvastatin is appropriate before starting therapy should try to gain control of hypercholesterolemia through adequate diet, increasing physical activity, lower body mass index in patients with obesity and treat other conditions. Gipoholestesterinovuju diet, patients must adhere to during the entire period of treatment.

The use of inhibitors of HMG-CoA reductase to reduce the level of lipids in the blood can lead to changes in biochemical parameters, reflecting liver function. Liver function should be monitored before therapy, through 6 weeks, 12 weeks after you start taking Atorvastatin and after each dose increase, and periodically, eg, every 6 months. Increase in liver enzymes in the serum may occur during therapy, atorvastatin is appropriate. In such cases, you should monitor the status of patients to normalize liver enzymes. If the value of the ALT or ACT in more than 3 times those of VGN, It is recommended to reduce the dose of atorvastatin or discontinue treatment. Active liver disease or persistent increase in the aminotransferaz ambiguous Genesis serve contraindications to prescription Atorvastatin.

Atorvastatin is appropriate treatment can cause myopathy. In patients with common mialgijami, pain or weakness of muscles and/or expressed by increased activity of KFK has the likelihood of myopathy (pain and weakness in the muscles, combined with the increased activity of the KLF more than 10 times compared with FHG). Atorvastatin is appropriate therapy should be discontinued in the case of explicit activity KLF or if there is a confirmed or suspected myopathy. The risk of myopathy during treatment of other drugs of this class has increased, while the use of Cyclosporine, fibrate, Erythromycin, Nicotinic Acid or azole antifungals. Many of these drugs inhibit the metabolism of, indirect izofermentom CYP3A4, and/or transport drugs. Atorvastatin biotransformiroetsa under the influence of CYP3A4. Assigning Atorvastatin in combination with fibratami, Erythromycin, immunosuppressants, azole antifungals or niacin in lipid-lowering doses should carefully weigh the potential benefits and risks of treatment and regularly monitor the status of patients in order to detect pain or weakness in muscles, especially during the first months of treatment and during periods of increasing doses of any medication. In such situations, it is possible to recommend periodic determination of activity of KFK, Although such control does not allow you to prevent the development of severe myopathy.

In applying atorvastatin, like other tools of this class, Describes cases of rhabdomyolysis with acute renal failure, caused by myoglobinuria. Atorvastatin is appropriate therapy should temporarily suspend or Cancel when you see signs of possible myopathy or the existence of a risk factor for the development of renal failure on the background of rhabdomyolysis (eg, severe acute infection, hypotension, a serious operation, trauma, heavy Exchange, metabolic and electrolyte disorders and uncontrolled convulsions).

Patients should be warned about, they should immediately consult a doctor if you have unexplained pain or weakness in muscles, particularly if observed malaise or fever.

Effects on ability to drive vehicles and management mechanisms

On the adverse effects of atorvastatin on the ability to drive and work with the mechanisms have not been reported.

Overdose

Treatment: No specific antidote, It is symptomatic therapy. Hemodialysis nyeeffyektivyen.

Drug Interactions

The risk of myopathy during treatment with other drugs derivatives of statins is increased with concomitant use of cyclosporin, fibrate, Erythromycin, antifungal funds, belonging to azolam, and Nicotinic Acid.

While ingestion of atorvastatin and suspension, contains magnesium hydroxide and aluminium hydroxide, Atorvastatin concentration in plasma decreased by about 35%, but the degree of reduction in LDL cholesterol levels at the same time did not change.

With simultaneous use of atorvastatin does not affect the pharmacokinetics of antipyrine (fenazona), Therefore, interaction with other tools, metabolized by the same cytochrome P450 isozymes system is not expected.

With simultaneous application of colestipol atorvastatin plasma concentration is reduced by about 25%. However hypolipidemic effect of the combination of atorvastatin and colestipol than that of each drug alone.

Repeated dose of digoxin and atorvastatin 10 mg C_ss digoxin in the blood plasma did not change. However, the application of digoxin in combination with atorvastatin 80 mg/day concentration of Digoxin increased by about 20%. In applying this combination should be monitored patient condition.

Together with the use of atorvastatin and erythromycin (500 mg 4 times / day) or == (500 mg 2 times / day), that inhibit CYP3A4 CYP, There was an increase in concentrations of atorvastatin in plasma.

Together with the use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day) plasma atorvastatin concentrations did not change.

Atorvastatin had no clinically significant impact on the concentration of terfenadine plasma, which is metabolized primarily by CYP3A4,; In this regard, it is unlikely, that atorvastatin can significantly influence the pharmacokinetic parameters of other substrates of CYP3A4 isoenzyme.

With simultaneous use of atorvastatin and oral contraceptive, containing norethindrone and ethinyl estradiol, There was a significant increase in AUC norethindrone and ethinyl estradiol by about 30% and 20% respectively. This effect should be taken into account when choosing oral contraceptive for women, receiving Atorvastatin.

The simultaneous use of drugs, reduces the concentration of endogenous steroid hormones (incl. with cimetidine, ketoconazole, spironolactone), It increases the risk of reducing the endogenous steroid hormones (when these combinations require careful).

It has been detected in studying the interaction of atorvastatin with warfarin and cimetidine evidence of clinically significant interaction.

With simultaneous use of atorvastatin 80 mg and amlodipine dose 10 mg pharmacokinetics of atorvastatin in equilibrium has not changed.

There were no clinically significant adverse interactions atorvastatin and antihypertensive agents.

The simultaneous use of atorvastatin with protease inhibitors, known as CYP3A4 inhibitors, accompanied by increases in the concentrations of atorvastatin in plasma.

Pharmaceutical incompatibility is unknown.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children, dry, protected from light, at a temperature no higher than 25 ° C. Shelf life – 3 year.