ALIPO

instructions for medical use of the medicinal product

Tradename

Alipo, Alipo

International non-proprietary name

Atorvastatin, Atorvastatin

Composition

Each film-coated tablet contains:

active ingredient: atorvastatin 10 mg

excipients: starch, dextrin, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, magnesium stearate, talc

Each film-coated tablet contains:

active substances: atorvastatin 20 mg

excipients: starch, dextrin, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, magnesium stearate, talc

Dosage form

Tablets.

Pharmacotherapeutic group

Lipid-lowering agent is an inhibitor of HMG-CoA reductase.

Pharmacological properties

Pharmacodynamics

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate-limiting rate of cholesterol biosynthesis responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into very low density lipoproteins (VLDL), enter the blood plasma and are transported to peripheral tissues. From VLDL, low-density lipoproteins (LDL) are formed, which are catabolized mainly through interaction with high-affinity LDL receptors.

Atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, as well as by increasing the number of "liver" LDL receptors on the cell surface, which increases the uptake and catabolism of LDL.

Atorvastatin reduces LDL production and the number of LDL particles. Causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable changes in the quality of circulating LDL particles.

Dose-dependently reduces the level of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering agents.

Dose-effect studies have shown that atorvastatin reduces total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14-33%), simultaneously causing, to varying degrees, an increase in the levels of HDL cholesterol and apolipoprotein A. These results were similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

Due to the reduction in total cholesterol, LDL cholesterol and apolipoprotein B , the risk of cardiovascular disease is reduced and, accordingly, the risk of death is reduced. Studies of the effect of atorvastatin on cardiovascular morbidity and mortality have not yet been completed.

When using the drug in elderly patients, there were no differences in the safety, efficacy, or achievement of the goals of lipid-lowering therapy in comparison with the general population.

Pharmacokinetics

After oral administration, atorvastatin is rapidly absorbed into the blood. The maximum concentration (C max ) in blood plasma is reached within 1-2 hours, C max in women is 20% higher, the area according to the concentration-time curve ( AUC ) is 10% lower; Cmax in patients with alcoholic liver cirrhosis increases 16 times, AUC - 11 times. Eating slightly reduces the rate and duration of absorption of the drug (by 25% and 9%, respectively), but cholesterol reduction is similar to that when taking atorvastatin without food. The absolute bioavailability of atorvastatin is approximately 12%, systemic bioavailability, which determines the inhibitory activity against HMG-CoA reductase, is 30%. Low systemic bioavailability is due to first pass metabolism in the mucosa of the gastrointestinal tract and during the "first pass" through the liver.

The mean volume of distribution of atorvastatin is approximately 381 L. Communication with blood plasma proteins - 98   %.

Atorvastatin is metabolized mainly in the liver with the participation of isoenzymes CYP 3 A 4, CYP 3 A 5 and CYP 3 A 7 of cytochrome P450 with the formation of pharmacologically active metabolites (ortho- and parahydroxylated derivatives, beta-oxidation products). In vitro ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

Atorvastatin is excreted primarily in the bile after hepatic and / or extrahepatic metabolism (not subject to pronounced enterohepatic recirculation).

The half-life is 14 hours. Inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Less than 2% of the ingested dose of the drug is determined in the urine. Not excreted during hemodialysis.

Indications for use

• in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia and combined (mixed) hyperlipidemia (Fredrickson types IIa and IIb ) in combination with a diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and increase HDL cholesterol levels;

• for the treatment of patients with elevated serum levels of triglycerides (Fredrickson type IV ) and patients with dysbetalipoproteinemia (Fredrickson type III ) in whom diet therapy does not give an adequate effect;

• in patients with homozygous familial hypercholesterolemia to reduce total cholesterol and LDL cholesterol, when diet therapy and other non-pharmacological treatments are not effective enough.

Contraindications

·        active liver disease or increased activity of liver enzymes of unknown origin (more than 3 times compared with VGN);

·        liver failure (Child-Pugh classification A and B);

·        pregnancy;

·        lactation period;

·        age up to 18 years (efficacy and safety have not been established);

·        hypersensitivity to the components of the drug.

Dosage and administration

Before prescribing Alipo, the patient should be recommended a standard lipid-lowering diet, which he should continue to follow throughout the entire period of therapy.

The drug is taken orally, at any time of the day with food or regardless of the time of the meal.

The dose is selected taking into account the initial levels of cholesterol / LDL, the goal of therapy and individual effect. The initial dose averages 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 time / day.

At the beginning of treatment and / or during an increase in the dose of the drug, it is necessary to monitor the content of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

In primary hypercholesterolemia and mixed hyperlipidemia, as well as type III and IV hyperlipidemia according to Fredrickson , in most cases it is enough to prescribe the drug at a dose of 10 mg 1 time / day. A significant therapeutic effect is observed, as a rule, after 2 weeks; the maximum therapeutic effect is usually observed after 4 weeks. With prolonged treatment, this effect persists.

In heterozygous familial hypercholesterolemia , treatment should begin with the appointment of 10 mg 1 time / day. Carrying out individual dose adjustment every 4 weeks, it should be brought up to 40 mg per day. After that, you can increase the dose to a maximum level of 80 mg per day.

With homozygous familial hypercholesterolemia , the drug is prescribed at a dose of 80 mg (4 tablets of 20 mg) 1 time / day.

The use of the drug in patients with renal insufficiency and kidney disease does not affect the level of atorvastatin in the blood plasma or the degree of reduction in cholesterol / LDL when it is used, therefore, a change in the dose of the drug is not required.

In hepatic insufficiency , the dose must be reduced.

When using the drug in elderly patients, there were no differences in the safety, efficacy, or achievement of the goals of lipid-lowering therapy in comparison with the general population.

Special instructions and precautions

The use of HMG-CoA reductase inhibitors to lower the concentration of lipids in the blood can lead to changes in biochemical parameters that reflect liver function. Liver function should be monitored before starting therapy, after 6 weeks, 12 weeks after the start of the drug and after each dose increase, as well as periodically, for example, every 6 months. An increase in the activity of liver enzymes in the blood serum can be observed during therapy. Patients who have an increase in enzyme activity should be monitored until the indicators return to normal values. In the event that ALT or ACT values are more than 3 times the ULN, it is recommended to reduce the dose of the drug or stop treatment.

Alipo should be used with caution in patients who abuse alcohol and/or have liver disease. Active liver disease or a persistent increase in the activity of aminotransferases of unknown origin are contraindications to the appointment of the drug.

Treatment with the drug can cause myopathy. The diagnosis of myopathy (pain and weakness in the muscles, combined with an increase in CPK activity more than 10 times compared with ULN) should be discussed in patients with widespread myalgia, muscle soreness or weakness and / or a marked increase in CPK activity. Patients should be warned that they should immediately tell the doctor about the appearance of unexplained pain or weakness in the muscles, if they are accompanied by malaise or fever. Therapy should be discontinued in the event of a marked increase in CPK activity or in the presence of confirmed or suspected myopathy. The risk of myopathy in the treatment of other drugs in this class increased with the simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid or antifungal agents from the azole group. Many of these drugs inhibit CYP3A4 mediated metabolism and/or drug transport. When prescribing Alipo in combination with fibrates, erythromycin, immunosuppressive agents, antifungal agents from the azole group, or nicotinic acid in lipid-lowering doses, the expected benefit and risk of treatment should be carefully weighed and patients should be monitored regularly for pain or muscle weakness, especially during the first months treatment and during periods of increasing the dose of any drug. In such situations, periodic determination of CPK activity can be recommended, although such monitoring does not prevent the development of severe myopathy.

Cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described. Therapy should be temporarily discontinued or completely canceled if there are signs of possible myopathy or the presence of risk factors for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances and uncontrolled convulsions).

Before initiating treatment with Alipo, an attempt should be made to control hypercholesterolemia through adequate dietary therapy, increased physical activity, weight loss in obese patients, and treatment of other conditions.

Patients should be warned that they should immediately consult a doctor if unexplained pain or weakness in the muscles occurs, especially if they are accompanied by malaise or fever.

Influence on the ability to drive vehicles and mechanisms

The adverse effect of the drug on the ability to drive a car and work with mechanisms was not reported.

Use during pregnancy and during breastfeeding

Alipo is contraindicated for use during pregnancy and during breastfeeding.

Interaction with other drugs

The risk of myopathy in the treatment of HMG-CoA reductase inhibitors increases with simultaneous use with cyclosporine, fibrates, macrolides (including erythromycin), azole antifungals or nicotinic acid.

In some rare cases, these combinations can cause rhabdomyolysis, accompanied by renal failure. In this regard, a careful assessment of the ratio of the possible risk and the expected benefit of combined treatment is necessary.

CYP3A4 isoenzyme inhibitors

The metabolism of atorvastatin is carried out with the participation of the CYP3A4 isoenzyme. With the simultaneous use of atorvastatin with inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, macrolide antibiotics, for example, erythromycin and clarithromycin, nefazodone, azole antifungals, for example, itraconazole, and HIV protease inhibitors), drug interactions may occur. With the combined use of drugs, there may be increased concentrations of atorvastatin in the blood plasma.

Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones.

OATP1B1 transport protein inhibitors

Atorvastatin and its metabolites are substrates for the transport protein OATP1B1. OATP1B1 transport protein inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin.

Itraconazole

With the simultaneous use of atorvastatin and itraconazole, an increase in AUC was detected to an indicator that exceeded the norm three times.

Protease inhibitors

The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, was accompanied by an increase in the concentration of atorvastatin in the blood plasma.

CYP3A4 isoenzyme inducers

Simultaneous use of atorvastatin with drugs that induce the CYP3A4 isoenzyme (rifampicin, phenazone, efavirenz, St. John's wort preparations) can significantly reduce the concentration of atorvastatin in plasma. The mechanism of interaction with atorvastatin and other substrates of the CYP3A4 isoenzyme is unknown; however, the possibility of these interactions should be considered when using drugs with a low therapeutic index - in particular, class III antiarrhythmic drugs, for example, amiodarone.

Ezetimibe, fusidic acid

With simultaneous use, the risk of undesirable effects from the musculoskeletal system, including rhabdomyolysis, increases.

gemfibrozil/fibrates

The risk of myopathy caused by atorvastatin may increase with simultaneous use with fibrates. In vitro studies indicate that gemfibrozil may also interact with atorvastatin by inhibiting its glucuronidation, which may cause an increase in plasma concentrations of atorvastatin.

Colestipol

With simultaneous use with colestipol, a decrease in plasma concentrations of atorvastatin by approximately 25% was noted. However, with the combined use of atorvastatin and colestipol, the effect on lipids was more pronounced than with the use of each of these drugs separately.

Antacids

With simultaneous ingestion of atorvastatin and a suspension containing magnesium and aluminum hydroxide, the concentration of atorvastatin in the blood plasma decreased by approximately 35%; however, the concentration of LDL did not change.

Phenazone

With simultaneous use, atorvastatin does not affect the pharmacokinetics of phenazone, so it can be assumed that interactions with other drugs that are metabolized by the same cytochrome P450 isoenzymes are not expected.

Cimetidine

A study of the simultaneous use of cimetidine and atorvastatin did not reveal a significant interaction between these drugs.

Amlodipine

With the simultaneous use of 80 mg of atorvastatin and 10 mg of amlodipine, changes in atorvastatin in the equilibrium state were not detected.

Side effect

From the nervous system: insomnia, dizziness, headache, asthenia, malaise, drowsiness, nightmares, paresthesia, peripheral neuropathy, emotional lability, ataxia, hyperkinesis, depression, hypesthesia, memory loss or decrease.

From the digestive system: nausea, heartburn, dry mouth, belching, constipation or diarrhea, flatulence, gastralgia, abdominal pain, decreased or increased appetite, gastroenteritis, pancreatitis, hepatitis, cholestasis.

On the part of the respiratory system, chest organs and mediastinum : nasopharyngitis, epistaxis, pain in the pharyngo-laryngeal region, interstitial lung disease, chest pain, palpitations, arrhythmia.

On the part of the senses: decreased clarity of vision, impaired visual perception, "noise" in the ears, hearing loss, loss of taste, taste perversion.

From the musculoskeletal system and connective tissue : myalgia, arthralgia, pain in the extremities, muscle spasm, swelling in the joints, neck pain, muscle weakness, myopathy, myositis, rhabdomyolysis, tendinopathy.

From the genital organs and mammary gland: urogenital infections, sexual dysfunction, gynecomastia.

From the urinary system: peripheral edema, dysuria.

From the blood and lymphatic system : anemia, thrombocytopenia.

On the part of laboratory parameters: hyperglycemia, hypoglycemia, increased activity of creatine kinase in the blood serum, increased activity of "liver" transaminases, albuminuria.

Allergic reactions: pruritus, skin rash, urticaria, bullous dermatitis, angioedema, anaphylactic shock, erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Other: weight gain, exacerbation of gout.

If any of the side effects listed in the instructions get worse, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

There is no specific antidote. In case of overdose, the necessary symptomatic and supportive therapy should be carried out. It is necessary to monitor liver function and serum CPK levels. Hemodialysis is ineffective.

Storage conditions

Store in a cool and dry place, at a temperature not exceeding 30 ^° C.

Keep out of the reach of children.

Best before date

3 years. Do not use after the expiry date stated on the packaging.

Holiday conditions

Released by prescription.

Release form

For all doses

10 tablets in an aluminum foil blister. 3 blisters with instructions for use in a cardboard box.