Atorvastatin-Vertex, 10 mg 90 pcs

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme converting 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor of steroids, including cholesterol; a synthetic hypolipidemic drug.

. In patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces plasma concentrations of total cholesterol (CH) low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo-B), as well as the concentration of very low density lipoproteins (VLDL-C) and triglycerides (TG), causes unstable increase in concentration of high density lipoprotein cholesterol (HDL-C).

Atorvastatin reduces plasma cholesterol and lipoprotein concentrations by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and, by increasing the number of “hepatic” LDL receptors on the cell surface, leads to increased capture and catabolism of Hs-LDL.

Atorvastatin decreases formation of LDL-C and LDL particle number, causes marked and persistent increase of LDL receptor activity in combination with favorable qualitative changes of LDL particles and decreases concentration of LDL-C in patients with homozygous hereditary familial hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Atorvastatin at doses of 10 to 80 mg reduces total cholesterol concentration by 30-46%, LDL-C by 41-61%, apo-B by 34-50% and TG by 14-33%. Results of therapy are similar in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with type 2 diabetes.

In patients with isolated hypertriglyceridemia, atorvastatin decreases the concentration of total cholesterol, chs-LDL, chs-LONP, apo-B and TG and increases the concentration of HDL-C. In patients with dysbetalipoproteinemia it reduces the concentration of intermediate density lipoprotein cholesterol (X-LDL).

In patients with hyperlipoproteinemia of type IIa and IIb according to Fredrickson classification the mean value of increase of HDL-C concentration during treatment with atorvastatin (10-80 mg) in comparison with baseline is 5.1-8.7% and it is not dose dependent. There is a significant dose-dependent decrease in the values of ratios: total cholesterol/Cs-LDL and Chs-LDL/Cs-LDL by 29-44% and 37-55%, respectively.

Atorvastatin at a dose of 80 mg significantly reduced the risk of ischemic complications and mortality by 16% after a 16-week course, and the risk of rehospitalization for angina with signs of myocardial ischemia by 26%. In patients with different baseline concentrations of CHD (with myocardial infarction without Q-wave and unstable angina, men and women, in patients younger and older than 65 years) atorvastatin causes reduction of risk of coronary complications and mortality.

Decrease in plasma concentration of Chs-LDL better correlates with the dose of atorvastatin than with its plasma concentration. The dose is adjusted taking into account the therapeutic effect (see section “Dosage and administration”).

Therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and lasts for the duration of therapy.

Indications

Active ingredient

Composition

1 tablet contains:

active ingredient:

atorvastatin calcium trihydrate (in terms of atorvastatin) – 10.00 mg;

auxiliary substances:

microcrystalline cellulose – 49.68 mg,

lactose monohydrate – 40.00 mg,

calcium carbonate – 33.00 mg,

crospovidone – 7.50 mg,

sodium carboxymethyl starch (sodium starch glycolate) – 4.50 mg,

Hyprolose (hydroxypropyl cellulose) – 3.00 mg,

Magnesium stearate – 1.50 mg;

film coating:

[hypromellose 2.250 mg, talc 0.882 mg, hyprolose (hydroxypropyl cellulose) 0.873 mg, titanium dioxide 0.495 mg] or [dry film coating mixture containing hypromellose (50.0%), talc (19.6%), hyprolose (hydroxypropyl cellulose) (19.4%), titanium dioxide (11.0%)] – 4,500 mg.

How to take, the dosage

Ingestion. Take at any time of the day regardless of meals.

Before starting treatment with Atorvastatin, an attempt should be made to achieve control of hypercholesterolemia through diet, exercise and weight loss in obese patients, as well as treatment of the underlying disease.

When the drug is prescribed, a standard hypocholesterolemic diet should be recommended for the patient to follow for the duration of treatment.

The dose of the drug varies from 10 mg to 80 mg once daily and is titrated taking into account the baseline concentration of Chs-LDL, the goal of therapy and the individual effect on the ongoing therapy.

The maximum daily dose is 80 mg.
At the beginning of treatment and/or during dose increase of Atorvastatin it is necessary to monitor plasma lipid concentrations every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia
Treatment begins with the recommended initial dose of 10 mg once daily, which is increased after four weeks depending on patient response. The maximum daily dose is 80 mg.

Homozygous familial hypercholesterolemia
The dose range is the same as for other types of hyperlipidemia. The initial dose is chosen individually depending on the severity of the disease. In most patients with homozygous hereditary hypercholesterolemia optimal effect is observed when using the drug in daily dose of 80 mg (once daily). Atorvastatin is used as additional therapy to other methods of treatment (plasmapheresis) or as main treatment if therapy with other methods is impossible.

In patients with hepatic impairment caution is necessary (due to delayed excretion of atorvastatin from the body). In such a situation clinical and laboratory parameters should be carefully controlled (regular monitoring of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT) activity). In case of significant increase of “hepatic” transaminases activity, the drug dose should be decreased or the treatment should be stopped.

In elderly patients and patients with renal disease the drug dose should not be changed. Renal impairment does not affect the plasma concentration of atorvastatin or the degree of decrease in concentration of X-LDL during atorvastatin therapy, therefore no adjustment of the drug dose is required.

Combination with other drugs
If simultaneous use with cyclosporine, telaprevir or tiprapavir/ritonavir combination is necessary, the drug dose should not exceed 10 mg per day.

Caution should be exercised and the lowest effective dose of atorvastatin used concomitantly with HIV protease inhibitors, hepatitis C inhibitors, clarithromycin and itraconazole.

Interaction

The risk of myopathy with rhabdomyolysis and renal failure during treatment with HMG-CoA reductase inhibitors is increased with concomitant use with cyclosporine, antibiotics (erythromycin, clarithromycin, quinupristine/dalfopristine), HIV protease inhibitors (indinavir, ritonavir), antifungal drugs (fluconazole, itraconazole, ketoconazole), nefazodone. All these drugs inhibit CYP3A4 isoenzyme, which is involved in metabolism of atorvastatin in the liver.

A similar interaction is possible in concomitant use of atorvastatin with fibrates and nicotinic acid in lipid-lowering doses (more than 1 g per day).

In concomitant use with HIV protease inhibitors, hepatitis C inhibitors, clarithromycin and itraconazole caution should be exercised and the lowest effective dose of atorvastatin should be used.

CYP3A4 isoenzyme inhibitors
Since atorvastatin is metabolized by CYP3A4 isoenzyme, co-administration of atorvastatin with CYP3A4 isoenzyme inhibitors may lead to increased plasma concentration of atorvastatin. The degree of interaction and potentiation effect are determined by the variability of effects on CYP3A4 isoenzyme.

Inhibitors of transport protein OATP1B1
Atorvastatin and its metabolites are substrates of transport protein OATP1B1. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin.

Eritromycin/Clarithromycin
When concomitant use of atorvastatin and erythromycin or clarithromycin, which inhibit CYP3A4 isoenzyme, increased plasma concentration of atorvastatin was observed.

Protease inhibitors
Concomitant use of atorvastatin with protease inhibitors, known as CYP3A4 isoenzyme inhibitors, is accompanied by an increase in plasma concentration of atorvastatin.

Diltiazem
Co-administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to increased plasma concentration of atorvastatin.
Itraconazole
Concomitant use of atorvastatin and itraconazole led to an increase in plasma concentration of atorvastatin.

Grapefruit juice
Since grapefruit juice contains one or more components that inhibit CYP3A4 isoenzyme, its excessive consumption (more than 1.2 liters per day) may increase the plasma concentration of atorvastatin.

Inductors of CYP3A4 isoenzyme
Co-administration of atorvastatin with inducers of CYP3A4 isoenzyme (such as efavirenz, phenytoin or rifampicin) may lead to decreased plasma concentration of atorvastatin. Due to dual mechanism of interaction with rifampicin (inducer of CYP3A4 isoenzyme and inhibitor of hepatocyte transport protein OATP1B1) it is recommended to use atorvastatin and rifampicin simultaneously, because delayed administration of atorvastatin after rifampicin administration leads to significant decrease of plasma concentration of atorvastatin.

Antacids
Simultaneous oral administration of atorvastatin and suspension containing magnesium and aluminum hydroxide decreases the plasma concentration of atorvastatin.

Phenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, so no interaction with other drugs metabolized by the same cytochrome enzymes is expected.

Colestipol
Concomitant use of colestipol decreased plasma concentrations of atorvastatin by approximately 25%, but the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Digoxin
When digoxin was used in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased by approximately 20%, so these patients should be monitored.

In concomitant use of atorvastatin and oral contraceptives containing norethisterone and ethinylestradiol may increase absorption and concentration of contraceptives in blood plasma. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.

Terfenadine
Atorvastatin had no clinically significant effect on terfenadine pharmacokinetics with concomitant use.

Warfarin
Concomitant use of atorvastatin with warfarin may in the first days increase the effect of warfarin on blood clotting (decrease in prothrombin time). This effect disappears after 15 days of concomitant use of these drugs.

Amlodipine
Atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg did not change pharmacokinetics of atorvastatin at equilibrium.

Fusidic acid
Cases of rhabdomyolysis have been reported in patients using atorvastatin and fusidic acid.

Colchicine
Cases of myopathy have been reported with concomitant use of atorvastatin and colchicine. Caution should be exercised when combining therapy with these drugs.

Cimetidin
In studying the interaction of atorvastatin with cimetidin no signs of clinically significant interaction were found.

Other concomitant therapy
Concomitant use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones (includingincluding cimetidine, ketoconazole, spironolactone), increases the risk of decrease of endogenous steroid hormones (caution should be exercised).
In clinical trials atorvastatin was used in combination with hypotensive agents and estrogens, which were prescribed as substitution therapy; no symptoms of clinically significant adverse interaction were observed. Interaction studies with specific drugs were not conducted.

Special Instructions

Before starting therapy with Atorvastatin, the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the entire period of treatment.

In case of severe adverse effects the use of Atorvastatin should be discontinued.

Liver effects
As with other hypolipidemic agents of this class, after treatment with atorvastatin moderate (more than 3 times the upper limit of normal) increase of serum activity of “hepatic” transaminases AST and ALT was observed. Increased activity of “hepatic” transaminases usually was not accompanied by jaundice or other clinical manifestations. When the dose of atorvastatin was decreased, temporarily or completely discontinued, hepatic transaminases activity returned to the initial level. Most patients continued receiving atorvastatin in reduced dose without any clinical consequences.

Before the start of therapy, 6 weeks and 12 weeks after the start of Atorvastatin or after increasing its dose, as well as during the whole course of treatment it is necessary to monitor liver function parameters. Liver function should also be monitored when clinical signs of liver damage appear. If the activity of “hepatic” transaminases increases, their activity should be monitored until they normalize. If increase of AST or ALT activity more than 3 times compared to the upper limit of normal remains, it is recommended to reduce the dose or cancel the drug.

Atorvastatin should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or persistently elevated plasma “hepatic” transaminase activity of unclear genesis are contraindications to the use of Atorvastatin.

Effects on skeletal muscles
Myalgia has been noted in patients receiving atorvastatin. The diagnosis of myopathy (muscle pain and weakness combined with an increase in creatine phosphokinase activity more than 10 times the upper limit of normal) should be assumed in patients with diffuse myalgia, muscle soreness or weakness and/or marked increase in CPK activity. Atorvastatin therapy should be discontinued in case of marked increase in CPK activity or in the presence of confirmed or suspected myopathy. Risk of myopathy during treatment with other drugs of this class was increased with concomitant use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g/day), nefasodone, some antibiotics, azole antifungal drugs, HIV protease inhibitors.

Many of these drugs inhibit CYP3A4 isoenzyme-mediated metabolism and/or drug transport. It is known that CYP3A4 isoenzyme is the main liver isoenzyme involved in biotransformation of atorvastatin. When prescribing Atorvastatin in combination with fibrates, erythromycin, immunosuppressants, azole antifungal drugs or nicotinic acid in lipid-lowering doses, the expected benefits and possible risks should be carefully weighed. Patients should be monitored regularly for muscle pain or weakness, especially during the first months of treatment and during periods of increasing doses of any of the above agents. If combination therapy is necessary, consideration should be given to using these drugs at lower initial and maintenance doses. Periodic determination of CPK activity may be recommended in these situations, although such monitoring does not prevent the development of severe myopathy.

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described with atorvastatin and other statins. If there are symptoms of possible myopathy or there are risk factors of renal failure on the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, extensive surgery, trauma, metabolic, endocrine and water-electrolyte disorders and uncontrolled convulsions) therapy with Atorvastatin should be temporarily stopped or completely discontinued.

In the differential diagnosis of sore throat pain, the possibility of increased serum CPK activity with Atorvastatin should be considered.

Caution. Patients should be warned to seek immediate medical attention if they experience unexplained pain or muscle weakness, especially if accompanied by malaise or fever.

Atorvastatin contains lactose, therefore its use in patients with lactase deficiency, lactose intolerance and glucose-galactose malabsorption syndrome is contraindicated.

Influence on driving and operating machinery

Cautious driving and other technical devices requiring increased concentration and rapid psychomotor reactions should be observed (risk of dizziness).

Contraindications

Cautions

The use in patients who abuse alcohol or in patients with a history of liver disease.

Side effects

World Health Organization (WHO) side effect frequency classification: very common – ≥1/10, common – ≥1/100 to < 1/10, infrequent – ≥1/1000 to < 1/100, rare – ≥1/10000 to < 1/1000, very rare – < 1/10000, including individual reports, frequency unknown – according to available data it was impossible to determine the frequency of occurrence.
Nervous system disorders:
often – insomnia, headache, dizziness, paresthesia, asthenic syndrome;
infrequently – peripheral neuropathy, amnesia, hypoesthesia.

Sense organs:
infrequent – tinnitus;
frequently – nasopharyngitis, nasal bleeding.

Cardiovascular system disorders:

sensation of palpitations, symptoms of vasodilation, migraine, postural hypotension, increased arterial pressure, phlebitis, arrhythmia.

With the hematopoietic system:
infrequently – thrombocytopenia.

In the respiratory system:
often – chest pain.

From the digestive system:
often – nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence (abdominal bloating);
infrequently – taste disorder, vomiting, pancreatitis;
frequently – hepatitis, cholestatic jaundice.

Musculoskeletal and connective tissue side:
often – myalgia, arthralgia, back pain, swollen joints;
infrequently – myopathy, muscle cramps;
frequently – myositis, rhabdomyolysis, tendopathy (in some cases with tendon rupture).

In the urinary tract:
infrequent – sexual dysfunction, secondary renal failure.

Side of the skin:
often – skin rash, skin itching;
infrequently – urticaria;
very rarely – Angioneurotic edema, alopecia, bullous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Allergic reactions:
often – allergic reactions;
very rarely – anaphylaxis.

Laboratory indices:
infrequent – increased activity of aminotransferases (AST, ALT), increased activity of serum creatine phosphokinase (CPK);
very rare – hypoglycemia, hyperglycemia.
Others:
often – peripheral edema;
frequently – weakness, increased fatigue, fever, anorexia, weight gain.

The following side effects have been reported during the postmarketing use of statins, including atorvastatin: memory loss or impairment, depression, sleep disturbance, including insomnia and “nightmares,” sexual dysfunction, gynecomastia, hyperglycemia, increased concentration of glycosylated hemoglobin, isolated cases of interstitial lung disease (especially with long-term use), cases of immune-mediated necrotizing myopathy, thrombocytopenia.

Overdose

No cases of overdose have been described.

In case of overdose the following general measures are required: monitoring and maintenance of vital body functions, as well as prevention of further absorption of the drug (gastric lavage, administration of activated charcoal or laxatives).
In case of myopathy with subsequent rhabdomyolysis and acute renal failure the drug should be immediately withdrawn and infusion of diuretic and sodium bicarbonate should be started.

Rhabdomyolysis may lead to hyperkalemia, which requires intravenous administration of calcium chloride solution or calcium gluconate solution, infusion

5% dextrose (glucose) solution with insulin, use of potassium exchange resins.
Since the drug actively binds to plasma proteins, hemodialysis is not effective.

Similarities