Vasator (Tablets) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

Contact Information

Edge Pharma Private Limited COO (India)

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN WHO registered)

Dosage Forms

	Vasator	Film-coated tablets, 10 mg: 10, 14, 28 or 30 pcs.
		Film-coated tablets, 20 mg: 10, 14, 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex; the cross-section shows two layers, the core is white to almost white.

Excipients : microcrystalline cellulose – 43.7 mg, lactose monohydrate – 54.95 mg, calcium carbonate – 5 mg, povidone – 5 mg, colloidal silicon dioxide – 5 mg, carmellose sodium – 7 mg, magnesium stearate – 3 mg.

Film coating composition hypromellose – 4.1 mg, macrogol 6000 – 1.2 mg, titanium dioxide – 0.6 mg, talc – 1.2 mg, yellow iron oxide dye – 0.07 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Film-coated tablets dark pink, round, biconvex; the cross-section shows two layers, the core is white to almost white.

Excipients : microcrystalline cellulose – 54.4 mg, lactose monohydrate – 54.95 mg, calcium carbonate – 5 mg, povidone – 5 mg, colloidal silicon dioxide – 5 mg, croscarmellose sodium – 7 mg, magnesium stearate – 3 mg.

Film coating composition hypromellose – 4.1 mg, macrogol 6000 – 1.2 mg, titanium dioxide – 0.6 mg, talc – 1.2 mg, red iron oxide dye – 0.07 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

Hypolipidemic agent from the statin group. Selective competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, a precursor of sterols, including cholesterol.

Triglycerides (TG) and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL), enter the bloodstream and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL during interaction with LDL receptors.

Atorvastatin reduces plasma concentrations of cholesterol and lipoproteins by inhibiting HMG-CoA reductase, cholesterol synthesis in the liver, and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL.

It reduces the formation of LDL and causes a pronounced and persistent increase in LDL receptor activity. It reduces LDL concentration in patients with homozygous familial hypercholesterolemia, which is usually resistant to therapy with hypolipidemic agents.

It reduces total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50% and TG by 14-33%; it causes an increase in HDL cholesterol (high-density lipoproteins) and apolipoprotein A concentrations.

It dose-dependently reduces LDL levels in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Pharmacokinetics

Absorption is high. C_max in blood plasma is reached in 1-2 hours; C_max in women is 20% higher, the area under the concentration-time curve (AUC) is 10% lower; C_max in patients with alcoholic liver cirrhosis is 16 times higher, AUC is 11 times higher than normal.

Food intake somewhat reduces the rate and duration of drug absorption (by 25% and 9%, respectively), but the reduction in LDL cholesterol is similar to that when atorvastatin is taken without food.

The concentration of atorvastatin when taken in the evening is lower than in the morning (by approximately 30%). A linear relationship between the degree of absorption and the drug dose has been identified.

Bioavailability is 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase is 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and during first-pass through the liver.

V_d is 381 L, plasma protein binding is 98%. It is metabolized mainly in the liver under the action of isoenzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products).

In vitro, ortho- and para-hydroxylated 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.

It is excreted through the intestine with bile after hepatic and/or extrahepatic metabolism (does not undergo significant enterohepatic recirculation). T_1/2 is 14 hours. The inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites.

Less than 2% of the orally administered dose is detected in urine. It is not excreted during hemodialysis.

Indications

• In combination with a diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and to increase HDL cholesterol levels 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 for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV) and patients with dysbetalipoproteinemia (Fredrickson type III) in whom diet therapy does not provide an adequate effect;
• To reduce total cholesterol and LDL cholesterol levels in patients with homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological treatments are insufficiently effective.

ICD codes

Dosage Regimen

Before prescribing Vasator, the patient should be recommended a standard hypolipidemic diet, which must be followed throughout the entire therapy period.

The initial dose is on average 10 mg once/day. The dose varies from 10 to 80 mg once/day.

The drug can be taken at any time of the day with food or regardless of meal time. The dose is selected taking into account the initial LDL cholesterol levels, the therapy goal and the individual effect. At the beginning of treatment and/or during dose increase, plasma lipid concentrations should be monitored every 2-4 weeks and the dose should be adjusted accordingly.

Primary hypercholesterolemia and mixed hyperlipidemia, as well as Fredrickson types III and IV: in most cases, a dose of 10 mg of Vasator once/day is sufficient. A significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. This effect is maintained during long-term treatment.

Homozygous familial hypercholesterolemia: the drug is used in a dose of 80 mg (4 tablets of 20 mg) once/day. Do not use more than 4 tablets of 10 mg dosage per day – it is not allowed to replace the 20 mg dosage with the 10 mg dosage for a daily dose of 80 mg.

Use of the drug in patients with renal failure and kidney diseases does not affect the level of atorvastatin in plasma or the degree of LDL cholesterol reduction during its use, therefore a change in the drug dose is not required.

In hepatic insufficiency, doses must be reduced (see sections “With caution” and “Special instructions”).

When using the drug in elderly patients, no differences in safety, efficacy or achievement of hypolipidemic therapy goals were noted compared to the general population.

Adverse Reactions

From the central nervous system insomnia, dizziness, headache, asthenia, malaise, drowsiness, nightmares, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial nerve paralysis, hyperkinesis, migraine, depression, hypoesthesia, loss of consciousness.

From the sensory organs amblyopia, tinnitus, conjunctival dryness, accommodation disturbance, retinal hemorrhage, deafness, glaucoma, parosmia, loss of taste, taste perversion.

From the cardiovascular system chest pain, palpitations, vasodilation symptoms, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.

From the hematopoietic system anemia, lymphadenopathy, thrombocytopenia.

From the respiratory system : bronchitis, rhinitis, pneumonia, dyspnea, exacerbation of bronchial asthma, nosebleed.

From the digestive system nausea, 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, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, gum bleeding, tenesmus.

From the musculoskeletal system arthritis; leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonia, joint contractures.

From the genitourinary system urogenital infections, peripheral edema; dysuria (including pollakiuria, nocturia, urinary incontinence or retention, imperative urination urges), nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorder.

From the skin alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Allergic reactions skin itching, skin rash, contact dermatitis, urticaria, angioedema, facial edema, photosensitivity, anaphylaxis, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Laboratory parameters hyperglycemia, hypoglycemia, increased serum creatine phosphokinase (CPK), albuminuria.

Other weight gain, gynecomastia, mastodynia, exacerbation of gout.

Contraindications

• Hypersensitivity to the drug components;
• Active liver diseases or unexplained increase in activity of liver enzymes (more than 3 times compared to the upper limit of normal); liver failure (severity by classes A and B according to Child-Pugh classification);
• Pregnancy;
• Lactation period;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Age under 18 years (efficacy and safety not established).

With caution: alcohol abuse, history of liver diseases, severe water-electrolyte balance disorders, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgical interventions, trauma, skeletal muscle diseases.

Use in Pregnancy and Lactation

Vasator is contraindicated for use during pregnancy and lactation (breastfeeding).

It is not known whether Atorvastatin is excreted in breast milk. Considering the possibility of adverse events in infants, if it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Women of reproductive age during treatment with Vasator should use adequate contraceptive methods.

Vasator can be prescribed to women of reproductive age only if the probability of pregnancy is very low and the patient is informed about the possible risk of treatment for the fetus.

Use in Hepatic Impairment

Contraindicated in active liver diseases or unexplained increase in activity of liver enzymes (more than 3 times compared to the upper limit of normal); in liver failure (severity by classes A and B according to Child-Pugh classification).

With caution: history of liver diseases.

Use in Renal Impairment

Use of the drug in patients with renal failure and kidney diseases does not affect the level of atorvastatin in plasma or the degree of LDL cholesterol reduction during its use, therefore a change in the drug dose is not required.

Pediatric Use

Contraindicated under the age of 18 years (efficacy and safety not established).

Geriatric Use

When using the drug in elderly patients, no differences in safety, efficacy or achievement of hypolipidemic therapy goals were noted compared to the general population.

Special Precautions

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

The use of HMG-CoA reductase inhibitors to reduce blood lipid concentrations may lead to changes in biochemical parameters reflecting liver function. Liver function should be monitored before starting therapy, 6 weeks, 12 weeks after starting Vasator 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 may be observed during therapy with Vasator. Patients who have an increase in enzyme activity should be monitored until the enzyme activity returns to normal. If ALT or AST values exceed the upper acceptable limit by more than 3 times, it is recommended to reduce the dose of Vasator or discontinue treatment.

Vasator should be used with caution in patients who abuse alcohol and/or have liver disease. Active liver disease or a persistent unexplained increase in the activity of liver transaminases are contraindications for prescribing Vasator.

Treatment with Vasator may cause myopathy. The diagnosis of myopathy (muscle pain and weakness in combination with an increase in CPK activity more than 10 times compared to the upper limit of normal) should be considered in patients with widespread myalgia, muscle tenderness or weakness and/or a pronounced increase in CPK activity. Patients should be warned that they should immediately inform their doctor about the appearance of unexplained muscle pain or weakness if they are accompanied by malaise or fever. Vasator therapy should be discontinued in case of a significant increase in CPK activity or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increased with simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses or azole antifungal agents. Many of these drugs inhibit metabolism mediated by the CYP3A4 isoenzyme and/or drug transport. Atorvastatin is biotransformed under the action of the CYP3A4 isoenzyme. When prescribing Vasator in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungal agents or nicotinic acid in lipid-lowering doses, the expected benefit and risk of treatment should be carefully weighed and patients should be regularly monitored for the detection of muscle pain or weakness, especially during the first months of treatment and during the dose increase 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.

When using Vasator, as with other agents of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described. Vasator therapy should be temporarily discontinued or completely withdrawn if signs of possible myopathy appear or if there is a risk factor for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, extensive surgical intervention, trauma, severe metabolic, endocrine and electrolyte disorders and uncontrolled convulsions).

Before starting therapy with Vasator, it is necessary to try to achieve control of hypercholesterolemia through adequate diet therapy, increased physical activity, weight loss in patients with obesity and treatment of other conditions. Patients should be warned that they should immediately consult a doctor if unexplained muscle pain or weakness appears, especially if they are accompanied by malaise or fever.

Effect on ability to drive vehicles and mechanisms

In some patients, the drug may cause dizziness and other side effects that may affect the ability to drive vehicles and operate machinery. In this regard, when treating with Vasator, caution should be exercised when driving vehicles and other complex mechanisms requiring increased attention.

Overdose

Treatment: there is no specific antidote, symptomatic therapy is performed. Hemodialysis is ineffective.

Drug Interactions

The risk of myopathy during treatment with other drugs of this class is increased with the concurrent use of cyclosporine, fibrates, erythromycin, antifungal agents belonging to azoles, and nicotinic acid. When atorvastatin and a suspension containing magnesium and aluminum hydroxides were taken orally concurrently, plasma concentrations of atorvastatin decreased by approximately 35%, however, the degree of reduction in cholesterol/LDL levels did not change.

When used concomitantly, Atorvastatin does not affect the pharmacokinetics of antipyrine (phenazone), therefore, interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

With the simultaneous use of colestipol, plasma concentrations of atorvastatin decreased by approximately 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug individually. Upon repeated administration of digoxin and atorvastatin at a dose of 10 mg, the steady-state plasma concentrations of digoxin did not change. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, the concentration of digoxin increased by approximately 20%. Patients receiving digoxin in combination with atorvastatin should be monitored.

With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times/day) or clarithromycin (500 mg 2 times/day), which inhibit the CYP3A4 isoenzyme, an increase in plasma concentration of atorvastatin was observed. With the simultaneous use of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily), the plasma concentration of atorvastatin did not change.

Atorvastatin did not have a clinically significant effect on the plasma concentration of terfenadine, which is metabolized primarily by CYP3A4; in this regard, it seems unlikely that Atorvastatin is able to significantly affect the pharmacokinetic parameters of other substrates of the CYP3A4 isoenzyme.

With the simultaneous use of atorvastatin and an oral contraceptive containing norethisterone and ethinyl estradiol, a significant increase in the AUC of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively, was observed. This effect should be considered when choosing an oral contraceptive for a woman receiving Atorvastatin.

Concomitant use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of a decrease in endogenous steroid hormones (caution should be exercised).

In a study of the interaction of atorvastatin with warfarin and cimetidine, no signs of a clinically significant interaction were found.

With the simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the steady-state pharmacokinetics of atorvastatin did not change.

No clinically significant adverse interaction between atorvastatin and antihypertensive agents was noted.

Concomitant use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, was accompanied by an increase in the plasma concentration of atorvastatin. Pharmaceutical incompatibility is not known.

Storage Conditions

Store out of reach of children, in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.