Liptonorm^® (Tablets) Instructions for Use

Marketing Authorization Holder

M.J. Biopharm Pvt. Ltd. (India)

Labeled By

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN registered by WHO)

Dosage Forms

	Liptonorm®	Film-coated tablets, 10 mg: 28 pcs.
		Film-coated tablets, 20 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; white or almost white in cross-section.

Excipients: calcium carbonate, microcrystalline cellulose, lactose, Tween 80, hydroxypropylcellulose, croscarmellose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol.

14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

Hypolipidemic drug from the group of statins. The main mechanism of action of atorvastatin is the inhibition of HMG-CoA reductase activity, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid. This conversion is one of the early stages in the chain of cholesterol synthesis in the body.

The suppression of cholesterol synthesis by atorvastatin leads to increased reactivity of LDL receptors in the liver, as well as in extrahepatic tissues. These receptors bind LDL particles and remove them from the blood plasma, which leads to a decrease in LDL-C.

The antiatherosclerotic effect of atorvastatin is a consequence of the drug’s effect on the vascular walls and blood components. The drug suppresses the synthesis of isoprenoids, which are growth factors for the cells of the inner lining of blood vessels.

Under the action of atorvastatin, endothelium-dependent vasodilation improves. Atorvastatin reduces the content of cholesterol, LDL, apolipoprotein B, and triglycerides. It causes an increase in the content of HDL-C and apolipoprotein A.

The effect of the drug usually develops after 2 weeks of administration, and the maximum effect is achieved after 4 weeks.

Pharmacokinetics

Absorption

When taken orally, the absorption of the drug is high. The time to reach C_max in blood plasma is 1-2 hours.

Food somewhat reduces the rate and duration of atorvastatin absorption (by 25% and 9%, respectively), but the reduction in LDL-C level is similar to that when atorvastatin is applied without food. A linear relationship between the degree of absorption and the dose of the drug was revealed.

Bioavailability is 14%, systemic bioavailability of inhibitory activity against HMG-CoA reductase is 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa during the “first pass” through the liver.

Distribution

Plasma protein binding is 98%.

The mean V_d is 381 L.

Metabolism

It is metabolized mainly in the liver with the participation of isoenzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, β-oxidation products). The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and persists for about 20-30 hours.

Excretion

T_1/2 is 14 hours.

It is excreted in the bile after hepatic and/or extrahepatic metabolism (does not undergo significant enterohepatic recirculation).

Less than 2% of the orally administered dose is determined in the urine.

Pharmacokinetics in special clinical cases

C_max in women is 20% higher, AUC is 10% lower; C_max in patients with alcoholic liver cirrhosis is 16 times higher, AUC is 11 times higher than in patients with normal liver function.

The concentration of atorvastatin when used in the evening is lower than in the morning by approximately 30%.

Atorvastatin is not excreted during hemodialysis.

Indications

• Primary hypercholesterolemia;
• Mixed hyperlipidemia;
• Heterozygous and homozygous familial hypercholesterolemia (as an adjunct to diet therapy).

ICD codes

Dosage Regimen

Before starting treatment with Liptonorm^®, the patient should be switched to a diet that ensures a reduction in blood lipid levels, which must be followed during the treatment process.

The drug is prescribed orally at the same time of day, regardless of food intake.

The recommended initial dose is 10 mg once/day. Then the dose is selected individually depending on the LDL-C content. The dose should be changed at intervals of at least 4 weeks. The maximum daily dose is 80 mg in one dose.

For primary (heterozygous hereditary and polygenic) hypercholesterolemia (type IIa) and mixed hyperlipidemia (type IIb), treatment is started with the recommended initial dose, which is increased after 4 weeks of therapy depending on clinical efficacy. The maximum daily dose is 80 mg.

For homozygous hereditary hypercholesterolemia, the dose range is the same as for other types of hyperlipidemia. The initial dose is set individually depending on the severity of the disease. In most cases, the optimal effect is observed when using Liptonorm^® at a daily dose of 80 mg once/day.

In patients with impaired liver function, the drug should be used with caution due to the slowing of atorvastatin elimination from the body.

During treatment, clinical and laboratory parameters of body function should be carefully monitored, and if significant pathological changes are detected, the dose should be reduced or treatment should be discontinued.

No dose adjustment of Liptonorm^® is required for patients with renal insufficiency and elderly patients.

Adverse Reactions

From the CNS: > 2% – insomnia, dizziness; < 2% - headache, asthenic syndrome, malaise, drowsiness, nightmares, amnesia, paresthesia, peripheral neuropathy, emotional lability, ataxia, facial nerve palsy, hyperkinesis, depression, hyperesthesia, loss of consciousness.

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

From the cardiovascular system > 2% – chest pain; < 2% - palpitations, vasodilation, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.

From the respiratory system > 2% – bronchitis, rhinitis; < 2% - pneumonia, dyspnea, bronchial asthma, epistaxis.

From the digestive system > 2% – nausea, heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, anorexia or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, hepatic colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, gum bleeding, tenesmus.

From the musculoskeletal system > 2% – arthritis; < 2% - leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonus, joint contractures.

From the hematopoietic system anemia, lymphadenopathy, thrombocytopenia.

From the genitourinary system > 2% – urogenital infections, peripheral edema; less than 2% – dysuria (including pollakiuria, nocturia, urinary incontinence or retention, imperative urination urges), nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorder.

Dermatological reactions< 2% - alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Allergic reactions< 2% - skin itching, skin rash, contact dermatitis; rarely - urticaria, angioedema, facial edema, photosensitivity, anaphylaxis, multiforme exudative erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

From laboratory parameters< 2% - hyperglycemia, hypoglycemia, increased serum CPK activity, increased ALP activity, albuminuria, increased ALT or AST activity.

Other< 2% - weight gain, gynecomastia, mastodynia, exacerbation of gout.

Contraindications

• Active liver diseases (including active chronic hepatitis, chronic alcoholic hepatitis);
• Increased activity of liver transaminases (more than 3 times compared to ULN) of unclear genesis;
• Liver failure (classes A and B according to the Child-Pugh scale);
• Liver cirrhosis of various etiologies;
• Childhood and adolescence under 18 years;
• Pregnancy;
• Lactation (breastfeeding);
• Hypersensitivity to the components of the drug.

The drug should be prescribed with caution in case of a history of liver diseases, severe electrolyte balance disorders, endocrine and metabolic disorders, chronic alcoholism, arterial hypotension, severe acute infections (sepsis), uncontrolled seizures, extensive surgical interventions, trauma.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

It is not recommended to use Liptonorm^® in women of childbearing age who do not use reliable methods of contraception. Liptonorm^® should be discontinued at least one month before the planned pregnancy.

Use in Hepatic Impairment

The drug is contraindicated in active liver diseases (including active chronic hepatitis, chronic alcoholic hepatitis); increased activity of liver transaminases (more than 3 times compared to ULN) of unclear genesis; liver failure (classes A and B according to the Child-Pugh scale); liver cirrhosis of various etiologies.

The drug should be prescribed with caution in case of a history of liver diseases.

Pediatric Use

Contraindication: childhood and adolescence under 18 years.

Geriatric Use

No dose adjustment of Liptonorm^® is required for elderly patients.

Special Precautions

Liver function should be monitored before starting treatment, after 6, 12 weeks of therapy with Liptonorm^® and after each dose increase, as well as periodically, for example, every 6 months. Changes in liver enzyme activity are usually observed within the first 3 months after starting Liptonorm^®.

Patients who have an increase in liver transaminase activity should be monitored until the enzyme activity returns to normal. If ALT or AST values are more than 3 times the ULN, it is recommended to reduce the dose of Liptonorm^® or discontinue treatment.

Patients with diffuse myalgia, muscle lethargy and weakness and/or a significant increase in CPK are at risk for developing myopathy (defined as muscle pain accompanied by an increase in CPK level more than 10 times compared to ULN).

When prescribing Liptonorm^® in combination with cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, immunosuppressants and antifungal drugs of the azole derivative class, as well as with nicotinic acid (in doses that cause a hypolipidemic effect), it is necessary to compare the potential benefit of therapy and the degree of risk and monitor the condition of patients who develop signs or symptoms of muscle pain, lethargy or weakness, especially during the first months of treatment and when increasing the dose of any of the drugs.

Treatment with Liptonorm^® should be temporarily suspended or discontinued if a severe condition develops that may be a consequence of myopathy, as well as in the presence of risk factors for the development of acute renal failure due to rhabdomyolysis (for example, acute severe infection, arterial hypotension, extensive surgical intervention, trauma, severe metabolic and endocrine disorders, as well as electrolyte balance disorders).

The patient should immediately consult a doctor if unexplained muscle pain or weakness appears, especially if they are accompanied by malaise and fever.

Use in pediatrics

The safety and efficacy of Liptonorm^® in children and adolescents under 18 years of age have not been studied.

Effect on the ability to drive vehicles and mechanisms

No adverse effects of Liptonorm^® on the ability to drive a car and perform work requiring increased attention have been reported.

Overdose

Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy, measures aimed at maintaining vital body functions. A specific antidote is unknown.

If signs and presence of risk factors for the development of acute renal failure against the background of rhabdomyolysis appear, the drug should be immediately discontinued.

Since Atorvastatin is largely bound to plasma proteins, hemodialysis is not effective.

Drug Interactions

With the simultaneous administration of Liptonorm^® and cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressants, antifungal drugs of the azole derivative class, nicotinamide, the concentration of atorvastatin in the blood plasma increases and the risk of developing myopathy increases.

Antacids reduce the concentration of atorvastatin by 35%, while the effect on LDL-C content does not change.

Simultaneous use of Liptonorm^® with protease inhibitors, which are inhibitors of CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

When using digoxin in combination with Liptonorm^® at a dose of 80 mg/day, the concentration of digoxin in the blood plasma increases by approximately 20%.

Liptonorm^® at a dose of 80 mg/day, when used simultaneously, increases the concentration of oral contraceptives containing norethindrone and ethinyl estradiol by 20%.

The hypolipidemic effect of the combination with colestipol exceeds that of each drug separately.

When taken simultaneously with warfarin, the prothrombin time decreases in the first days, but after 15 days this indicator normalizes. In this regard, patients taking Liptonorm^® with warfarin should monitor prothrombin time more often than usual.

Consumption of grapefruit juice during therapy with Liptonorm^® may lead to an increase in the concentration of atorvastatin in the blood plasma. In this regard, patients taking the drug should avoid consuming this juice.

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 2 years.

Dispensing Status

The drug is dispensed 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.