Instructions for use Liprimar film-coated tablets 10 mg blister No. 30
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to 10 mg of atorvastatin;
excipients: calcium carbonate; microcrystalline cellulose; lactose, monohydrate; croscarmellose sodium; polysorbate 80; hydroxypropylcellulose; magnesium stearate; film-coating material (hydroxypropylmethylcellulose, macrogol 8000, titanium dioxide (E 171), talc); simethicone emulsion (simethicone, emulsifier stearate, thickener, benzoic acid, sorbic acid).
Dosage form
Film-coated tablets.
Main physicochemical properties: white, round, film-coated tablets engraved with “10” on one side and “ATV” on the other for 10 mg tablets, respectively.
Pharmacotherapeutic group
Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.
Pharmacological properties
Pharmacodynamics
Lipitor is a synthetic lipid-lowering drug. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.
Liprimar is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that regulates the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
In experimental animal models, Liprimar lowers plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis and by increasing the number of hepatic LDL receptors on the cell surface to enhance LDL uptake and catabolism; Liprimar also reduces LDL production and particle size.
Lipitor and some of its metabolites are pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which plays a major role in cholesterol synthesis and LDL clearance. The dose of the drug, in contrast to the systemic concentration of the drug, correlates better with the reduction in LDL cholesterol. Individual selection of the dose of the drug should be carried out depending on the therapeutic response (see the section "Method of administration and dosage").
Pharmacokinetics
Absorption. Lipitor is rapidly absorbed after oral administration and peak plasma concentrations are achieved within 1–2 hours. The extent of absorption increases in proportion to the dose of Lipitor®. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is associated with presystemic clearance in the gastrointestinal mucosa and/or presystemic biotransformation in the liver. Although food reduces the rate and extent of absorption of the drug by approximately 25% and 9%, respectively, based on Cmax and AUC (area under the concentration-time curve), the reduction in LDL-C is similar when Lipitor is taken with or without food. When atorvastatin was administered in the evening, its plasma concentration was lower (approximately 30% in terms of Cmax and AUC) than when administered in the morning. However, the reduction in LDL-C was the same regardless of the time of administration (see section 4.2).
Distribution. The mean volume of distribution of Liprimar is approximately 381 liters. More than 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on observations in rats, it is believed that Liprimar is able to penetrate into breast milk (see sections "Contraindications" and "Special Instructions").
Metabolism. Liprimar is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies have shown that the inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Liprimar. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with the active metabolites. In vitro studies suggest the importance of metabolism of Liprimar by cytochrome P450 3A4 (CYP 3A4), which is consistent with the increased plasma concentrations of Liprimar in humans after concomitant administration with erythromycin, a known inhibitor of this isoenzyme (see section 4.5).
Excretion: Liprimar and its metabolites are eliminated primarily in the bile after hepatic and/or extrahepatic metabolism, but the drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of Liprimar from human plasma is approximately 14 hours, but the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the action of the active metabolites. Less than 2% of the dose is excreted in the urine after oral administration.
Elderly patients. Plasma concentrations of Liprimar are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (aged 65 years and older) than in young adult patients. Clinical data suggest a greater degree of LDL-C reduction at any dose in elderly patients compared with young patients (see section 4.4).
Children: Apparent oral clearance of atorvastatin in children was similar to that in adults when scaled allometrically for body weight, as body weight was the only significant covariate in a population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29) in an open-label 8-week study.
Gender: Lipitor plasma concentrations differ in women compared to men (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in LDL-C reduction between men and women with Lipitor.
Renal impairment: Renal disease does not affect the plasma concentrations of Lipitor or the reduction in LDL-C, and therefore no dose adjustment is required for patients with renal impairment (see sections 4.2 and 4.4).
Hemodialysis: Although no studies have been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase the clearance of Lipitor because the drug is highly bound to plasma proteins.
Hepatic impairment. Plasma concentrations of Liprimar are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC are 4-fold higher in patients with Child-Pugh Class A liver disease. In patients with Child-Pugh Class B liver disease, Cmax and AUC are increased approximately 16-fold and 11-fold, respectively (see Contraindications).
Drug interaction studies. Atorvastatin is a substrate of the hepatic transporters OATP1B1 and OATP1B3. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin has also been identified as a substrate of the efflux transporter breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.
Effect of concomitant medications on the pharmacokinetics of atorvastatin
| Concomitant medications and dosage regimen | Atorvastatin | | |
| Dose (mg) | AUC& ratio | Cmax& ratio | |
| #Cyclosporin 5.2 mg/kg/day, stable dose | 10 mg once daily for 28 days | 10 mg once daily for 28 days | 10.66 |
| #Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days | 10 mg single dose | 9.36 | 8.58 |
| #Glecaprevir 400 mg once daily/pibrentasvir 120 mg once daily, 7 days | 10 mg once daily for 7 days | 8.28 | 22.00 |
| #Telaprevir 750 mg every 8 hours, 10 days | 20 mg single dose | 7.88 | 10.60 |
#, ‡Saquinavir 400 mg twice daily/
ritonavir 400 mg twice daily, 15 days | 40 mg once daily for 4 days | 3.93 | 4.31 |
| #Elbasvir 50 mg once daily/ grazoprevir 200 mg once daily, 13 days | 10 mg single dose | 1.94 | 4.34 |
| #Simeprevir 150 mg once daily, 10 days | 40 mg single dose | 2.12 | 1.70 |
| #Clarithromycin 500 mg twice daily, 9 days | 80 mg once daily for 8 days | 4.54 | 5.38 |
| #Darunavir 300 mg twice daily/ritonavir 100 mg twice daily, 9 days | 10 mg once daily for 4 days | 3.45 | 2.25 |
| #Itraconazole 200 mg once daily, 4 days | 40 mg single dose | 3.32 | 1.20 |
| Letermovir 480 mg once daily, 10 days | 20 mg single dose | 3.29 | 2.17 |
| #Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days | 10 mg once daily for 4 days | 2.53 | 2.84 |
| #Fosamprenavir 1400 mg twice daily, 14 days | 10 mg once daily for 4 days | 2.30 | 4.04 |
| #Nelfinavir 1250 mg 2 times a day, 14 days | #Nelfinavir 1250 mg 2 times a day, 14 days | 1.74 | 2.22 |
| #Grapefruit juice, 240 ml once a day* | 40 mg once daily | 1.37 | 1.16 |
| Diltiazem 240 mg once daily, 28 days | 40 mg once daily | 1.51 | 1.00 |
| Erythromycin 500 mg 4 times a day, 7 days | 10 mg once daily | 1.33 | 1.38 |
| Amlodipine 10 mg, single dose | 80 mg once daily | 1.18 | 0.91 |
| Cimetidine 300 mg 4 times a day, 2 weeks | 10 mg once daily for 2 weeks | 1.00 | 0.89 |
| Colestipol 10 g twice daily, 24 weeks | 40 mg once daily for 8 weeks | Not applicable | 0.74** |
| Maalox TC® 30 ml 4 times a day, 17 days | 10 mg once daily for 15 days | 0.66 | 0.67 |
| Efavirenz 600 mg once daily, 14 days | 10 mg for 3 days | 0.59 | 1.01 |
| #Rifampin 600 mg once daily, 7 days (when used concomitantly) † | 40 mg once daily | 1.12 | 2.90 |
#Rifampin 600 mg once daily, 5 days (in divided doses) † | 40 mg once daily | 0.20 | 0.60 | | #Gemfibrozil 600 mg twice daily, 7 days | 40 mg once daily | 1.35 | 1.00 |
| #Fenofibrate 160 mg once daily, 7 days | 40 mg once daily | 1.03 | 1.02 |
| #Boceprevir 800 mg 3 times a day, 7 days | 40 mg once daily | 2.32 | 2.66 |
& Treatment ratio (co-administration of the drug with atorvastatin compared to atorvastatin alone).
# For information on clinical significance, see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”.
* Larger increases in AUC (AUC ratio of 2.5) and/or Cmax (Cmax ratio of 1.71) have been reported with excessive consumption of grapefruit juice (750 ml - 1.2 liters per day or more).
**Ratio based on a single sample taken 8–16 h after dosing.
† Due to the dual interaction mechanism of rifampin, concomitant use of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after rifampin has been shown to be associated with a significant decrease in atorvastatin plasma concentrations.
‡ The dose of saquinavir + ritonavir in this study is not the clinically applicable dose. The increase in atorvastatin exposure in clinical use is likely to be greater than that observed in this study. Therefore, the drug should be used with caution and at the lowest dose necessary.
Effect of atorvastatin on the pharmacokinetics of concomitant medications
| Atorvastatin | Concomitant drug and dosage regimen | | |
| Drug/dose (mg) | AUC ratio | Cmax ratio | |
| 80 mg once daily for 15 days | Antipyrine 600 mg once | 1.03 | 0.89 |
| 80 mg once daily for 10 days | #Digoxin 0.25 mg once daily, 20 days | 1.15 | 1.20 |
| 40 mg once daily for 22 days | Oral contraceptives once daily, 2 months: norethisterone 1 mg; ethinylestradiol 35 mcg. | 1.28 1.19 | 1.23 1.30 |
| 10 mg once daily | Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days | 1.08 | 0.96 |
| 10 mg once daily for 4 days | Fosamprenavir 1400 mg twice daily, 14 days | 0.73 | 0.82 |
| 10 mg once daily for 4 days | Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days | 0.99 | 0.94 |
# For information on clinical significance, see section “Interaction with other medicinal products and other types of interactions”.
Indication
Prevention of cardiovascular disease in adults
For adult patients without clinically apparent coronary heart disease but with multiple risk factors for coronary heart disease, such as age, smoking, hypertension, low HDL, or a family history of early coronary heart disease, Lipitor is indicated for:
reducing the risk of myocardial infarction; reducing the risk of stroke; reducing the risk of revascularization procedures and angina.
For adult patients with type 2 diabetes mellitus and without clinically significant coronary heart disease, but with multiple risk factors for coronary heart disease, such as retinopathy, albuminuria, smoking or arterial hypertension, Liprimar is indicated for:
reducing the risk of myocardial infarction; reducing the risk of stroke.
For adult patients with clinically significant coronary heart disease, Liprimar is indicated for:
reduced risk of non-fatal myocardial infarction; reduced risk of fatal and non-fatal stroke; reduced risk of revascularization procedures; reduced risk of hospitalization for congestive heart failure; reduced risk of angina.
Hyperlipidemia
In adult patients
As an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides, and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).
As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to the Fredrickson classification).
For the treatment of patients with primary dysbetalipoproteinemia (type III according to the Fredrickson classification) in cases where diet is not effective enough.
To reduce total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g. LDL apheresis) or when such therapies are unavailable.
In children
LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or LDL cholesterol ≥ 160 mg/dL (4.14 mmol/L) and: there is a family history of early cardiovascular disease or two or more other risk factors for cardiovascular disease are present in the patient as a child.
Contraindication
Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology.
Hypersensitivity to any of the components of this medicinal product.
Pregnancy.
Lactation.
Interaction with other medicinal products and other types of interactions
The risk of myopathy during statin treatment is increased by concomitant use of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or potent inhibitors of cytochrome P450 3A4 (CYP 3A4) (e.g. clarithromycin, HIV and hepatitis C protease inhibitors, and itraconazole) (see sections 4.4 and 5.1).
Potent CYP 3A4 inhibitors. Liprimar is metabolized by cytochrome P450 3A4. Concomitant use of Liprimar with potent CYP 3A4 inhibitors may result in increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and potentiation is dependent on the variability of CYP 3A4 exposure. Concomitant use with potent CYP 3A4 inhibitors (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antivirals for the treatment of HCV (e.g. elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use of these drugs with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 3).
Moderate CYP 3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to evaluate the effects of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP 3A4 activity, and therefore, co-administration of these drugs with atorvastatin may result in increased exposure to atorvastatin. Therefore, lower maximum doses of atorvastatin should be considered when atorvastatin is co-administered with these moderate CYP 3A4 inhibitors and clinical monitoring of the patient should be considered. Clinical monitoring of the patient is also recommended after initiation of treatment with the inhibitor or after dose adjustment.
Grapefruit juice: Contains one or more components that inhibit CYP 3A4 and may increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (more than 1.2 liters per day).
Clarithromycin: Atorvastatin AUC was significantly increased when clarithromycin (500 mg twice daily) was co-administered with Lipitor 80 mg compared to Lipitor alone (see section 5.1). Therefore, Lipitor doses above 20 mg should be used with caution in patients taking clarithromycin (see sections 4.4 and 4.2).
Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when Liprimar® was co-administered with several protease inhibitor combinations (see section 5.1). Co-administration of Liprimar® with tipranavir + ritonavir or glecaprevir + pibrentasvir should be avoided in patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir. Liprimar should be used at the lowest dose necessary in patients taking lopinavir + ritonavir or simeprevir. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir or elbasvir + grazoprevir, the dose of Liprimar should not exceed 20 mg. When used in patients taking nelfinavir, the dose of Liprimar should not exceed 40 mg and close clinical monitoring of patients is recommended (see sections "Special instructions for use" and "Method of administration and dosage").
Cyclosporine. Atorvastatin is a substrate of hepatic transporters. Metabolites of atorvastatin are substrates of the OATP1B1 transporter. OATP1B1 inhibitors (e.g. cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin was significantly increased when Liprimar 10 mg was co-administered with cyclosporine 5.2 mg/kg/day compared to Liprimar alone (see section 5.1). Concomitant use of Liprimar and cyclosporine should be avoided (see section 4.4).
Letermovir: Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased exposure to atorvastatin (AUC ratio: 3.29) (see section 5.2).
Letepmovir is an inhibitor of the efflux transporters P-gp, BCRP, MRP2, OAT2 and the hepatic transporter OATP1B1/1B3, thus increasing the exposure of atorvastatin. The dose of Liprimar should not exceed 20 mg per day (see section 4.2).
The extent of CYP3A and OATP1B1/1B3-mediated drug interactions on concomitant medications may vary when letermovir is co-administered with cyclosporine. The use of Liprimar is not recommended in patients taking letermovir concomitantly with cyclosporine.
Glecaprevir and pibrentasvir, elbasvir and grazoprevir: Concomitant use of glecaprevir and pibrentavir or elbasvir and grazoprevir may result in increased plasma concentrations of atorvastatin and an increased risk of myopathy.
When glecaprevir and pibrentavir are co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partly due to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, concomitant use of Lipitor is not recommended in patients taking concomitant medications containing glecaprevir and pibrentasvir.
When elbasvir and grazoprevir are co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold, partly due to BCRP, OATP1B1/1B3 and CYP3A inhibition; therefore, the dose of Liprimar should not exceed 20 mg per day in patients receiving concomitant medicinal products containing elbasvir and grazoprevir (see sections 4.2 and 4.4).
Medical recommendations for the use of interacting drugs are summarized in Table 3 (see also sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacological properties”).
Drug interactions associated with increased risk of myopathy/rhabdomyolysis
| Interacting drugs | Medical recommendations for use |
| Cyclosporine, tipranavir + ritonavir, glecaprevir + pibrentasvir, letermovir when used concomitantly with cyclosporine | Avoid using atorvastatin |
| Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir | Do not exceed a dose of 20 mg of atorvastatin per day. |
| Nelfinavir | Do not exceed a dose of 40 mg of atorvastatin per day. |
| Lopinavir + ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine | Use with caution and in the lowest dose necessary. |
* Use in the smallest dose necessary.
Gemfibrozil: Due to the increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the concomitant use of Liprimar with gemfibrozil should be avoided (see section 4.4).
Other fibrates: Since the risk of myopathy during treatment with HMG-CoA reductase inhibitors is known to be increased by concomitant administration of other fibrates, Lipitor should be used with caution when co-administered with other fibrates (see section 4.4).
Niacin: The risk of skeletal muscle adverse events may be increased when used in combination with niacin, and therefore, in such conditions, a reduction in the dose of Lipitor should be considered (see section 4.4).
Rifampin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampin) may result in an unstable decrease in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampin, concomitant use of Liprimar with rifampin is recommended, as delayed administration of the drug after rifampin administration has been shown to be associated with a significant decrease in atorvastatin plasma concentrations.
Diltiazem hydrochloride.
Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.
Cimetidine.
As a result of the conducted studies, no signs of interaction between atorvastatin and cimetidine were detected.
Antacids.
Simultaneous oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide is accompanied by a decrease in the concentration of atorvastatin in the blood plasma by approximately 35%. The hypolipidemic effect of atorvastatin was not changed.
Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when atorvastatin and colestipol were coadministered. The lipid-lowering effect of the combination of atorvastatin and colestipol was greater than that of either drug alone.
Azithromycin.
Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not accompanied by changes in atorvastatin plasma concentrations.
Transport inhibitors.
Transporter protein inhibitors (e.g. cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of storage transporters on atorvastatin concentrations in liver cells is unknown. If co-administration cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).
Ezetimibe.
The use of ezetimibe as monotherapy has been associated with the development of muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is recommended.
Fusidic acid.
Concomitant systemic administration of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatalities) have been reported in patients receiving the combination of these drugs.
If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the entire period of fusidic acid administration (see section 4.4).
Digoxin.
When multiple doses of Lipitor are administered simultaneously with digoxin, steady-state plasma concentrations of digoxin are increased (see Pharmacokinetics). Patients taking digoxin should be monitored closely.
Oral contraceptives.
Concomitant use of Liprimar with oral contraceptives increased the AUC values for norethisterone and ethinylestradiol (see section 5.1). These increases should be taken into account when choosing an oral contraceptive for a woman taking Liprimar.
Warfarin.
Liprimar had no clinically significant effect on prothrombin time in patients receiving long-term warfarin treatment.
Colchicine.
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin should be prescribed with caution with colchicine.
Other medicines.
Clinical studies have shown that the simultaneous use of atorvastatin and antihypertensive drugs and its use during estrogen replacement therapy was not accompanied by clinically significant side effects. Interaction studies with other drugs have not been conducted.
Application features
Skeletal muscles
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Liprimar and other drugs of this class. A history of renal impairment may be a risk factor for rhabdomyolysis. Such patients should be monitored closely for skeletal muscle disorders.
Atorvastatin, like other statins, has occasionally been associated with myopathy, defined as muscle pain or weakness in association with an elevation of creatine phosphokinase (CPK) >10 times the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain drugs, such as cyclosporine and potent CYP 3A4 inhibitors (e.g. clarithromycin, itraconazole, and HIV and hepatitis C protease inhibitors), increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use. IMMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy reveals necrotizing myopathy without significant inflammation; and positive dynamics are observed with the use of immunosuppressive agents.
The risk of myopathy with this class of drugs is increased by concomitant use of the drugs listed in Table 3. Physicians considering the combination of Lipitor and any of these drugs should carefully weigh the potential benefits and risks and monitor patients closely for any signs of muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any up-titration periods for either drug. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above drugs (see Interactions). Periodic monitoring of CPK may be considered in such situations, but there is no guarantee that such monitoring will prevent severe myopathy.
Lipitor therapy should be temporarily or permanently discontinued in any patient with an acute, serious condition suggestive of myopathy or in the presence of a risk factor for renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine and electrolyte disturbances, and uncontrolled seizures).
Liver dysfunction
Statins, like some other lipid-lowering agents, have been associated with abnormal liver function tests. Persistent elevations (>3 times the upper limit of normal, occurring on two or more occasions) of serum transaminases were observed in 0.7% of patients treated with Lipitor in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for the 10, 20, 40, and 80 mg doses, respectively.
During clinical trials, one patient developed jaundice. Elevated liver function tests (LFTs) in other patients were not associated with jaundice or other clinical symptoms. After dose reduction, interruption, or discontinuation of the drug, transaminase levels returned to or near pretreatment levels without adverse effects. 18 of 30 patients with persistent elevations in liver function tests continued treatment with Liprimar at lower doses.
It is recommended that liver enzyme tests be obtained before initiating therapy with Lipitor and repeated as clinically indicated. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients treated with statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during the use of Lipitor, treatment should be discontinued immediately. Unless an alternative etiology is identified, Lipitor should not be restarted.
Liprimar should be used with caution in patients who abuse alcohol and/or have a history of liver disease. Liprimar is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").
Endocrine function
Increases in HbA1c and fasting serum glucose have been reported with HMG-CoA reductase inhibitors, including Lipitor.
Statins inhibit cholesterol synthesis and theoretically may weaken the
