Instructions for use Liprimar film-coated tablets 20 mg blister No. 30
Composition
active ingredient: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to 10 mg or 20 mg, or 40 mg, or 80 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”, “20”, “40” or “80” on one side and “ATV”, “ATV”, “ATV”, “ATV” on the other for 10 mg, 20 mg, 40 mg and 80 mg tablets, respectively.
Pharmacotherapeutic group
Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.
Pharmacological properties
Pharmacodynamics.
Liprimar® 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®, as well as some of its metabolites, are pharmacologically active in humans. The main 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 excreted 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 active metabolites. After oral administration, less than 2% of the dose is excreted in the urine.
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 Liprimar® 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®, as 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 values 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 values 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.
Table 1
Effect of concomitant medications on the pharmacokinetics of atorvastatin
| Concomitant medications and dosage regimen | Atorvastatin |
| Dose (mg) | Correlation AUC& | Correlation Cmax& |
| #Cyclosporin 5.2 mg/kg/day, stable dose | 10 mg once daily for 28 days | 8.69 | 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 | 10 mg once daily for 28 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.
Table 2
Effect of atorvastatin on the pharmacokinetics of concomitant medications
| Atorvastatin | Concomitant drug and dosage regimen |
| Drug/dose (mg) | Correlation AUC | Correlation Cmax |
| 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”.
The use of Liprimar® had no clinically significant effect on prothrombin time in patients receiving long-term warfarin treatment.
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:
reducing the risk of non-fatal myocardial infarction;
reducing the risk of fatal and non-fatal stroke;
reducing the risk of revascularization procedures;
reducing the risk of hospitalization due to congestive heart failure;
reducing the risk of angina pectoris.
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.
As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B levels in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if, after appropriate diet therapy, the test results are as follows:
a) LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or
b) LDL cholesterol ≥ 160 mg/dL (4.14 mmol/L) and:
family history of early cardiovascular disease or
two or more other risk factors for cardiovascular disease are present in the pediatric patient.
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
Liprimar® is a substrate of CYP3A4 and transporters (e.g. OATP1B1/1B3, P-gp or BCRP). Plasma levels of Liprimar® may be significantly increased by concomitant use of inhibitors of CYP3A4 and transporters. Table 3 lists drugs that may increase Liprimar® exposure and the risk of myopathy and rhabdomyolysis with concomitant use, and recommendations for their treatment and prevention of such risks (see sections 4.4 and 5.1).
Table 3
Interactions with other drugs that may increase the risk of myopathy and rhabdomyolysis when using Liprimar®
| Cyclosporine or gemfibrozil |
| Clinical impact | Plasma levels of atorvastatin were significantly increased when Liprimar® was co-administered with cyclosporine, an inhibitor of CYP3A4 and OATP1B1 (see section 5.1). Monotherapy with gemfibrozil may cause myopathy. There is an increased risk of myopathy and rhabdomyolysis when cyclosporine or gemfibrozil are co-administered with Liprimar®. |
| Activities | Concomitant use of cyclosporine or gemfibrozil with Lipitor® is not recommended. |
| Antivirals |
| Clinical impact | Atorvastatin plasma levels were significantly increased when Liprimar® was co-administered with many antiviral agents that are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) (see section 5.1). Myopathy and rhabdomyolysis have been reported with the concomitant use of the combination of ledipasvir + sofosbuvir with Liprimar®. |
| Activities | The simultaneous use of the combination of tipranavir + ritonavir or glecaprevir + pibrentasvir with Lipitor® is not recommended. In patients receiving lopinavir + ritonavir or simeprevir, the benefit/risk of co-administration with atorvastatin should be assessed. In patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir or letermovir, the dose of Liprimar® should not exceed 20 mg. In patients receiving nelfinavir, the dose of Liprimar® should not exceed 40 mg (see section “Method of administration and dosage”). The benefit/risk of concomitant use of the combination of ledipasvir + sofosbuvir with Lipitor® should be assessed. All patients should be monitored for signs and symptoms of myopathy, especially at the beginning of treatment and during dose increases of any drug. |
| Examples | Tipranavir + ritonavir, glecaprevir + pibrentasvir, lopinavir + ritonavir, simeprevir, saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir, nelfinavir, and ledipasvir + sofosbuvir. |
| Certain azole antifungals or macrolide antibiotics |
| Clinical impact | Plasma levels of atorvastatin were significantly increased when Liprimar was co-administered with certain azole antifungals or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters (see section 5.1). |
| Activities | In patients receiving clarithromycin or itraconazole, the dose of Liprimar® should not exceed 20 mg (see section "Dosage and Administration"). The benefit/risk of concomitant use of individual azole antifungals or macrolide antibiotics with Liprimar® should be assessed. All patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of any drug. |
| Examples | Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. |
| Niacin |
| Clinical impact | Cases of myopathy and rhabdomyolysis have been observed with the simultaneous use of lipid-modifying doses of niacin (> 1 g/day of niacin) with the drug Lipitor®. |
| The benefit of concomitant use of lipid-modifying doses of niacin with Liprimar® should be weighed against the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided upon, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug. |
| Fibrates (except gemfibrozil) |
| Clinical impact | The use of fibrates as monotherapy can cause myopathy. The risk of myopathy and rhabdomyolysis is increased when fibrates are used concomitantly with Lipitor®. |
| Activities | The benefit of concomitant use of fibrates with Lipitor should be weighed against the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided upon, patients should be monitored for signs and symptoms of myopathy, particularly at the start of therapy and during dose increases of either drug. |
| Colchicine |
| Clinical impact | Cases of myopathy and rhabdomyolysis have been observed during the concomitant use of colchicine with Lipitor®. |
| Activities | The benefits/risks of concomitant use of colchicine with Lipitor® should be weighed. If a decision is made to co-administer, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug. |
| Grapefruit juice |
| Clinical impact | Consumption of grapefruit juice, especially in large quantities (more than 1.2 liters per day), may lead to increased plasma levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis. |
| Activities | Consumption of large amounts of grapefruit juice (more than 1.2 liters per day) should be avoided while taking Lipitor®. |
Table 4
Interaction with drugs that may reduce exposure to Liprimar®
| Rifampicin |
| Clinical impact | Concomitant use of Liprimar® with rifampicin, an inducer of cytochrome P450 3A4 and an inhibitor of OATP1B1, may result in an unstable decrease in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, delayed administration of Liprimar® after administration of rifampicin has been associated with a significant decrease in atorvastatin plasma concentrations. |
| Activities | Concomitant use of Liprimar® and rifampicin is recommended. |
Table 5
Effect of Liprimar® on other medicinal products
| Oral contraceptives |
| Clinical impact | Concomitant use of Lipitor® and oral contraceptives increased the plasma concentrations of norethisterone and ethinyl estradiol (see section "Pharmacological properties"). |
| Activities | This fact should be taken into account when choosing an oral contraceptive for patients taking Lipitor®. |
| Digoxin |
| Clinical impact | With simultaneous use of multiple doses of Lipitor® and digoxin, the equilibrium plasma concentrations of digoxin increase (see section "Pharmacological properties"). |
| Activities | Patients taking digoxin should be monitored appropriately. |
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.
Colestipol.
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.
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).
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
Myopathy and rhabdomyolysis
Lipitor® can cause myopathy (muscle pain, tenderness, or weakness associated with an elevation of creatine kinase (CK) greater than 10 times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare cases of fatal rhabdomyolysis have been reported with statins, including Lipitor®.
Risk factors for developing myopathy
Risk factors for the development of myopathy include age 65 years and older, uncontrolled hypothyroidism, impaired renal function, concomitant use with certain other drugs, and increased doses of Lipitor® (see section “Interaction with other medicinal products and other types of interactions”).
Measures to reduce or prevent the risk of myopathy and rhabdomyolysis
Exposure to Liprimar® may be increased by interactions with other medicinal products through inhibition of the cytochrome P450 3A4 enzyme (CYP3A4) and/or transporters (e.g., breast cancer resistance protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3], and P-glycoprotein [P-gp]), leading to an increased risk of myopathy and rhabdomyolysis. Concomitant use of ciclosporin, gemfibrozil, tipranavir + ritonavir, or glecaprevir + pibrentasvir with Liprimar® is not recommended. Dosage adjustments of Liprimar® are recommended in patients taking certain antivirals, azole antifungals, or macrolide antibiotics (see section 4.2). Myopathy/rhabdomyolysis has been reported with concomitant use of atorvastatin with lipid-modifying doses (> 1 g/day) of niacin, fibrates, colchicine, and the combination of ledipasvir + sofosbuvir. It should be assessed whether the benefit of using these drugs outweighs the increased risk of myopathy and rhabdomyolysis (see section 4.5).
The simultaneous intake of grapefruit juice in large quantities (more than 1.2 liters per day) is not recommended for patients taking Lipitor® (see section “Interaction with other medicinal products and other types of interactions”).
Lipitor® should be discontinued if markedly elevated CK levels are observed or myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve after Lipitor® is discontinued. Lipitor® should be temporarily discontinued in patients with acute or serious conditions at high risk of developing renal failure due to rhabdomyolysis (e.g. sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disturbances; uncontrolled epilepsy).
Patients should be informed of the risk of myopathy and rhabdomyolysis when initiating treatment or increasing the dose of Liprimar®. Patients should be advised to report immediately any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.
Immunologically mediated necrotizing myopathy
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive HMG-CoA reductase antibodies; muscle biopsy reveals necrotizing myopathy and improvement with immunosuppressant therapy. Additional neuromuscular and serological studies may be necessary. Immunosuppressant therapy may be required. The risk of IMNM should be carefully weighed before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.
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 2 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, treatment with the drug should not be restarted.
Liprimar® should be administered with caution to 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 reduce adrenal steroid secretion and/or gonadal steroid secretion. Clinical studies have shown that Lipitor® does not reduce basal plasma cortisol concentrations or impair adrenal reserve. The effect of statins on sperm fertilisation has not been studied in a sufficient number of patients. It is not known how, or if, the drug affects the gonadal-pituitary-hypothalamic system in premenopausal women. Caution should be exercised when co-administering statins with medicinal products that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Use in patients with recent stroke or transient ischemic attack
In a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which Lipitor® 80 mg was administered versus placebo to 4,731 patients without coronary heart disease and who had a history of stroke or transient ischemic attack within the previous 6 months, a higher incidence of hemorrhagic stroke was observed in the Lipitor® 80 mg group compared to the placebo group (55 cases, 2.3% in the atorvastatin group compared to 33 cases, 1.4% in the placebo group; HR: 1.68, 95% CI: 1.09, 2.59; p=0.001).
