INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASTPIN 10 VASTPIN 20 VASTPIN 40 (VASTPIN 10 VASTPIN 20 VASTPIN 40)

Composition:

Active ingredient: atorvastatin;

1 tablet contains atorvastatin calcium trihydrate equivalent to 10 mg or 20 mg or 40 mg of atorvastatin;

Excipients: calcium carbonate; lactose monohydrate; microcrystalline cellulose (PH101); sodium croscarmellose; Tween 80; hydroxypropylcellulose; purified water; microcrystalline cellulose (PH102); lactose monohydrate DCL-11; magnesium stearate;

Tablet coating: Sheff Coat White PVA (5Y00122), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex film-coated tablets, white to almost white, with an engraving "AT" on one side and "10", "20", "40" on the other side for 10 mg, 20 mg, and 40 mg tablets, respectively.

Pharmacotherapeutic group. Agents that lower serum cholesterol and triglycerides. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological Properties

Pharmacodynamics

Vastpin is a synthetic hypolipidemic medicinal product. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the conversion of HMG-CoA to mevalonate — the initial and rate-limiting step in cholesterol biosynthesis.

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the enzyme responsible for the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols including cholesterol.

In animal experimental models, atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis, and by increasing the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, thereby enhancing the uptake and catabolism of LDL. Atorvastatin also reduces the production of LDL and the number of LDL particles.

Atorvastatin, as well as some of its metabolites, is pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which plays a central role in cholesterol synthesis and clearance of LDL. The drug dose, rather than systemic drug concentration, correlates better with the reduction in LDL cholesterol levels. Individual dose titration should be based on therapeutic response (see section "Dosage and administration").

Pharmacokinetics

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentration (Cmax) reached within 1–2 hours. The extent of absorption increases proportionally with the dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic availability of atorvastatin is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as measured by Cmax and area under the concentration-time curve (AUC), the reduction in LDL cholesterol (LDL-C) levels is similar when the drug is taken with or without food. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% lower for both Cmax and AUC) compared to morning dosing. However, the reduction in LDL-C levels is similar regardless of the time of administration (see section "Dosage and administration").

Distribution. The mean volume of distribution of atorvastatin is approximately 381 liters. Over 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, atorvastatin is considered capable of passing into breast milk (see sections "Contraindications" and "Special warnings and precautions for use").

Metabolism. Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies show that the ortho- and para-hydroxylated metabolites exhibit HMG-CoA reductase inhibition equivalent to that of the parent drug. Approximately 70% of the circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that atorvastatin metabolism is primarily mediated by cytochrome P450 3A4 (CYP3A4), consistent with increased plasma concentrations of atorvastatin in humans when co-administered with erythromycin, a known inhibitor of this isoenzyme (see section "Interaction with other medicinal products and other forms of interaction").

Excretion. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism. However, this drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours, while the half-life of HMG-CoA reductase inhibitory activity ranges from 20 to 30 hours due to the contribution of active metabolites. Less than 2% of an orally administered dose is excreted in urine.

Special patient populations

Elderly patients. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly volunteers (aged 65 years and older) compared to younger adults. Clinical data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger patients (see section "Special warnings and precautions for use").

Children. Apparent oral clearance of atorvastatin in children was found to be similar to that in adults when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin, based on data from an open 8-week study in children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Gender. Atorvastatin plasma concentrations in women differ from those in men (approximately 20% higher Cmax and 10% lower AUC). However, there is no clinically significant difference in LDL cholesterol reduction between men and women when the drug is administered.

Renal impairment. Renal disease does not affect atorvastatin plasma concentrations or LDL-C reduction; therefore, dose adjustment in patients with renal impairment is not required (see sections "Special warnings and precautions for use" and "Dosage and administration").

Hemodialysis. Although no studies have been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance atorvastatin clearance due to the drug's extensive plasma protein binding.

Hepatic impairment. Atorvastatin plasma concentrations 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 section "Contraindications").

Drug interaction studies. Atorvastatin is a substrate of hepatic transporters OATP1B1 and OATP1B3. Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also 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 concomitantly administered drugs on the pharmacokinetics of atorvastatin

Concomitantly administered drugs and dosing regimen	Atorvastatin
	Dose (mg)	Ratio AUC&	Ratio Cmax&
#Cyclosporine 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 twice daily, 14 days	10 mg once daily for 28 days	1.74	2.22
#Grapefruit juice, 240 ml once daily*	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 four times daily, 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 four times daily, 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 four times daily, 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
#Rifampicin 600 mg once daily, 7 days (co-administered) †	40 mg once daily	1.12	2.90
#Rifampicin 600 mg once daily, 5 days (separate 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 three times daily, 7 days	40 mg once daily	2.32	2.66

& Comparison by treatment methods (co-administration of the medicinal product with atorvastatin versus atorvastatin administered alone).

For information on clinical significance, see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".

* Greater increases in AUC (AUC ratio up to 2.5) and/or Cmax (Cmax ratio up to 1.71) have been reported with excessive consumption of grapefruit juice (750 mL – 1.2 L per day or more).

** Ratios based on single samples taken 8–16 hours after dose administration.

† Due to the dual interaction mechanism of rifampicin, co-administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin following rifampicin intake has been shown to be associated with a significant reduction in atorvastatin plasma concentrations.

‡ The dose combination of saquinavir + ritonavir used in this study is not a clinically applicable dose. The increase in atorvastatin exposure under clinical use conditions is likely to be higher than that observed in this study. Therefore, the medicinal product should be used with caution and at the lowest necessary dose.

Table 2

Effect of atorvastatin on the pharmacokinetics of concurrently administered medicinal products

Atorvastatin	Concomitantly administered medicinal product and dosing regimen
	Drug/dose (mg)	Ratio AUC	Ratio Cmax
80 mg once daily for 15 days	Antipyrine 600 mg single dose	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 forms of interaction".

The use of atorvastatin had no clinically significant effect on prothrombin time in patients receiving long-term warfarin therapy.

Clinical Characteristics

Indications

Prevention of Cardiovascular Disease in Adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for developing ischemic heart disease, such as age, smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) cholesterol, or a family history of premature ischemic heart disease, the medicinal product Vastpin 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 evident ischemic heart disease, but with multiple risk factors for developing ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the medicinal product Vastpin is indicated for:

• reducing the risk of myocardial infarction;
• reducing the risk of stroke.

For adult patients with clinically evident ischemic heart disease, the medicinal product 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.

Hyperlipidemia

In Adults

• As an adjunct to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and to increase high-density lipoprotein cholesterol (HDL-C) levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification).
• As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification).
• For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification) when dietary measures are insufficient.
• To reduce total cholesterol and LDL-C 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

• As an adjunct to diet to reduce levels of total cholesterol, LDL-C, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy laboratory results are as follows:

a) LDL-C remains ≥ 190 mg/dL (4.91 mmol/L), or

b) LDL-C ≥ 160 mg/dL (4.14 mmol/L) and

• there is a family history of premature cardiovascular disease, or
• two or more other cardiovascular risk factors are present in the pediatric patient.

Contraindications

• Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology.
• Hypersensitivity to any component of this medicinal product.
• Pregnancy.
• Lactation.

Interaction with Other Medicinal Products and Other Forms of Interaction

Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-glycoprotein (P-gp), or BCRP). Plasma levels of atorvastatin may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Table 3 lists medicinal products that may increase exposure to atorvastatin and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for managing and preventing such risks (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Table 3

Interaction with other medicinal products that may increase the risk of myopathy and rhabdomyolysis during atorvastatin use

Cyclosporine or gemfibrozil
Clinical effect	Plasma levels of atorvastatin were significantly increased when atorvastatin was co-administered with cyclosporine, an inhibitor of CYP3A4 and OATP1B1 (see section "Pharmacological properties"). Monotherapy with gemfibrozil may cause myopathy. The risk of developing myopathy and rhabdomyolysis is increased when cyclosporine or gemfibrozil is used concomitantly with atorvastatin.
Precautions	Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended.
Antiviral agents
Clinical effect	Plasma levels of atorvastatin were significantly increased when atorvastatin 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 "Pharmacological properties"). Cases of myopathy and rhabdomyolysis have been reported with concomitant use of the combination ledipasvir + sofosbuvir and atorvastatin.
Precautions	Concomitant use of the combination tipranavir + ritonavir or glecaprevir + pibrentasvir with atorvastatin is not recommended. In patients receiving lopinavir + ritonavir or simeprevir, the benefit/risk of concomitant use with atorvastatin should be evaluated. In patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, or letermovir, the atorvastatin dose should not exceed 20 mg. In patients receiving nelfinavir, the atorvastatin dose should not exceed 40 mg (see section "Dosage and administration"). The benefit/risk of concomitant use of the combination ledipasvir + sofosbuvir with atorvastatin should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the start of treatment and during dose escalation 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.
Specific azole antifungals or macrolide antibiotics
Clinical effect	Plasma levels of atorvastatin were significantly increased when atorvastatin was co-administered with specific azole antifungals or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters (see section "Pharmacological properties").
Precautions	In patients receiving clarithromycin or itraconazole, the atorvastatin dose should not exceed 20 mg (see section "Dosage and administration"). The benefit/risk of concomitant use of specific azole antifungals or macrolide antibiotics with atorvastatin should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the start of therapy and during dose escalation of any drug.
Examples	Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical effect	Cases of myopathy and rhabdomyolysis have been observed when lipid-modifying doses of niacin (>1 g/day of niacin) were used concomitantly with atorvastatin.
Precautions	Consider whether the benefit of concomitant use of lipid-modifying doses of niacin with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose escalation of either drug.
Fibrates (other than gemfibrozil)
Clinical effect	Use of fibrates as monotherapy may cause myopathy. The risk of developing myopathy and rhabdomyolysis increases when fibrates are used concomitantly with atorvastatin.
Precautions	Consider whether the benefit of concomitant use of fibrates with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose escalation of either drug.
Colchicine
Clinical effect	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of colchicine and atorvastatin.
Precautions	The benefit/risk of concomitant use of colchicine with atorvastatin should be considered. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose escalation of either drug.
Daptomycin
Clinical effect	Cases of myopathy and/or rhabdomyolysis have been observed with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin.
Precautions	If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions for use").
Grapefruit juice
Clinical effect	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 developing myopathy and rhabdomyolysis.
Precautions	Consumption of large quantities of grapefruit juice (more than 1.2 liters per day) should be avoided during atorvastatin therapy.

Table 4

Interaction with medicinal products that may reduce atorvastatin exposure

Rifampicin
Clinical effect	Concomitant use of atorvastatin with rifampicin, a cytochrome P450 3A4 inducer and OATP1B1 inhibitor, may result in variable reduction in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, delayed administration of atorvastatin after rifampicin dosing has been associated with a significant reduction in atorvastatin plasma concentrations.
Management	Concomitant administration of atorvastatin and rifampicin is recommended.

Table 5

Effect of atorvastatin on other medicinal products

Oral contraceptives
Clinical effect	Concomitant administration of atorvastatin and oral contraceptives increases plasma concentrations of norethisterone and ethinylestradiol (see section "Pharmacological properties").
Precautions	This fact should be taken into account when selecting an oral contraceptive for patients taking atorvastatin.
Digoxin
Clinical effect	Concomitant administration of multiple doses of atorvastatin and digoxin increases the steady-state plasma concentration of digoxin (see section "Pharmacological properties").
Precautions	Patients taking digoxin should be appropriately monitored.

Diltiazem hydrochloride

Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) results in increased plasma concentrations of atorvastatin.

Cimetidine

Studies have shown no evidence of interaction between atorvastatin and cimetidine.

Antacids

Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminium hydroxide is associated with approximately a 35% reduction in atorvastatin plasma concentration. However, the hypolipidemic effect of atorvastatin remains unchanged.

Cholestyramine

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when administered concomitantly with cholestyramine. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and cholestyramine exceeds the effect achieved with either agent alone.

Azithromycin

Concomitant use of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentrations.

Transport inhibitors

Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The impact of inhibition of uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant use of these agents cannot be avoided, dose reduction of atorvastatin and clinical monitoring of efficacy are recommended (see Table 1).

Ezetimibe

Ezetimibe monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, concomitant use of ezetimibe and atorvastatin may increase the risk of such events. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid

Concomitant systemic use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic fusidic acid therapy is required, atorvastatin should be discontinued for the duration of fusidic acid treatment (see section "Special precautions").

Other medicinal products

Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents or during estrogen replacement therapy is not associated with clinically significant adverse reactions. Interactions with other drugs have not been studied.

Special precautions for use

Myopathy and rhabdomyolysis

Atorvastatin may cause myopathy (muscle pain, tenderness or weakness in combination with elevated creatine kinase (CK) more than 10 times the upper limit of normal (ULN)) and rhabdomyolysis (with or without acute renal failure due to myoglobinuria). Rare fatal cases of rhabdomyolysis have been reported with statins, including atorvastatin.

Myopathy risk factors

Risk factors for myopathy include age 65 years and older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other medications, and higher doses of atorvastatin (see section "Interaction with other medicinal products and other forms of interaction").

Measures to reduce or prevent the risk of myopathy and rhabdomyolysis

Exposure to atorvastatin may increase due to 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-gp), leading to an increased risk of myopathy and rhabdomyolysis. Concomitant use with atorvastatin is not recommended for cyclosporine, gemfibrozil, the combination of tipranavir + ritonavir, or glecaprevir + pibrentasvir. Dose modifications of atorvastatin are recommended for patients taking certain antiviral agents, azole antifungals, or macrolide antibiotics (see section "Method of administration and dosage"). Cases of myopathy/rhabdomyolysis have been reported with concomitant use of atorvastatin and lipid-modifying doses (>1 g/day) of niacin, fibrates, colchicine, and the combination of ledipasvir + sofosbuvir. The benefit of using these agents should be weighed against the increased risk of myopathy and rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant intake of large quantities of grapefruit juice (more than 1.2 liters per day) is not recommended for patients taking atorvastatin (see section "Interaction with other medicinal products and other forms of interaction").

Discontinue the drug if markedly elevated CK levels are observed or if myopathy is diagnosed or suspected. Muscle symptoms and elevated CK resolve after discontinuation of atorvastatin. Temporarily discontinue the drug in patients with acute or serious conditions at high risk of 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 at the start of treatment or when increasing the dose. Patients should be advised to immediately report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Immune-mediated necrotizing myopathy

Rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, have been reported. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological testing may be required. Immunosuppressive therapy may be needed. The risk of IMNM should be carefully considered before initiating another statin. If another statin is started, monitoring for signs and symptoms of IMNM is necessary.

In isolated cases, statins have been reported to induce de novo or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, discontinue the drug. Recurrences have been reported upon re-administration of the same or another statin.

Hepatic function

Statins, like some other lipid-lowering therapeutic agents, have been associated with abnormalities in liver function tests. Persistent elevations (more than 3 times the ULN occurring on two or more occasions) of serum transaminases were observed in 0.7% of patients treated with the drug in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg doses, respectively.

During clinical trials, jaundice developed in one patient. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to pre-treatment levels or near those levels after dose reduction, treatment interruption, or discontinuation, without adverse consequences. Eighteen of 30 patients with persistent elevations in liver function tests continued treatment with the drug at lower doses.

Liver enzyme tests should be obtained before starting therapy and repeated as clinically indicated. Rare post-marketing reports of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. Treatment should be immediately discontinued if serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment. Reinitiation of treatment with the drug should not be attempted if no alternative etiology is identified.

The drug should be used with caution in patients who abuse alcohol and/or have a history of liver disease. The drug is contraindicated in patients with active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").

Endocrine function

Elevations in HbA1c and fasting plasma glucose levels have been reported with HMG-CoA reductase inhibitors, including this drug.

Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects or has any effect on the "gonadal-pituitary-hypothalamus" system in premenopausal women. Caution should be exercised when concomitantly using statin drugs with medicinal products that may reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use of atorvastatin in patients with recent stroke or transient ischemic attack (TIA)

In a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which 4731 patients without ischemic heart disease but with a history of stroke or TIA within the previous 6 months were treated with atorvastatin 80 mg versus placebo, a higher incidence of hemorrhagic stroke was observed in the atorvastatin 80 mg group compared to the placebo group (55 cases, 2.3% in the atorvastatin group versus 33 cases, 1.4% in the placebo group; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) compared to the placebo group (16, 0.7%). Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

Among 39,828 patients who received atorvastatin in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients, nor were there differences in treatment response between elderly and younger patients according to other clinical experience; however, increased sensitivity in some elderly patients cannot be ruled out. Since advanced age (over 65 years) is a predisposing factor for myopathy, the drug should be used with caution in elderly patients.

Hepatic impairment

Atorvastatin is contraindicated in patients with active liver disease, including persistent elevations of hepatic transaminases of unknown etiology (see sections "Pharmacological properties" and "Contraindications").

Before starting treatment

Atorvastatin should be used with caution in patients predisposed to rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CK levels should be measured in the following cases:

• renal impairment;
• hypothyroidism;
• family or personal history of hereditary muscle disorders;
• previous history of statin or fibrate myotoxicity;
• previous history of liver disease and/or alcohol abuse.

For elderly patients (aged 70 years or older), the need for these measures should be evaluated considering the presence of other predisposing factors for rhabdomyolysis.

Increased plasma levels of the drug are possible, particularly due to interactions (see section "Interaction with other medicinal products and other forms of interaction") and use in special patient populations (see section "Pharmacological properties"), including patients with hereditary diseases.

In such cases, the risk-benefit ratio of treatment should be evaluated, and clinical monitoring of patients is recommended. If CK levels are markedly elevated before treatment initiation (exceeding ULN by more than 5 times), treatment should not be started.

Measurement of creatine kinase levels

CK levels should not be measured after strenuous physical exertion or in the presence of any possible alternative causes of elevated CK, as this may complicate interpretation of results. If markedly elevated CK (exceeding ULN by more than 5 times) is observed at baseline, repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

Patients should be informed of the need to immediately report muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during atorvastatin treatment, CK levels should be measured. If CK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should be discontinued.

The need to discontinue treatment should also be considered if CK elevation does not reach fivefold ULN but muscle symptoms are severe and cause daily discomfort.

After symptom resolution and normalization of CK levels, resumption of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and careful patient monitoring is maintained.

Atorvastatin treatment must be discontinued if clinically significant elevation of CK (exceeding ULN by more than 10 times) is observed or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentration. Examples include potent inhibitors of CYP3A4 or transport proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the telaprevir/ritonavir combination. If possible, alternative medicinal products (that do not interact with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant treatment with atorvastatin and the mentioned drugs is necessary, the benefit and risk should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma concentration, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. Statin therapy should be suspended for the entire duration of systemic fusidic acid treatment in patients for whom systemic fusidic acid is considered necessary. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if symptoms of muscle weakness, pain, or tenderness occur.

Statin therapy may be resumed 7 days after the last dose of fusidic acid.

Under exceptional circumstances, when long-term systemic fusidic acid treatment is required (e.g., for treatment of severe infections), the need for concomitant use of the drug and fusidic acid should be considered only on an individual basis and under strict medical supervision.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consider temporary discontinuation of the drug in patients receiving daptomycin unless the benefit of concomitant use outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with some statins, particularly during long-term treatment. Manifestations may include dyspnea, non-productive cough, and general deterioration in health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Excipients

The drug contains lactose. This drug should not be taken by patients with rare hereditary conditions associated with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Lipid-modifying drug therapy should be part of a comprehensive treatment approach for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Pharmacological therapy is recommended as an adjunct to diet when dietary restriction of saturated fat and cholesterol and other non-pharmacological measures have been insufficient. Patients with ischemic heart disease or multiple risk factors for ischemic heart disease may initiate the drug concurrently with dietary measures.

Limitations of use

Atorvastatin has not been studied under conditions where the primary lipoprotein abnormality was elevated chylomicrons (types I and V according to Fredrickson classification).

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

Atorvastatin is contraindicated in pregnant women, as its safety in pregnancy has not been established and there is no clear benefit of lipid-lowering drugs during pregnancy. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may have a harmful effect on the fetus. The drug should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

The background risk of major congenital malformations and miscarriage for the indicated population is unknown. In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Contraception

Atorvastatin may harm the fetus if used during pregnancy. Women of childbearing potential should be informed of the need for effective contraception during treatment with this drug.

Clinical data

Limited published data from observational studies, meta-analyses, and clinical cases on the use of calcium atorvastatin did not show an increased risk of major congenital malformations or miscarriage.

Rare reports of congenital anomalies have been reported after intrauterine exposure to other HMG-CoA reductase inhibitors. Prospective monitoring of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the rates of fetal congenital anomalies, miscarriages, and intrauterine deaths/stillbirths did not exceed those expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal developmental anomalies compared to the background rate. In 89% of the pregnant women monitored prospectively, treatment with the drug was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of atorvastatin on the breastfed child or on lactation. It is unknown whether atorvastatin passes into human milk, but it has been shown that another drug in this class enters breast milk; atorvastatin is present in rat milk. Since statins may potentially cause serious adverse reactions in breastfed infants, women requiring treatment with the drug should not breastfeed (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery

The medicinal product has a negligible influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Hyperlipidemia and Mixed Dyslipidemia

The recommended initial dose of atorvastatin is 10 or 20 mg once daily. For patients requiring a large reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of the drug is from 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day, independent of food intake. Initial and maintenance doses should be individually adjusted according to treatment goals and patient response. After initiation of treatment and/or dose titration, lipid levels should be analyzed within 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Aged 10 to 17 Years)

The recommended initial dose of the drug is 10 mg/day. The usual dosage range is 10 to 20 mg orally once daily. Doses should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

The dosage of the drug for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg daily. The medicinal product should be used as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such lipid-lowering treatments are unavailable.

Concomitant Lipid-Lowering Therapy

Atorvastatin may be used concomitantly with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be prescribed with caution (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Dosing in Patients with Renal Impairment

Renal disease does not affect plasma concentrations or LDL-C reduction with the use of the drug; therefore, dose adjustment in patients with renal impairment is not required (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Dosing in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors

The use of atorvastatin should be avoided in patients taking cyclosporine or the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. In HIV patients taking lopinavir + ritonavir, atorvastatin should be used at the lowest necessary dose. In patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV patients taking combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the therapeutic dose of the drug should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of atorvastatin. In patients taking the HIV protease inhibitor nelfinavir, treatment with the drug should be limited to a dose of 40 mg (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Children

Heterozygous Familial Hypercholesterolemia

The safety and efficacy of atorvastatin have been established in children aged 10 to 17 years with heterozygous familial hypercholesterolemia as an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels when, after an adequate dietary trial, the following are observed:

• LDL-C ≥ 190 mg/dL (4.91 mmol/L), or
• LDL-C ≥ 160 mg/dL (4.14 mmol/L) and

o a family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives, or

o the presence of two or more other cardiovascular risk factors.

Indications for the use of atorvastatin are supported by the following studies:

• A 6-month placebo-controlled clinical study involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin 10 mg or 20 mg daily had an overall adverse reaction profile similar to those receiving placebo. In this small, controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
• A 3-year open-label, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom the dose was titrated to achieve a target LDL-C level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in reducing LDL-C were generally consistent with those observed in adult patients, despite limitations of the uncontrolled study design.

Counseling on contraception should be provided to girls after onset of menstruation, if appropriate for the patient.

The long-term efficacy of atorvastatin therapy initiated in childhood for reducing morbidity and mortality in adulthood has not been established.

The safety and efficacy of atorvastatin therapy have not been established in children under 10 years of age with heterozygous familial hypercholesterolemia.

Homozygous Familial Hypercholesterolemia

Clinical efficacy of the drug at doses up to 80 mg/day over 1 year was evaluated in an uncontrolled study in 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose

There is no specific antidote for overdose with the drug. In case of overdose, the patient should be treated symptomatically and supportive measures should be applied as needed. Due to the high degree of plasma protein binding of the drug, significant enhancement of atorvastatin clearance by hemodialysis is not expected.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed during clinical trials of a drug cannot be directly compared with those of another drug, and may not reflect the rates observed in practice.

In the database of placebo-controlled clinical trials of atorvastatin, among 16,066 patients (8,755 receiving atorvastatin and 7,311 receiving placebo; age range 10–93 years, 39% women, 91% Caucasian, 3% Black, 2% Asian, 4% other), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of patients receiving placebo discontinued treatment due to adverse reactions, regardless of causal relationship to the drug. The five most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a higher frequency than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).

In patients treated with atorvastatin in placebo-controlled trials (n = 8,755), the most commonly reported adverse reactions (occurring in ≥2% of patients and more frequently than in the placebo group), regardless of causal relationship, were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infection (5.7%).

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in ≥2% of patients and at a higher frequency than in the placebo group, among patients treated with atorvastatin (n = 8,755) from 17 placebo-controlled trials.

Table 6

Clinical adverse reactions occurring in ≥2% of patients treated with any dose of atorvastatin and at a higher frequency than in the placebo group, regardless of causal relationship (% of patients).

Adverse reaction*	Any dose N = 8755	10 mg N = 3908	20 mg N = 188	40 mg N = 604	80 mg N = 4055	Placebo N = 7311
Nasopharyngitis	8.3	12.9	5.3	7	4.2	8.2
Arthralgia	6.9	8.9	11.7	10.6	4.3	6.5
Diarrhea	6.8	7.3	6.4	14.1	5.2	6.3
Limb pain	6	8.5	3.7	9.3	3.1	5.9
Urinary tract infection	5.7	6.9	6.4	8	4.1	5.6
Dyspepsia	4.7	5.9	3.2	6	3.3	4.3
Nausea	4	3.7	3.7	7.1	3.8	3.5
Back pain	3.8	5.2	3.2	5.1	2.3	3.6
Muscle spasms	3.6	4.6	4.8	5.1	2.4	3
Myalgia	3.5	3.6	5.9	8.4	2.7	3.1
Insomnia	3	2.8	1.1	5.3	2.8	2.9
Pharyngolaryngeal pain	2.3	3.9	1.6	2.8	0.7	2.1

* Adverse reaction > 2% in any dose more than in the placebo group.

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

Gastrointestinal disorders: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis;

Musculoskeletal and connective tissue disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture);

Metabolism and nutrition disorders: increased transaminases, abnormal liver function tests, increased blood alkaline phosphatase, increased creatine phosphokinase activity, hyperglycemia;

Nervous system disorders: nightmares;

Respiratory system disorders: epistaxis;

Skin and subcutaneous tissue disorders: urticaria;

Eye disorders: blurred vision, visual disturbance;

Ear and labyrinth disorders: tinnitus;

Renal and urinary disorders: leukocyturia;

Reproductive system and breast disorders: gynecomastia.

The frequency of adverse reactions was defined as follows: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

Nervous system disorders: common – headache; uncommon – dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia; rare – peripheral neuropathy; frequency not known – myasthenia gravis.

Vascular disorders: rare – vasculitis.

Gastrointestinal disorders: common – constipation; uncommon – pancreatitis, vomiting.

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain; rare – myopathy, myositis, rhabdomyolysis.

General disorders: uncommon – asthenia, chest pain, peripheral edema, fatigue.

Metabolism and nutrition disorders: uncommon – hypoglycemia, weight gain, anorexia.

Hepatobiliary disorders: very rare – liver failure.

Skin and subcutaneous tissue disorders: uncommon – skin rash, pruritus, alopecia; rare – angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced lichenoid reaction.

Respiratory, thoracic and mediastinal disorders: common – throat and laryngeal pain.

Blood and lymphatic system disorders: rare – thrombocytopenia.

Immune system disorders: common – allergic reactions; very rare – anaphylaxis.

Eye disorders: uncommon – blurred vision; frequency not known – ocular myasthenia.

Laboratory test abnormalities: common – abnormal liver function tests, increased blood creatine phosphokinase activity; uncommon – positive test for leukocytes in urine.

As with other HMG-CoA reductase inhibitors, increased serum transaminase activity has been observed in patients taking atorvastatin. These changes were generally mild, transient, and did not require intervention or treatment. Clinically significant increases in serum transaminase activity (exceeding ULN by more than 3 times) were observed in 0.8% of patients treated with atorvastatin. This increase was dose-dependent and reversible in all patients.

An increase in serum CK activity exceeding ULN by more than 3 times was observed in 2.5% of patients treated with atorvastatin. This is consistent with observations from clinical trials of other HMG-CoA reductase inhibitors. A level exceeding ULN by more than 10 times was observed in 0.4% of patients receiving atorvastatin.

Adverse reactions observed during clinical trials: urinary tract infection, diabetes mellitus, stroke.

In the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), which included 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasian, 2.6% Black, 1.5% South Asian, and 1.3% mixed/other), who received atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of atorvastatin was comparable to that of the placebo group over a median follow-up period of 3.3 years.

In the CARDS (Collaborative Atorvastatin Diabetes Study), which included 2,838 patients (age range 39–77 years, 32% women; 94.3% Caucasian, 2.4% South Asian, 2.3% Afro-Caribbean, and 1% other) with type 2 diabetes, who received atorvastatin 10 mg/day (n = 1,428) or placebo (n = 1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 3.9 years. No cases of rhabdomyolysis were reported.

In the TNT (Treating to New Targets Study), which included 10,001 patients (age range 29–78 years, 19% women; 94.1% Caucasian, 2.9% Black, 1.0% Asian, and 2.0% other) with clinically evident coronary heart disease, who received atorvastatin 10 mg/day (n = 5,006) or atorvastatin 80 mg/day (n = 4,995), more serious adverse reactions and cases of treatment discontinuation due to adverse reactions were observed in the high-dose atorvastatin group (92; 1.8%; 497, 9.9%, respectively) compared to the low-dose group (69; 1.4%; 404, 8.1%, respectively) over a median follow-up period of 4.9 years. Persistent elevation of transaminases (≥3 times ULN on two occasions 4–10 days apart) was observed in 62 (1.3%) patients receiving atorvastatin 80 mg and in 9 (0.2%) patients receiving atorvastatin 10 mg. Elevation of CK levels (≥10 times ULN) was generally low but higher in the high-dose atorvastatin group (13; 0.3%) compared to the low-dose group (6; 0.1%).

In the IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study), which included 8,888 patients (age range 26–80 years, 19% women; 99.3% Caucasian, 0.4% Asian, 0.3% Black, and 0.04% other), who received atorvastatin 80 mg/day (n = 4,439) or simvastatin 20–40 mg/day (n = 4,449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 4.8 years.

In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), which included 4,731 patients (age range 21–92 years, 40% women; 93.3% Caucasian, 3.0% Black, 0.6% Asian, and 3.1% other) without clinically evident coronary heart disease but with a history of stroke or TIA within the previous 6 months, who received atorvastatin 80 mg (n = 2,365) or placebo (n = 2,366), over a median follow-up period of 4.9 years, a higher incidence of persistent elevation of liver transaminases (≥3 times ULN on two occasions 4–10 days apart) was observed in the atorvastatin group (0.9%) compared to the placebo group (0.1%). Cases of CK elevation (≥10 times ULN) were rare but occurred more frequently in the atorvastatin group (0.1%) than in the placebo group (0.0%). Diabetes mellitus was reported as an adverse reaction in 144 patients (6.1%) in the atorvastatin group and in 89 patients (3.8%) in the placebo group (see section "Special precautions for use").

Post-hoc analysis showed that atorvastatin 80 mg reduced the incidence of ischemic stroke (218 of 2365, 9.2% vs. 274 of 2366, 11.6%) but increased the incidence of hemorrhagic stroke (55 of 2365, 2.3% vs. 33 of 2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 cases in the atorvastatin group vs. 18 in the placebo group). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38 non-fatal hemorrhagic strokes) compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the study with a history of hemorrhagic stroke had an increased risk of hemorrhagic stroke (7 (16%) in the atorvastatin group vs. 2 (4%) in the placebo group).

No significant differences between treatment groups in all-cause mortality were observed: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportion of patients who died from cardiovascular causes was numerically lower in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportion of patients who died from non-cardiovascular causes was numerically higher in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Adverse reactions during clinical trials of atorvastatin in children

In a 26-week controlled study in boys and girls after menarche with heterozygous familial hypercholesterolemia (aged 10 to 17 years) (n = 140, 31% female; 92% Caucasian, 1.6% Black, 1.6% Asian, and 4.8% other ethnic groups), the safety and tolerability profile of atorvastatin 10–20 mg daily as an adjunct to diet for lowering total cholesterol, LDL-C, and apolipoprotein B levels was generally similar to that of placebo.

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of atorvastatin. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin treatment reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal liver failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions for use").

Rare post-marketing reports of cognitive disorders (such as memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders were reported with all statins. Generally, they were not considered serious adverse reactions and were reversible after discontinuation of statins, with variable onset time (from 1 day to several years) and resolution time (median duration of 3 weeks).

Adverse reactions such as sexual dysfunction have been described with some statins. Rare cases of interstitial lung disease, particularly with long-term treatment, have also been reported.

Adverse reactions reported during post-marketing surveillance

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypoaesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

General disorders: chest pain, peripheral edema, malaise, fatigue.

Laboratory abnormalities: increased alanine aminotransferase activity, increased blood creatine phosphokinase activity.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store at a temperature not exceeding 30 °C. Store in a place protected from light and moisture. Keep out of reach of children.

Packaging

10 tablets in a blister; 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Pinnacle Life Sciences Private Limited.

Manufacturer's location and address of place of business

Houseno. 1328-1330, Village-Manpura, Tehsil-Baddi, District-Solan, Himachal Pradesh - 174101, India.