Atorvastatin-K, 40 mg 30 pcs

• Hypercholesterolemia:

– As adjunct to diet to decrease elevated total cholesterol, LDL-C, apo-B, and TG in adults, adolescents, and children aged 10 years or older with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant) or combined (mixed variant) hyperlipidemia (Fredrickson classification type IIa and IIb respectively) when response to diet and other nonmedicamental treatments is not sufficient;

– to reduce elevated total CH, LDL-C in adults with homozygous familial hypercholesterolemia as a supplement to other hypolipidemic therapies (such as LDL-apheresis), or if such treatments are not available.

• Prevention of cardiovascular diseases:

– prevention of cardiovascular events in adult patients at high risk of developing primary cardiovascular events, as an adjunct to correction of other risk factors;

“secondary prevention of cardiovascular complications in patients with CHD in order to reduce mortality, MI, strokes, repeated hospitalizations for angina and the need for revascularization.

Active ingredient

Composition

1 film-coated tablet, 10 mg/20 mg/30 mg contains:

nucleus

Active substance:

Atorvastatin calcium trihydrate 10.845 mg/21.69 mg/32.535 mg (equivalent to atorvastatin 10.00 mg/20.00 mg/30.00 mg)

Excipients:

Calcium carbonate, hyprolose, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, polysorbate 80, magnesium stearate

Wrap film

Opadray YS-1-7040*

* Opadray YS-1-7040:

Hypromellose 6 cp, titanium dioxide (E171), macrogol 8000, talc

1 film-coated tablet, 40 mg/60 mg/80 mg contains:

nucleus

Active substance:

Atorvastatin calcium trihydrate 43.38 mg/65.07 mg/86.76 mg (equivalent to atorvastatin 40.00 mg/60.00 mg/80.00 mg)

Excipients:

Calcium carbonate, hyprolose, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, polysorbate 80, magnesium stearate

Wrap film

Opadray YS-1-7040*

* Opadray YS-1-7040:

Hypromellose 6 cp, titanium dioxide (E171), macrogol 8000, talc

How to take, the dosage

Orally. To be taken at any time of the day irrespective of the time of meal.

Before starting treatment with Atorvastatin – K, one should try to control hypercholesterolemia by diet, exercise and weight loss in obese patients as well as by therapy of the underlying disease.

The patient should be advised a standard hypocholesterolemic diet to follow throughout the duration of therapy when the drug is prescribed.

The dose of Atorvastatin – Quarian is adjusted from 10 mg to 80 mg once daily with consideration of plasma HC-LDL concentration, purpose of therapy and individual response to therapy.

Maximum daily dose of Atorvastatin-K is 80 mg.

At the beginning of treatment and/or during dose increase of Atorvastatin-K, plasma lipid concentrations should be controlled every 2-4 weeks and the dose of drug should be adjusted accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

For most patients the recommended dose of Atorvastatin-K is 10 mg once daily, therapeutic effect is seen within 2 weeks and usually reaches a maximum after 4 weeks. With prolonged treatment the effect is maintained.

Homozygous familial hypercholesterolemia

In most cases 80 mg once a day (decrease of plasma HC-LDL concentration by 18-45%) is prescribed.

heterozygous familial hypercholesterolemia

The initial dose is 10 mg daily. The dose should be adjusted individually and the relevance of the dose assessed every 4 weeks with a possible increase to 40 mg per day. Then either the dose can be increased to the maximum – 80 mg per day, or it is possible to combine bile acid sequestrants with intake of atorvastatin at a dose of 40 mg per day.

Prevention of cardiovascular disease

In studies of primary prevention, the dose of atorvastatin was 10 mg daily. It may be necessary to increase the dose in order to achieve LDL-C values in accordance with the current recommendations.

Application in children 10 to 18 years of age in heterozygous familial hypercholesterolemia

The recommended starting dose is 10 mg once daily. The dose can be increased up to 80 mg per day depending on the clinical effect and tolerability.

The dose of Atorvastatin-K should be adjusted depending on the goal of hypolipidemic therapy. Dose adjustment should be carried out at intervals of 4 weeks or more.

Liver function impairment

In case of liver dysfunction, the dose of Atorvastatin-K should be decreased with regular monitoring of serum activity of “hepatic” transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).

Kidney function disorder

Renal dysfunction does not affect atorvastatin concentration or the degree of reduction of plasma LDL-C concentration, therefore no dose adjustment is required.

Elderly patients

There are no differences in therapeutic efficacy and safety of Atorvastatin-K in elderly patients compared to the general population; no dose adjustment is required (see section “Pharmacological properties. Pharmacokinetics”).

Simultaneous use with other drugs

If concomitant use with cyclosporine, telaprevir or the combination tipranavir/ritonavir is necessary, the dose of Atorvastatin-K should not exceed 10 mg/day (see section “Special Precautions”).

Caution should be exercised and the lowest effective dose of atorvastatin should be used concomitantly with HIV protease inhibitors, hepatitis C virus protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin and itraconazole. In patients concomitantly using HCV antiviral drugs (elbasvir/grazoprevir) with atorvastatin, the dose of atorvastatin should not exceed 20 mg per day.

Interaction

During treatment with HMG-CoA reductase inhibitors, concomitant use of cyclosporine, fibrates, lipid-lowering nicotinic acid (more than 1 g/day) or CYP3A4 isoenzyme inhibitors (e.g., erythromycin, clarithromycin, azole-derived antifungals) increases the risk of myopathy (see See section “Special Precautions”).

Inhibitors of CYP3A4 isoenzyme

Since atorvastatin is metabolized by CYP3A4 isoenzyme, concomitant use of atorvastatin with CYP3A4 isoenzyme inhibitors may lead to increased plasma concentration of atorvastatin. The degree of interaction and potentiation effect is determined by the variability of effects on CYP3A4 isoenzyme.

It was found that potent inhibitors of CYP3A4 isoenzyme lead to a significant increase in plasma concentration of atorvastatin. If possible, avoid concomitant use of potent inhibitors of CYP3A4 isoenzyme (such as cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, Pozaconazole, some HCV antiviral drugs (e.g., elbasvir/grazoprevir) and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.).). If concomitant use of these drugs is necessary, the possibility of starting therapy with the minimum dose should be considered, and the possibility of reducing the maximum dose of atorvastatin should be assessed.

Moderate inhibitors of CYP3A4 isoenzyme (for example, erythromycin, diltiazem, verapamil and fluconazole) can lead to increased concentration of atorvastatin in plasma. Against the background of concomitant use of HMG-CoA reductase inhibitors (statins) and erythromycin an increased risk of myopathy was noted. Studies of interaction of amiodarone or verapamil and atorvastatin have not been conducted. It is known that both amiodarone and verapamil inhibit CYP3A4 isoenzyme activity, and concomitant use of these drugs with atorvastatin may lead to increased atorvastatin exposure. In this regard, it is recommended to reduce the maximum dose of atorvastatin and conduct appropriate monitoring of the patient when concomitant use with moderate inhibitors of CYP3A4 isoenzyme. Monitoring should be performed after initiation of therapy and against the background of CYP3A4 isoenzyme inhibitor dose changes.

OATP1B1 transport protein inhibitors

Atorvastatin and its metabolites are substrates of the OATP1B1 transport protein. OATP1B1 inhibitors (e.g., cyclosporine) may increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in plasma concentration of atorvastatin by 7.7 times (see section “Dosage and administration”). The effect of inhibition of “hepatic” transporter function on atorvastatin concentration in hepatocytes is unknown. If it is impossible to avoid concomitant use of such drugs, it is recommended to reduce the dose and control the effectiveness of therapy.

Gemfibrozil/fibrates

In the background of using fibrates in monotherapy, adverse reactions involving the musculoskeletal system, including rhabdomyolysis, have occasionally been noted. The risk of such reactions increases with concomitant use of fibrates and atorvastatin. If concomitant use of these drugs cannot be avoided, the lowest effective dose of atorvastatin should be used, and patients should be monitored regularly.

Ezetimibe

The use of ezetimibe is associated with the development of adverse reactions in the musculoskeletal system, including the development of rhabdomyolysis. The risk of such reactions increases with concomitant use of ezetimibe and atorvastatin. Close monitoring is recommended for these patients.

Eritromycin/Clarithromycin

When concomitant use of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg 2 times daily), CYP3A4 isoenzyme inhibitors, increased plasma concentration of atorvastatin was observed (see sections “Pharmacological properties. Pharmacokinetics” and “Special indications”).

Protease inhibitors

The concomitant use of atorvastatin with protease inhibitors, known as CYP3A4 isoenzyme inhibitors, is accompanied by an increase in plasma concentration of atorvastatin.

Diltiazem

Continuous administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to increased concentration of atorvastatin in plasma (see section “Pharmacological properties. Pharmacokinetics”).

Cimetidine

No clinically significant interaction of atorvastatin with cimetidine was found (see section “Pharmacological properties. Pharmacokinetics”).

Itraconazole

The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in dose 200 mg led to the increase of AUC value of atorvastatin (see “Pharmacological properties. Pharmacokinetics”).

Grapefruit juice

Since grapefruit juice contains one or more components that inhibit CYP3A4 isoenzyme, its excessive consumption (more than 1.2 L per day) may increase the plasma concentration of atorvastatin (see “Pharmacological properties. Pharmacokinetics”).

Transport protein inhibitors

Atorvastatin is a substrate of liver enzyme transporters, OATP1B1 and OATP1B3 transporters. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of efflux transporters MDR1 and BCRP, which may limit intestinal absorption and biliary clearance of atorvastatin (see section “Pharmacological properties. Pharmacokinetics”).

Concomitant administration of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day resulted in increased systemic exposure of atorvastatin (8.7-fold increase of AUC) (see “Pharmacological properties. Pharmacokinetics”). Cyclosporine is an inhibitor of transport polypeptide of organic anions 1B1 (OATP1B1), 1B3 (OATP1BZ), MDL1 and BCRP-associated protein and CYP3A4 isoenzyme, therefore, it increases atorvastatin systemic exposure. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and administration”).

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1BZ, MLU1 and BCRP; therefore, they increase systemic exposure to atorvastatin. Atorvastatin-K should be used with caution and in the lowest dose necessary (see section “Dosage and administration”).

Inductors of CYP3A4 isoenzyme

Concomitant use of atorvastatin with CYP3A4 isoenzyme inducers (e.g., efavirenz, rifampicin or St. John’s Wort preparations) may lead to decreased blood plasma concentration of atorvastatin. Due to the dual mechanism of interaction with rifampicin (inducer of CYP3A4 isoenzyme and inhibitor of hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after rifampicin administration leads to a significant decrease in plasma concentration of atorvastatin (see section “Pharmacological properties. Pharmacokinetics”). However, the effect of rifampicin on atorvastatin concentration in hepatocytes is unknown, and in case concomitant use cannot be avoided, the effectiveness of such a combination should be carefully monitored during therapy.

Antacids

Concomitant oral administration of suspension containing magnesium hydroxide and/or aluminum hydroxide decreased the plasma concentration of atorvastatin (change in AUC: 0.66), but the degree of decrease in plasma concentration of LDL-C did not change.

Phenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, so no interaction with other drugs metabolized by the same cytochrome system isoenzymes is expected.

Colestipol

Concomitant use of colestipol decreased plasma concentrations of atorvastatin (AUC change: 0.74), but the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Digoxin

The equilibrium plasma concentrations of digoxin and atorvastatin at a dose of 10 mg did not change when digoxin and atorvastatin were repeatedly administered. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, digoxin concentration was increased (AUC change: 0.74). Patients receiving digoxin concomitantly with atorvastatin require appropriate monitoring.

Asithromycin

The plasma concentrations of atorvastatin at a dose of 10 mg once daily and azithromycin at a dose of 500 mg once daily did not change.

Orral contraceptive drugs

The concomitant use of atorvastatin and oral contraceptive drugs containing norethisterone and ethinylestradiol showed a significant increase in the AUC of norethisterone (change in AUC: 1.28) and ethinylestradiol (change in AUC: 1.19). This effect should be considered when choosing oral contraceptives for women taking atorvastatin.

Terfenadine

No clinically significant changes in terfenadine pharmacokinetics were observed with concomitant use of atorvastatin and terfenadine.

Varfarin

In a clinical study in patients regularly treated with warfarin, concomitant use of atorvastatin at a dose of 80 mg daily resulted in a slight increase in prothrombin time of approximately 1.7 seconds during the first 4 days of therapy. The index returned to normal within 15 days of atorvastatin therapy. Despite the fact that only in rare cases significant interaction affecting anticoagulant function has been noted, prothrombin time should be determined before atorvastatin therapy in patients receiving coumarin anticoagulants therapy, and regularly – during therapy to prevent significant changes in prothrombin time. As soon as stable values of prothrombin time are noted, it can be controlled in the same way as recommended for patients receiving coumarin anticoagulants. If the dose of atorvastatin is changed or therapy is discontinued, control of prothrombin time should be performed according to the same principles as described above. Atorvastatin therapy has not been associated with the development of bleeding or changes in prothrombin time in patients who were not treated with anticoagulants.

Colchicine

Although there have been no studies of concomitant use of colchicine and atorvastatin, there have been reports of myopathy with this combination. Caution should be exercised when using atorvastatin and colchicine concomitantly.

Amlodipine

In a drug interaction study in healthy volunteers, concomitant use of atorvastatin at a dose of 80 mg and amlodipine 10 mg resulted in a clinically insignificant increase in plasma concentration of atorvastatin (AUC change: 1.18).

Fusidic acid

In post-marketing studies, cases of rhabdomyolysis have been reported in patients taking statins, including atorvastatin, and fusidic acid at the same time. The mechanism of this interaction is unknown. In patients for whom the use of fusidic acid is considered necessary, statin therapy should be discontinued for the duration of fusidic acid use. Therapy with statins may be resumed 7 days after the last fusidic acid administration. In exceptional cases, where prolonged systemic therapy with fusidic acid is necessary, such as for the treatment of severe infections, the necessity of simultaneous use of atorvastatin and fusidic acid should be considered on a case-by-case basis and be conducted under close medical supervision. The patient should immediately seek medical attention if symptoms of muscle weakness, sensitivity or pain occur.

Other related therapy

In clinical trials atorvastatin was used simultaneously with hypotensive agents and estrogens as part of hormone replacement therapy. No signs of clinically significant adverse interactions have been observed, the studies of interaction with specific drugs have not been conducted.

In addition, atorvastatin concentrations were observed to increase when concomitant use with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C virus protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin and itraconazole. Caution should be exercised when using these drugs concomitantly, and the lowest effective dose of atorvastatin should be used.

Special Instructions

In patients with the presence of risk factors for rhabdomyolysis (impaired renal function, hypothyroidism, hereditary muscle disorders in the patient’s history or family history, already suffered toxic effects of HMG-CoA reductase inhibitors [statins] or fibrates on muscle tissue, history of liver disease and/or patients who consume significant amounts of alcohol, age older than 70 years, situations in which atorvastatin plasma concentrations are expected to increase [e.g., interaction with other medicinal products]).

It is contraindicated before the age of 18 years (there are insufficient clinical data on the efficacy and safety of the drug in this age group), except for heterozygous familial hypercholesterolemia (use contraindicated in children under 10 years).

Application in children 10 to 18 years of age in heterozygous familial hypercholesterolemia

The recommended starting dose is 10 mg once daily. The dose can be increased up to 80 mg per day depending on the clinical effect and tolerability.

Liver function impairment

In liver dysfunction, the dose of Atorvastatin-K should be decreased with regular monitoring of serum activity of “hepatic” transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).

Kidney function disorder

Renal dysfunction does not affect atorvastatin concentration or the degree of reduction of plasma LDL-C concentration, therefore no dose adjustment is required.

Elderly patients

There are no differences in therapeutic efficacy and safety of Atorvastatin-K in elderly patients compared to the general population; no dose adjustment is required (see section “Pharmacological properties. Pharmacokinetics”).

Impact on liver

As with other hypolipidemic agents of this class, a moderate increase (more than 3 times the upper limit of normal) in the activity of “hepatic” transaminases ACT and ALT in plasma was observed when using atorvastatin. A persistent increase in serum activity of “hepatic” transaminases (more than 3 times the upper limit of normal) was observed in 0.7% of patients receiving atorvastatin. Frequency of similar changes while using Atorvastatin in doses of 10 mg, 20 mg, 40 mg and 80 mg was 0.2%, 0.2%, 0.6% and 2.3%, respectively. Elevation of “hepatic” transaminases activity in blood plasma was usually not accompanied by jaundice or other clinical manifestations. When the dose of atorvastatin was decreased, temporarily or completely discontinued, plasma hepatic transaminase activity returned to the baseline level. Most patients continued taking atorvastatin in a reduced dose without any clinical consequences.

Before the beginning of therapy, 6 weeks and 12 weeks after the beginning of Atorvastatin – Kili administration after increasing its dose it is necessary to monitor liver function indexes. Liver function should also be monitored when clinical signs of liver damage appear. In case of increased plasma activity of “hepatic” transaminases, plasma ALT and ACT activity should be monitored until it normalizes. If the increase of ACT or ALT activity in plasma more than 3 times compared to the upper limit of normal remains, it is recommended to reduce the dose or cancel the drug Atorvastatin – K (see section “Side effects”).

Atorvastatin-K should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or persistently elevated activity of “hepatic” plasma transaminases of unclear genesis are contraindications to the use of Atorvastatin-K (see section “Contraindications”).

Effects on skeletal muscles

Myalgia has been reported in patients receiving atorvastatin (see side effects). The diagnosis of myopathy should be assumed in patients with diffuse myalgia, muscle soreness or weakness and/or a marked increase in serum CPK activity (more than 10 times the upper limit of normal). Atorvastatin-K therapy should be discontinued in case of significant increase in serum CPK activity, in the presence of confirmed or suspected myopathy. The risk of myopathy increases with concomitant use of drugs that increase plasma concentrations of atorvastatin (see sections “Interaction with other medicinal products” and “Pharmacological properties. Pharmacokinetics”), such as potent inhibitors of CYP3A4 isoenzyme or carrier proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc.), gemfibrozil or other fibrates, HCV antiviral drugs (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, nicotinic acid in lipid-lowering doses (over 1 g/day), ezetimibe, azole antifungals, colchicine. Many of these drugs inhibit CYP3A4 isoenzyme-mediated metabolism and/or drug transport. It is known that CYP3A4 isoenzyme is the main liver isoenzyme involved in biotransformation of atorvastatin. When using Atorvastatin-K in combination with fibrates, erythromycin, immunosuppressants, azole antifungal agents or nicotinic acid in lipid-lowering doses (more than 1 g/day), a physician should carefully weigh the expected benefit of treatment against possible risk. Patients should be regularly monitored for muscle pain or weakness, especially during the first months of therapy and during the period of increasing the dose of any of these drugs. If combined therapy is necessary, consideration should be given to using lower initial and maintenance doses of the above agents (see section “Dosage and administration”). Concomitant use of atorvastatin and fusidic acid is not recommended, therefore temporary withdrawal of atorvastatin is recommended during treatment with fusidic acid. In such situations, periodic monitoring of serum CPK activity may be recommended, although such monitoring does not prevent the development of severe myopathy (see section “Interaction with other medicinal products”).

Before treatment

Atorvastatin should be prescribed with caution in patients with factors predisposing to the development of rhabdomyolysis. Before initiating therapy with atorvastatin, plasma CPK activity should be monitored in the following cases:

– renal function impairment,

– hypothyroidism,

– a patient has a history or family history of hereditary muscle disorders,

– already suffered toxic effects of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue,

– history of liver disease and/or patients consuming significant amounts of alcohol,

– in patients aged over 70 years old the necessity of plasma CPK control should be assessed, considering that these patients already have factors predisposing to rhabdomyolysis development,

– situations in which atorvastatin concentration in blood plasma is expected to increase, such as interactions with other drugs (see section “Interaction with other medicinal products”).

In such situations, the risk/benefit ratio should be assessed and the patient should be medically monitored.

In case of significant increase of serum CPK activity (more than 5 times upper limit of normal) atorvastatin therapy should not be started.

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described with Atorvastatin-K and other HMG-CoA reductase inhibitors. Prior renal dysfunction may be a risk factor for rhabdomyolysis. Such patients should be monitored more closely for the musculoskeletal system. If there are symptoms of myopathy or risk factors of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, extensive surgery, trauma, metabolic, endocrine and water-electrolyte disorders, uncontrolled convulsions) Atorvastatin-K therapy should be temporarily stopped or completely discontinued.

Very rare cases of immune-mediated necrotizing myopathy during therapy or when stopping statins have been reported. Immune-mediated necrotizing myopathy is clinically characterized by persistent proximal muscle weakness and elevated serum CPK activity that persists despite discontinuation of statin treatment.

Cautions! Patients should be warned to seek immediate medical attention if they experience unexplained pain or muscle weakness, especially if accompanied by malaise or fever.

Stroke prevention through active plasma cholesterol reduction (SPARCL)

In a retrospective analysis of stroke subtypes in patients without CHD who had recently had a stroke or TIA and initially received atorvastatin at a dose of 80 mg, there was a higher incidence of hemorrhagic stroke compared with patients receiving placebo. The increased risk was particularly marked in patients with a history of hemorrhagic stroke or lacunar infarction at baseline. In this group of patients the benefit/risk ratio when taking atorvastatin at a dose of 80 mg/day is insufficiently defined, therefore the possible risk of hemorrhagic stroke in such patients should be carefully evaluated before starting therapy.

A special analysis of a clinical trial involving 4,731 patients without CHD who had had a stroke or TIA within the previous 6 months and were prescribed atorvastatin 80 mg/day revealed a higher rate of hemorrhagic strokes in the atorvastatin 80 mg group compared with the placebo group (55 in the atorvastatin group versus 33 in the placebo group). Patients with hemorrhagic stroke at the time of inclusion in the study had a higher risk for recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group). However, patients who received atorvastatin 80 mg/day had fewer strokes of any type (265 versus 311) and fewer cardiovascular events (123 versus 204).

Diabetes

Some evidence supports that HMG-CoA reductase inhibitors (statins) as a class can lead to elevated blood glucose concentrations, and individual patients at high risk for diabetes may develop a state of hyperglycemia requiring correction as in diabetes mellitus. However, this risk does not exceed the benefit of therapy with HMG-CoA reductase inhibitors (statins) in terms of vascular risks, so this may not be a reason to discontinue therapy. Patients related to the risk group (fasting blood glucose concentration from 5.6 to 6.9 mmol/l, BMI > 30 kg/m2 body surface area, increased concentration of triglycerides in plasma, arterial hypertension) should be under medical control, including monitoring of biochemical blood parameters, according to the National guidelines.

Interstitial lung disease

Anecdotal cases of interstitial lung disease have been reported during therapy with some HMG-CoA reductase inhibitors (statins), especially during long-term therapy. Dyspnea, non-productive cough and deterioration of general health (fatigue, weight loss and fever) may be observed. If interstitial lung disease is suspected in a patient, atorvastatin therapy should be stopped.

Endocrine function

In the use of HMG-CoA reductase inhibitors (statins), including atorvastatin, there have been cases of increased HbA1 and fasting blood glucose concentrations. Nevertheless, the risk of hyperglycemia is lower than the degree of reduction of risk of vascular complications against the background of taking HMG-CoA reductase inhibitors (statins).

Application in children

In a 3-year study, there were no clinically significant effects on growth and puberty as measured by general maturation and development, Tanner stage scores, and height and body weight measurements.

Special information on excipients

The drug Atorvastatin – K contains lactose, therefore it is contraindicated in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

There are no data about the effect of Atorvastatin-K on the ability to drive vehicles and engage in potentially dangerous activities that require increased concentration and rapid psychomotor reactions. However, taking into account the possibility of dizziness, caution should be exercised when performing the above activities.

Synopsis

Tablets 10 mg, 20 mg, 30 mg and 40 mg:

round, biconvex, film-coated tablets, white or almost white, with a bevel.

Breakage appearance: white or almost white rough mass with white or almost white film coating.

Tablets 60 mg, 80 mg:

oval, biconvex, film-coated white or almost white tablets.

Breakage appearance: white or nearly white rugged mass with white or nearly white film coating.

Contraindications

Side effects

The drug Atorvastatin-K is usually well tolerated; adverse reactions are usually mild and transient.

World Health Organization (WHO) recommended side effect frequency classification:

very often ≥1/10

often from ≥1/100 to < 1/10

infrequently from ≥ 1/1000 to < 1/100

rarely from ≥ 1/10000 to < 1/1000

very rarely < 1/10000

frequency is unknown cannot be estimated from available data.

Infectious and parasitic diseases:

often: nasopharyngitis.

Blood and lymphatic system disorders:

rare: thrombocytopenia.

immune system disorders:

often: allergic reactions;

very rarely: anaphylaxis.

Disorders of metabolism and nutrition:

often: hyperglycemia;

infrequently: hypoglycemia, weight gain, anorexia;

frequent unknown: diabetes mellitus (frequency of development depends on the presence or absence of risk factors [fasting blood glucose concentration ≥ 5.6 mmol/L, body mass index [BMI] > 30 kg/m2 body surface area, increased plasma TG concentration, history of hypertension]).

Mental disorders:

infrequent: “nightmare” dreams, insomnia;

frequency unknown: depression.

Nervous system disorders:

infrequent: dizziness, paresthesia, hypoesthesia, taste disorder, amnesia;

rarely: peripheral neuropathy;

frequency unknown: loss or reduction of memory.

Visual disorders:

infrequent: the appearance of “shadows” before the eyes;

rare: visual disturbances.

Hearing organ and labyrinth disorders:

infrequent: tinnitus;

very rare: hearing loss.

Disorders of the respiratory system, thoracic and mediastinal organs:

often: sore throat, nasal bleeding;

frequency unknown: isolated cases of interstitial lung disease (usually with long-term use).

digestive system disorders:

often: constipation, flatulence, dyspepsia, nausea, diarrhea;

infrequently: vomiting, abdominal pain, belching, pancreatitis, abdominal discomfort.

Liver and biliary tract disorders:

infrequent: hepatitis;

rare: cholestasis.

Skin and subcutaneous tissue disorders:

seldom: angioneurotic edema, bullous rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Muscular and connective tissue disorders:

often: myalgia, arthralgia, pain in the extremities, muscle cramps, joint swelling, back pain, musculoskeletal pain;

infrequently: neck pain, muscle weakness;

rarely: myopathy, myositis, rhabdomyolysis, tendinopathy (in some cases with tendon rupture);

very rare: lupus-like syndrome;

frequency unknown: immune-mediated necrotizing myopathy.

Kidney and urinary tract disorders:

very rare: secondary renal failure.

Gender and breast disorders:

infrequently: impotence;

very rarely: gynecomastia.

General disorders and disorders at the site of administration:

infrequent: malaise, asthenic syndrome, chest pain, peripheral edema, increased fatigue, fever.

Laboratory and instrumental findings:

often: abnormal results of “liver” tests (ACT and ALT) in plasma, increased serum creatine phosphokinase (CPK) activity;

infrequent: leukocyturia;

frequency unknown: increased concentration of glycosylated hemoglobin (HbAl).

children

Atorvastatin-treated children aged 10 to 17 years had an adverse event profile similar to that of patients receiving placebo, with infections being the most common adverse event in both groups, regardless of causality assessment. In the 3-year study, there were no clinically significant effects on growth and puberty as measured by general maturation and development, Tanner stage scores, and height and body weight measurements. The safety and tolerability profile in children was similar to the known safety profile of atorvastatin in adults.

The clinical safety database includes safety data for 520 children receiving atorvastatin, among whom 7 patients were aged < 6 years, 121 patients were aged 6 to 9 years, and 392 patients were aged 10 to 17 years. Based on the available data, the incidence, type, and severity of adverse reactions in children were similar to those in adults.

Overdose

The specific antidote for treatment of overdose with Atorvastatin is Knet. In case of overdose, symptomatic treatment should be administered as necessary. Liver function tests should be performed and serum CPK activity should be monitored. Since atorvastatin is actively bound to blood plasma proteins, hemodialysis is ineffective.

Pregnancy use

The drug Atorvastatin-K is contraindicated in pregnancy.

Women of reproductive age should use adequate contraception methods during treatment. Atorvastatin-K is contraindicated in women of childbearing age who do not use adequate contraception methods.

Rare cases of congenital anomalies have been reported following fetal exposure to HMG-CoA reductase inhibitors (statins). Toxic effects on reproductive function have been shown in animal studies. Atorvastatin-K is contraindicated during lactation. It is unknown whether atorvastatin is excreted with breast milk. If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped to avoid the risk of adverse effects in infants.

Similarities