Atoris, 30 mg 30 pieces

Prevention of heart attacks and strokes, Cholesterol, Reducing cholesterol

• Hypercholesterolemia:

– to reduce elevated total CH, LDL-C in adults with homozygous familial hypercholesterolemia as an adjunct to other hypolipidemic treatments (such as LDL-apheresis) or if such therapies 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, myocardial infarction, strokes, repeated hospitalizations for angina and need for revascularization.

Active ingredient

Composition

1 film-coated tablet, 30 mg/60 mg/80 mg contains:

Active substance:

Calcium atorvastatin 31.08 mg/62.16 mg/82.88 mg (equivalent to atorvastatin 30.00 mg/60.00 mg/80.00 mg)

Excipients:

Lactose monohydrate, microcrystalline cellulose, PH 102, hyprolose, croscarmellose sodium, crosspovidone, type A, polysorbate 80, sodium hydroxide, magnesium stearate

Wrap film:

*Opadray IIHP 85F28751 white

*Opadray IIHP 85F28751 white:

Polyvinyl alcohol, titanium dioxide (E171), macrogol – 3000, talcum

How to take, the dosage

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

Before starting treatment with Atoris®, an attempt should be made to control hypercholesterolemia and decrease body weight in obese patients through diet, exercise and adequate therapy of the underlying disease.

The patient should be advised a standard hypocholesterolemic diet to follow during the entire therapy period when the drug is prescribed.

The dose of Atoris® varies from 10 mg to 80 mg once daily and is chosen taking into account plasma concentration of LDL-C, purpose of therapy and individual response to therapy.

Maximum daily dose of Atoris® is 80 mg.

At the beginning of treatment and/or during dose increase of Atoris® it is necessary to monitor the blood plasma lipid concentration every 2-4 weeks and adjust the drug dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

For most patients, the recommended dose of Atoris® is 10 mg once daily; the 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

For patients with heterozygous familial hypercholesterolemia aged 10 years or older, the recommended starting dose of atorvastatin is 10 mg daily. The dose may be increased to 80 mg daily depending on response and tolerability. The dose should be adjusted individually according to the recommended therapy. Adjustments may be made at intervals of 4 weeks or more. Recommendations for dose titration up to 80 mg daily are based on data from studies involving adult patients and limited data from clinical trials involving children with heterozygous familial hypercholesterolemia.

There are limited data on safety and efficacy in children with heterozygous familial hypercholesterolemia aged 6 to 10 years from open studies. Atoris® is contraindicated for the treatment of patients younger than 10 years of age. The currently available data are described in the section “Side effects”; there are no dosing recommendations for this age group of patients.

Liver function impairment

In patients with impaired liver function, the dose of Atoris® should be decreased with regular monitoring of serum alanine transaminase (ACT) and alanine aminotransferase (ALT) activity.

Kidney function impairment

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 Atoris® in elderly patients compared to the general population; no dose adjustment is required (see “Pharmacological properties. Pharmacokinetics”).

Use in combination with other drugs

When used concomitantly with cyclosporin, telaprevir or the tipranavir/ritonavir combination, the dose of Atoris® should not exceed 10 mg per day (see “Pharmacological properties of the drug” in the sections “Pharmacological properties of the drug”). See “Pharmacological properties. Pharmacokinetics”, “Interaction with other medicinal products”, “Cautions”).

Caution should be exercised and the lowest effective dose of atorvastatin used concomitantly with protease inhibitors human immunodeficiency virus (HIV), protease inhibitors of hepatitis C virus

Interaction

During treatment with HMG-CoA reductase inhibitors, concomitant use of cyclosporin, fibrates, nicotinic acid in lipid-lowering doses (>1 g/day) or inhibitors of CYP3A4 isoenzyme (e.g., erythromycin, clarithromycin, antifungal agents – azole derivatives) increases the risk of myopathy (see section “Special Precautions. Separate instructions).

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. Concomitant use of potent CYP3A4 isoenzyme inhibitors (such as cyclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, pozaconazole, some antiviral drugs used in the therapy of viral hepatitis C (e.g., elbasvir/razoprevir

Special Instructions

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

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

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

For patients with heterozygous familial hypercholesterolemia aged 10 years or older, the recommended starting dose of atorvastatin is 10 mg daily. The dose may be increased to 80 mg daily depending on response and tolerability. The dose should be adjusted individually according to the recommended therapy. Adjustments may be made at intervals of 4 weeks or more. Recommendations for dose titration up to 80 mg daily are based on data from studies involving adult patients and limited data from clinical trials involving children with heterozygous familial hypercholesterolemia.

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. No clinically significant effects on growth and puberty were observed in the 3-year study (as measured by general maturation and development, Tanner pubertal stage assessment, and height and body weight measurements). The safety and tolerability profile of atorvastatin in children was similar to the known profile of atorvastatin in adults.

The clinical safety database includes data from 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.

In an 8-week open-label study, children (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C concentrations ≥4 mmol/L received atorvastatin therapy as 5 mg or 10 mg chewable tablets or film-coated tablets at a dose of 10 mg or 20 mg once daily, respectively. The only significant covariate in the pharmacokinetic model of the population receiving atorvastatin was body weight. The apparent clearance of atorvastatin in children did not differ from that in adult patients when measured allometrically by body weight. In the range of atorvastatin and o-hydroxyatorvastatin there was a consistent decrease in LDL-C and CHD.

Liver function impairment

In patients with impaired liver function, the dose of Atoris® should be decreased with regular monitoring of serum alanine transaminase (ACT) and alanine aminotransferase (ALT) activity.

Kidney function impairment

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 Atoris® in elderly patients compared to the general population; no dose adjustment is required.

Impact on the liver

As with other hypolipidemic agents of this class, a moderate increase (more than 3 times the upper limit of normal) in plasma ACT and ALT values was observed during treatment with atorvastatin. A persistent increase (more than 3 times the upper limit of normal) was observed in 0.7% of patients treated with 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 with jaundice or other clinical manifestations. When the dose of atorvastatin was decreased, temporarily or completely discontinued, plasma hepatic transaminase activity returned to the initial level. Most patients continued taking atorvastatin in a reduced dose without any clinical consequences.

Before the start of therapy, 6 weeks and 12 weeks after the start of Atoris® or after increasing its dose liver function parameters should be controlled. Liver function should also be monitored when clinical signs of liver damage appear. In case of increased activity of “hepatic” transaminases in plasma, the activity of ALT and ACT in plasma should be monitored until they normalize. If the increase of ACT or ALT activity in plasma remains more than 3 times the upper limit of normal, it is recommended to reduce the dose or discontinue Atoris® (see section “Side effects”).

Atoris® 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 Atoris® (see section “Contraindications”).

Action 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). Atoris® therapy should be discontinued in case of marked increase of serum CPK, in presence of confirmed or suspected myopathy. The risk of myopathy during treatment with this class of drugs was increased when concomitant use of potent CYP3A4 isoenzyme inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, The use of the following inhibitors of the CYP3A4 isoenzyme (e.g., cyclosporine, cyclothromycin, clarithromycin, delavirdine, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, Darunavir, tipranavir/ritonavir, etc.)), gemfibrozil or other fibrates, boceprevir, erythromycin, lipid-lowering nicotinic acid (more than 1 g per day), ezetimibe, azole antifungals, colchicine, antiviral agents used to treat viral hepatitis C (telaprevir, boceprevir or elbasvir/grazoprevir). 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 the biotransformation of atorvastatin. When using Atoris® in combination with fibrates, erythromycin, immunosuppressants, azole antifungal agents or nicotinic acid in lipid-lowering doses (more than 1 g daily), a physician should carefully evaluate the ratio of expected treatment benefit to possible risk. Patients should be regularly monitored to detect muscle pain or weakness, especially during the first months of therapy and during the period of increasing the dose of any of the mentioned drugs. If combined therapy is necessary, consideration should be given to using lower initial and maintenance doses of the aforementioned agents. 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 CPK index 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:

In these situations the risk/benefit ratio should be assessed and the patient’s condition should be monitored.

To avoid initiate atorvastatin therapy if serum CPK is significantly elevated (>5 times the upper limit of normal).

Atoris®, like other HMG-CoA reductase inhibitors, has described rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria. Prior renal dysfunction may be a risk factor for rhabdomyolysis. Such patients should be closely monitored in 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 electrolyte disorders, uncontrolled convulsions) Atoris® therapy should be temporarily stopped or completely stopped.

Very rare cases of immune-mediated necrotizing myopathy during therapy or upon discontinuation of 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.

Prevention of stroke by actively reducing plasma concentrations of CHC(SPARCL)

In a retrospective analysis of stroke subtypes, patients without CHD who had recently had a stroke or TIA and initially received atorvastatin at a dose of 80 mg had 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 has not been determined sufficiently, therefore, the possible risk of hemorrhagic stroke in these patients should be carefully evaluated before starting therapy.

After a specific analysis of the results 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 daily, a higher rate of hemorrhagic strokes was found in the atorvastatin 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 daily 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 plasma 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 it 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 TG in plasma, arterial hypertension) should be under medical control including control 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, no clinically significant effects on growth and puberty were observed (as measured by general maturation and development, Tanner’s pubertal stage assessment, and height and body weight measurements).

Special infopinformation on excipients

Atoris® contains lactose; therefore it is contraindicated in the following conditions: lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

There are no data on the effect of atorvastatin on the ability to drive vehicles and engage in potentially hazardous 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 30 mg:

Circular, slightly biconvex film-coated tablets, white or almost white, with bevel.

tablets 60 mg:

Oval, biconvex, film-coated tablets, white or almost white in color.

tablets 80 mg:

Capsule-shaped, biconvex film-coated tablets, white or nearly white.

Contraindications

Side effects

The drug Atoris® 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;

incidence unknown: diabetes mellitus – incidence 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, elevated 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: single 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 extremities, muscle cramps, joint swelling, back pain, musculoskeletal pain;

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 ACT and ALT results in plasma, increased creatine phosphokinase (CPK) activity in serum;

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. No clinically significant effects on growth and puberty were observed in the 3-year study (as measured by general maturation and development, Tanner pubertal stage assessment, and height and body weight measurements). The safety and tolerability profile of atorvastatin in children was similar to the known profile of atorvastatin in adults.

The clinical safety database includes data from 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

There is no specific antidote for treatment of overdose with Atoris®. In case of overdose, if necessary, symptomatic treatment should be carried out. Liver function tests should be performed and serum CPK should be monitored. Since atorvastatin is actively bound to blood plasma proteins, hemodialysis is ineffective.

Pregnancy use

The drug Atoris® is contraindicated in pregnancy.

Women of reproductive age should use adequate contraceptive methods during treatment. The use of Atoris® is contraindicated in women of childbearing age who do not use adequate contraception methods.

Rare cases of congenital abnormalities have been reported following fetal exposure to HMG-CoA reductase inhibitors (statins). Toxic effects on reproductive function have been shown in animal studies. Atoris® 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