Atoris, 20 mg 90 pcs.

Cholesterol, Heart attack and stroke prevention, Cholesterol reduction

Hypercholesterolemia:

– 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.

– Prevent cardiovascular disease:

– 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 cardiac–-vascular complications in patients with CHD to reduce mortality, MI, strokes, repeat hospitalizations for angina and need for revascularization.

Active ingredient

Composition

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

nucleus

Active substance:

Calcium atorvastatin 10.36 mg/20.72 mg, equivalent to atorvastatin 10.00 mg/20.00 mg

Associates:

Povidone-K25, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate

Film film jacket

Opadray IIHP 85F28751 white*

*Opadray IIHP 85F28751 white:

Polyvinyl alcohol, titanium dioxide (E171), macrogol-3000, 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 Atoris® one should try to control hypercholesterolemia by diet, exercise and weight loss in obese patients as well as by therapy of the main disease.

The patient should be advised a standard hypocholesterolemic diet to be followed throughout therapy 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 plasma lipid concentration every 2- 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 and 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 daily (18-45% reduction in plasma LDL-C concentration).

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 Atoris® must be adjusted depending on the goal of hypolipidemic therapy. Dose adjustments should be made at intervals of 4 weeks or more.

Liver function impairment

In patients with impaired liver function, the dose of Atoris® should be decreased with regular monitoring of serum activity of “liver” 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 Atoris® 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 Atoris® 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.

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 patients who consume significant amounts of alcohol, age over 70 years, situations in which an increase in plasma concentration of atorvastatin is expected [e.g., interaction with other medicinal products]).

Contraindicated in persons under 18 years of age (insufficient clinical data on the effectiveness and safety of the drug in this age group), except for heterozygous familial hypercholesterolemia (use contraindicated in children under 10 years).

In children aged 10 to 17 years who received atorvastatin, the adverse event profile was 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.

In an 8-week open-label study, children with a Tanner score of 1 (N = 15) and ≥2 (N = 24) (ages 6-17) with heterozygous familial hypercholesterolemia and a baseline LDL-C concentration ≥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 action of atorvastatin and o-hydroxyatorvastatin, there was a consistent decrease in CH – LDL and CH

Kidney function impairment

Renal dysfunction does not affect the plasma concentration of atorvastatin or lipid metabolism parameters, therefore, there is no need to change the dose in patients with impaired renal function.

There have been no studies of atorvastatin use in patients with end-stage renal failure. Atorvastatin is not excreted during hemodialysis due to intense binding to blood plasma proteins.

Liver function impairment

The drug concentration is significantly increased (Cmax-about 16-fold, AUC-about 11-fold) in patients with alcoholic cirrhosis (Child-Pugh class B).

Hepatic uptake of all HMG-CoA-reductase inhibitors, including atorvastatin, involves the OATP1B1 transporter. Patients with SLCO1B1 genetic polymorphism are at risk of increased atorvastatin exposure, which may lead to an increased risk of rhabdomyolysis. Polymorphism of the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with 2.4 times higher exposure (AUC) to atorvastatin compared to patients without such a genotypic change (c.521TT). Impaired hepatic uptake of atorvastatin associated with genetic abnormalities may also be observed in these patients. Possible effects with regard to efficacy are unknown.

Elderly patients

Plasma concentrations of atorvastatin are higher (Cmax by approximately 40%, AUC by approximately 30%) in patients older than in young adult patients. No differences in efficacy and safety of the drug, as well as in achieving the goals of hypolipidemic therapy in elderly patients compared to the general population were found.

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 activity of “hepatic” transaminases ACT and ALT was noted with 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 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 more than 3 times compared to the upper limit of normal is still observed, it is recommended to reduce the dose or cancel Atoris® (see section “Side effects”).

The drug 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 “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® should be discontinued in case of marked 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 the plasma concentration 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 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/day), a physician should carefully weigh the expected benefit of treatment against the 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 disorder,

– 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 plasma concentrations are expected to increase, such as interactions with other drugs.

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.

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 monitored more closely for the musculoskeletal system. If there are symptoms of myopathy or risk factors of renal failure against the background of rhabdomyolysis (e.g., severe acute infection, arterial hypotension, extensive surgery, trauma, metabolic, endocrine and water-electrolyte disorders, uncontrolled convulsions), treatment with Atoris therapy should be provided.sup>® should be temporarily discontinued or completely stopped.

Very rare cases of immune-mediated necrotizing myopathy have been reported during therapy or when statins are stopped. 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.

Preventing stroke by actively reducing plasma cholesterol concentrations (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 these 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 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, 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 Atoris® 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 the drug Atoris® on the ability to drive vehicles and engage in potentially dangerous activities that require high concentration and quick psychomotor reactions. However, taking into account the possibility of development of dizziness, caution should be exercised when performing the listed activities.

Synopsis

Round, slightly biconvex tablets with white or almost white film coating.

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

Contraindications

– Hypersensitivity to any component of the drug.

Active liver disease or an increase in plasma “liver” transaminases of unknown origin of more than 3 times the upper limit of normal.

– Pregnancy.

Breast-feeding period.

– Women of childbearing age not using adequate contraception.

– Age under 18 years (there is 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).

– Concurrent use with fusidic acid.

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;

frequent 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, 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: 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 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

There is no specific antidote for treatment of overdose with Atoris®. 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 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 events in infants.

Similarities