APPROVED BY

Order of Ministry of Healthcare

of Ukraine

                                №________

     Registration certificate

                            №________

 

 

INSTRUCTION

for medical use of the preparation

AZI-ATOR

 

Composition:

Active substance: atorvastatin, ezetimibe;

Each film-coated tablet contains atorvastatin calcium in recalculation on atorvastatin 10 mg, ezetimibe 10 mg.

Excipients: calcium carbonate; lactose monohydrate; microcrystalline cellulose; polysorbate 80; croscarmellose sodium; hydroxypropylcellulose; magnesium stearate; crospovidone; sodium lauryl sulfate; hypromellose; polyethylene glycol 6000; titanium dioxide (E 171); talc; Yellow sunset dye (E 110).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties: orange, round, biconvex, film-coated tablets.

Pharmaceutical group. Hypolipidemic agents, combinations HMG-CoA-reductase inhibitors in combination with other hypolipidemic agents. Atorvastatin and ezetimibe.

ATC Code: С10В А05.

Pharmacological properties.

Pharmacodynamics.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic low-density lipoprotein receptors on the cell surface for enhanced uptake and catabolism of low-density lipoprotein.

Atorvastatin reduces the general level of cholesterol, low-density lipoprotein, apolipoprotein B (Apo-B) and triglycerides and causes the increase of HDL cholesterol and apolipoprotein A levels. These results are recorded in patients with heterozygous familial hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-dependent diabetes mellitus.

Ezetimibe belongs to the class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and free plant fats. The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. Ezetimibe inhibited the absorption of [¹⁴C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D. Ezetimibe co-administered with atorvastatin significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia..

Pharmacokinetics.

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (C_max) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The bioavailability of the preparation is 95-99 %. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Mean volume of distribution of atorvastatin is approximately 565 l. Atorvastatin is bound to plasma proteins in more than 98%. Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. The preparation is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites. There are no pharmacokinetic data concerning children.

After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (C_max) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media. Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as Azi-Ator 10-mg tablets. Azi-Ator can be administered with or without food. 

Ezetimibe and ezetimibe-glucuronide are bound 99.7 % and 88 to 92 % to plasma proteins, respectively.

Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours. It is eliminated from the body with faeces (78%) and urine (11%) within 48 hours

Clinical particulars.

Indications.

Azi-Ator contains cholesterol absorption inhibitor and HMG-CoA reductase inhibitors (statins), therefore it is used as an adjunct to diet when the diet is limited in fats and cholesterol, or when other non-pharmacological measures are inadequate.

Primary hyperlipidaemia.

Azi-Ator is indicated to reduce elevated total cholesterol, LDL-cholesterol (LDL), apolipoprotein B (apoB), triglycerides (TG) and very low-density lipoproteins cholesterol (VLDLC) and to increase the level of cholesterol lipoproteins in patients with primary hyperlipidemia (heterozygous familial and non-family), or mixed hyperlipidemia.

Homozygous familial  hypercholesterolaemia.

Azi-Ator is indicated to reduce elevated total cholesterol, LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Homozygous sitosterolemia. Azi-Ator is indicated as an adjunctive therapy to diet for reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

Azi-Ator is indicated for prevention of cardiovascular disease in patients with diabetes mellitus 2 type with several risk factors of ischemic heart disease; in patients without clinically significant ischemic heart disease with several risk factors of ischemic heart disease development.

Contraindications.

Hypersensitivity to any component of this medicinal product.

Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.

Myopathy.

Pregnancy.

In women of child-bearing potential not using appropriate contraceptive measures.

During breast-feeding.

Children.

Interaction with other medicinal products and other forms of interaction.

The risk of myopathy during the treatment with inhibitors of HMG-CoA reductase is increased in concomitant use of cyclosporine, derivatives of fibric acid, erythromycin, azole group of antifungal drugs, HIV protease inhibitors and niacin.

CYP3A4 inhibitors. Concomitant administration of atorvastatin with CYP3A4 inhibitors (e.g. ciclosporin, erythromycin, clarithromycin, nefazodolom, antifungal azole group drugs, HIV protease inhibitors, including combination of saquinavir / ritonavir, lopinavir / ritonavir, typranavir / ritonavir) is accompanied by increased concentrations of atorvastatin in plasma. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended

In patients treated with HIV protease inhibitors darunavir + ritonavir, fosamprenavir + ritonavir or fosamprenavir, the dose of atorvastatin should not exceed 20 mg.

In patients treated with HIV protease inhibitor nelfinavir or protease inhibitor of HCV boceprevir, the dose of atorvastatin should not exceed 40 mg, and it is recommended a thorough clinical monitoring of patients. In concomitant use of tipranavir 500 mg and ritonavir 200 mg two times per day for 8 days (14 to 21) or 5.2 mg/kg/day of cyclosporine the daily dose of atorvastatin should not exceed 10 mg.

Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin.

CYP3A4 inducers. Concomitant administration of atorvastatin with CYP3A4 inducers (e.g. phenytoin, efavirenz, rifampin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin.

Gemfibrozil / fibric acid derivatives. The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. This interaction may lead to increase of atorvastatin concentrations in plasma. In the dose of 600 mg 2 times a day the concomitant use of gemfibrozil and atorvastatin increases the bioavailability of atorvastatin by 24%.

Ezetimibe. The risk of myopathy development is increased with concomitant use.

Diltiazem hydrochloride. Concomitant use of atorvastatin 40 mg and diltiazem 240 mg causes the increase of plasma concentrations of the first one.

Colestipol. Plasma concentrations of atorvastatin were lower (by approx. 25%) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone.

Fusidic acid. There is possible development of side effects in muscles, including when rhabdomyolysis is co-administrated.

Digoxin. Plasma concentrations of digoxin were not changed in prolonged use of digoxin and concomitant use of atorvastatin 10 mg. However, digoxin concentrations were increased approximately by 20%, when digoxin was co-administered with atorvastatin 80 mg per day. Patients taking digoxin should be monitored appropriately.

Oral contraceptives. Co-administration of atorvastatin with oral contraceptives containing norethindrone and ethinyl oestradiol, increases AUC of these preparations by 30 and 20%. This effect should be considered when choosing a contraceptive for women treated with atorvastatin.

Warfarin. Concomitant use of atorvastatin and warfarin may result in a slight decrease of prothrombin time during the first days after the start of therapy. So, often it is necessary to control the rate at the beginning of treatment and when changing the dosage. After its stabilization the prothrombin time control can be done in regular intervals recommended for patients treated with coumarin anticoagulants. In case when atorvastatin is discontinued the mentioned above procedure should be repeated.

Cimetidine. There were no significant interaction effects between these two drugs.

Itraconasole. Concomitant administration of atorvastatin (20-40 mg) and itraconasole (200 mg) causes the increase of atorvastatin AUC (area under the curve "concentration-time").

Antacids. Concomitant administration of oral antacid suspension containing aluminum hydroxide and magnesium reduces the plasma concentrations of atorvastatin approximately by 35%, but this had no effect on lowering of LDL cholesterol.

Amlodipine. Concomitant administration of atorvastatin 80 mg and amlodipine 10 mg showed the increase of AUC of atorvastatin by 18%.

Niacin. The risk of skeletal muscle adverse reactions can be increased by the combination of atorvastatin and niacin. Therefore, in such circumstances the lowering dose should be considered.

Rifampin or other P450 3A4 cytochrome inducers. Concomitant administration of atorvastatin and P450 3A4 cytochrome inducers (e.g. efavirenz, rifampin) can lead to the unstable reduce of plasma concentrations of atorvastatin. By means of the dual mechanism of rifampin interaction, the concomitant administration of atorvastatin and rifampin is recommended, as it has been shown that after rifampin administration the delayed use of the drug is associated with a significant decrease in plasma concentrations of atorvastatin.

Azithromycin. Concomitant administration of atorvastatin (10 mg 1 time per day) and azithromycin (500 mg 1 time per day) was not accompanied by changes in plasma concentrations of atorvastatin.

Colchicine. There were reported the cases of myopathy in concomitant administration of atorvastatin with colchicine, including rhabdomyolysis, so atorvastatin co-administrated with colchicine should be used with caution.

Grapefruit juice. It contains substances that are CYP3A4 inhibitors and can increase atorvastatin concentrations, especially when using 1.2 liters of grapefruit juice a day.

Other concomitant therapy. Atorvastatin is co-administrated with antihypertensive and hypoglycemic agents without significant interaction effects.

Ezetimibe.

Antacids.

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe.

Cholestyramine.

Concomitant administration of cholestyramine reduces AUC of ezetimibe by approximately 55%. Cholestyramine reduces low-density lipoprotein due to adding ezetimibe.

Fibrates

In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease.

If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued.

Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold respectively).

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.

Ciclosporin.

Caution should be exercised when initiating ezetimibe in the setting of ciclosporin. Ezetimibe level should be monitored.

Anticoagulants.

If ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, INR (INR ‒ international normalized ratio) should be appropriately monitored.

Special precautions for use.

Liver effects. Liver function tests should be performed before the initiation of treatment and periodically thereafter, and in any signs or symptoms suggestive of liver injury. Patients who develop increased transaminase levels should be monitored until the abnormality resolve. In case when increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist the treatment should be discontinued.

There were reports of lethal and non-lethal liver failure in patients treated with drugs of statins, including atorvastatin. In case of serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during the therapy, the treatment should be stopped immediately. If there is no alternative etiology, the drug treatment should not be re-started.

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

Hemorrhagic stroke. Atorvastatin 80 mg increases the risk of hemorrhagic stroke in patients without coronary heart disease, who had a recent stroke or transient ischemic attack. The increased risk of recurrent stroke was noted in patients with prior hemorrhagic stroke before atorvastatin therapy. At the beginning of atorvastatin treatment, for such patients, the balance of risks and benefits should be considered. As the elderly age (over 65 years) is a factor of predisposition to myopathy, the drug should be used with caution in elderly people.

Skeletal muscle effects.Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis. Rhabdomyolysis is a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.

Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis.

A CK level should be measured before starting statin treatment in the following situations: Renal impairment; hypothyroidism; personal or familial history of hereditary muscular disorders; previous history of muscular toxicity with a statin or fibrate; previous history of liver disease and/or where substantial quantities of alcohol are consumed; treating the elderly (age ≥ 70 years).

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.

Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped.If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.

If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products, such as: telithromycin, delavirdine, stiripentol, voriconazole, posaconazole. The risk of myopathy may be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin and niacin.

If possible, alternative therapies should be considered.

The risk of myopathy is also increased with concomitant use of ezetimibe and atorvastatin. It should be considered the possibility of alternative therapy by drugs that do not interact with atorvastatin. If the concomitant use of these drugs with atorvastatin is necessary, the balance of risks and benefits should be considered.

In concomitant use of drugs that increase the plasma concentrations of atorvastatin, it is recommended to reduce the initial dose of atorvastatin. Concomitant administration of cyclosporine, itraconazole and clarithromycin should reduce the maximum dose of atorvastatin and provide relevant clinical observation.

The effect on the endocrine system. There was reported that increase of HbA1c and glucose in plasma concentration was occurred due to use of HMG CoA reductase inhibitors.

Statins can effect on cholesterol synthesis and theoretically able to inhibit the secretion of steroid hormones by the adrenal glands. Caution must be exercised with the concomitant administration of statins with drugs such as ketoconazole, spironolactone, cimetidine, able to reduce the amount or activity of endogenous steroid hormones.

Interstitial lung disease.  Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus. Some data suggest that statins can lead to increased levels of glucose in the blood plasma and promote the development of diabetes in patients with high risk of development of this disease. Before treatment with statins the risk group patients (with a glucose level 5.6 to 6.9 mmol / L, body mass index> 30 kg/m², increased triglycerides and hypertension) should be examined and at the beginning of atorvastatin therapy for such patients the risk-benefit ratio should be evaluated.

Fibrates.

If cholelithiasis is suspected in a patient treated with ezytimib and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued.

Ciclosporin.

Caution should be exercised in a patient treated with ezytimib and ciclosporin. Ciclosporin concentrations should be monitored.

Anticoagulants.

If ezytimib is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored.

Excipient.

The drug contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

The therapy by means of lipidomodificated drugs should be one of the components of complex therapy for patients with a significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the result of diet, limiting consumption of saturated fats and cholesterol, as well as the use of other non-drug measures were not enough. Patients with coronary heart disease or multiple risk factors for coronary heart disease can start to take the drug with diet concomitantly.

Azi-Ator contains less than 1 mmol (23 mg) / dose of sodium that is substantially free of sodium.

Pregnancy and lactation.

Azi-Ator is contraindicated during pregnancy. Women of childbearing age should take appropriate contraceptive measures. Azi-Ator can be prescribed to women of childbearing age only when they refuse flatly its contraindications and they are well informed about the potential risk to the fetus. If the patient decides to become pregnant during the course of the treatment, she should stop taking the drug.

Azi-Ator is contraindicated during breastfeeding. It is not known whether atorvastatin is excreted in human milk. Since there is a potential risk to infants receiving breast milk during the therapy, the breastfeeding should be stopped.

Effects on ability to drive and use machines.

During the course of drug treatment dizziness, headache may occur, so you should be careful when driving vehicles or operating machines.

Way of administration and dosage.

During the course of Azi-Ator treatment patients should follow the standard hypocholesterol diet. The drug is administered at any time of the day regardless of the meal. Azi-Ator should be used from the beginning of the lipid-lowering therapy or added to mono-drugs of atorvastatin in their lack of effectiveness.

The recommended initial dose of Azi-Ator 10/10 – 1 tablet 1 time a day every day. Lipid-lowering effect becomes noticeable in 2 weeks, the maximum effect is observed in 4 weeks. After 2-4 weeks of the treatment, lipidogram should be determined to assess the initial results of the treatment and dose adjustment.

Sufficient clinical data for the use of ezetimibe in doses over 10 mg per day both individually, and in combination with HMG-CoA reductase inhibitors are not available, so it is recommended to increase the daily dose Azi-Ator. On the prevention of cardiovascular disease the therapeutic effect of atorvastatin is increased with prolonged use, so it is recommended to take Azi-Ator for a long time.

Tablets Azi-Ator should be swallowed whole. If a dose is missed, there is no need to take an extra dose.

Children.

Azi-Ator is contraindicated for children.

Overdose.

Symptoms: myopathy, rhabdomyolysis, liver dysfunction, nausea, vomiting, diarrhea.

Treatment: Specific treatment is not available for Azi-Ator overdose. In case of overdose gastric lavage should be done and activated carbon should be prescribed. Symptomatic, supportive therapy, correction of acid-base balance, electrolyte balance and eliminate the symptoms of intoxication should be carried out.

Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.

Adverse reactions.

Infections and infestations: bronchitis, sinusitis, nasopharyngitis.

General disorders: chest pain, face edema, fever, fatigue, rigid neck, weakness, malaise, photosensitivity reaction, generalized and peripheral edema, fatigue, exceptional cases of interstitial lung disease especially when long-term treatment is carried out;

Nervous system disorders: dizziness, paresthesia, drowsiness, insomnia, decreased libido, emotional lability, incoordination, peripheral neuropathy, paresthesia, torticollis, facial palsy, hyperkinesia, hypoesthesia, hypertension, headache, dysgeusia and cognitive disorders (e.g. amnesia, memory impairment, confusion);

Psychiatric disorders: depression, nightmare, insomnia;

Gastrointestinal disorders: gastrointestinal discomfort, gastroenteritis, liver dysfunction, colitis, nausea, vomiting, gastritis, dry mouth, hemorrhage rectum, esophagitis, glossitis, mouth ulcers, anorexia, increased appetite, stomatitis, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gastric ulcer, tenesmus, ulcerative stomatitis, hepatitis, esophageal reflux, pancreatitis, cholestatic jaundice, diarrhea, abdominal pain, dyspepsia, constipation, flatulence, belching, cholestasis, loss of appetite;

Skin and subcutaneous tissue disorders: alopecia, pruritus, contact dermatitis, dry skin, increased sweating, acne, hives, eczema, seborrhea, skin ulcers, rash, angioedema, bullous dermatitis (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) angioedema;

Musculoskeletal and connective tissue disorders: arthritis, arthralgia, myopathy, myalgia, myositis, muscle spasms, bursitis, tenosynovitis, myasthenia gravis, tendon contracture, rhabdomyolysis, musculoskeletal pain, muscle spasms, increased muscle fatigue, pain in extremity, neck pain, joint swelling, tendonopathy (sometimes complicated by rupture of a tendon), back pain;

Reproductive and urinary system disorders: urinary tract infection, leukocyturia, hematuria, albuminuria, urinary frequency, cystitis, dysuria, urolithiasis, nocturia, epididymitis, mastopathy, vaginal hemorrhage, uterine bleeding, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, severe delay incontinence, impotence, ejaculation disorder, gynecomastia, sexual function disorders;

Sense organ disorders: amblyopia, parosmia, loss of taste, pica;

Eye disorders: visual disturbance, vision blurred, dry eye, refraction disorder, cataract, eye hemorrhage, glaucoma;

Ear and labyrinth disorders: tinnitus, hearing loss;

Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, bronchitis, rhinitis, pneumonia, cough, dyspnea, dyspnea, asthma, epistaxis, nasopharyngitis;

Cardiovascular disorders: palpitations, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, stenocardia, hypotension, hypertension, stroke;

Metabolism and nutrition disorders: peripheral edema, hyperglycemia, increased creatine phosphokinase levels, gout, weight gain, hypoglycemia, anorexia, increased transaminases, abnormal liver function tests, increased alkaline phosphatase levels, diabetes;

Hepatobiliary disorders: abnormal liver function tests, hepatitis, holetiaz, cholecystitis, cholestatic jaundice, hepatic failure, hepatitis, cholelithiasis;

Blood and lymphatic system disorders: ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechiae;

Immune system disorders: hypersensitivity reactions, including anaphylaxis and anaphylactic shock

Laboratory tests: abnormal results of liver function tests, increased activity of blood creatine phosphokinase and gammaglutamiltransferase, increased alkaline phosphatase levels, positive analysis of the leukocytes presence in urine.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children.

Store in the original package at temperature not exceeding 25 °С.

Package. 10 tablets in a blister. 3 blisters in a box.

Terms of dispensing. On prescription.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer’s registered address

Е-28, Opp. Fire Brigade, M.I.D.C., Taloja, Dist. Raigad, Maharashtra, IN-410208, India

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of last update.