Aspavor Tablet

Hypercholesterolaemia: ASPAVOR is indicated:

• As an adjunct to diet for reduction of elevated total-cholesterol, LDL-cholesterol, apolipoprotein-B, and triglyceride levels and to moderately increase HDL-cholesterol in patients with primary hypercholesterolaemia (heterozygous familial and non-familial hypercholesterolaemia) and combined/mixed dyslipidaemia;
• To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Paediatric patients (10 u2013 17 years of age): ASPAVOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, > 10 to 17 years of age, with heterozygous familial hypercholesterolaemia if after an adequate trial of diet therapy, the following findings are present:

• LDL-C remains u2265 4,98 mmol/L (190 mg/dL) or
• LDL-C remains u2265 4,04 mmol/L (160 mg/dL) and:
• There is a positive family history of premature cardiovascular disease or
• Two or more other CVD risk factors are present in the paediatric patient

Prevention of cardiovascular complications: In patients without clinically evident cardiovascular disease, and with or without dyslipidaemia, but with multiple risk factors for coronary heart disease such as smoking, hypertension, diabetes, low HDL-C, or a family history of early coronary heart disease, ASPAVOR is indicated to:

• Reduce the risk of ischaemic cardiovascular and cerebrovascular diseases.

Secondary prevention: Prevention of cardiovascular events in patients with clinically evident coronary heart disease and increased cholesterol levels.

The patient should be placed on a standard cholesterol-lowering diet before receiving ASPAVOR and should continue on this diet during treatment with ASPAVOR. The usual starting dose is 10 mg once a day and should be individualised according to the baseline LDL-C levels, the goal of therapy, and patient response. Adjustment of dosage should only be made after an interval of 4 weeks or more. The maximum recommended daily dose will depend on the indication (see below). Doses may be given at any time of day with or without food.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia: The majority of patients are controlled with 10 mg ASPAVOR once a day. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Heterozygous familial hypercholesterolaemia in paediatric patients (> 10 u2013 17 years of age): Experience in paediatrics is limited to a small number of patients (age 10 u2013 17 years) with severe dyslipidaemias, such as familial hypercholesterolaemia. Patients should be started with ASPAVOR 10 mg daily, the maximum recommended dose is 20 mg/day.

Homozygous familial hypercholesterolaemia: In a compassionate-use, uncontrolled study of patients with homozygous familial hypercholesterolaemia, most patients responded to a dose of 80 mg of ASPAVOR, with a greater than 15 % reduction in LDL-C (18 % u2013 45 %).

Prevention of cardiovascular complications: The dosage range is 10 to 80 mg once daily.

Dosage in patients with renal insufficiency: Renal disease has no influence on the plasma concentrations or on lipid effects of ASPAVOR; thus, no adjustment of dose is required (see WARNINGS AND SPECIAL PRECAUTIONS).

Dosage in patients with hepatic dysfunction: In patients with moderate to severe hepatic dysfunction, the therapeutic response to ASPAVOR is unaffected but serum levels of the medicine are greatly increased. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Child-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease. Therefore, caution with dosage should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease (see CONTRAINDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS).

Hypersensitivity to atorvastatin or to any of the components of ASPAVOR. Active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal (see WARNINGS AND SPECIAL PRECAUTIONS). Concomitant use with rifampicin, diltiazem and grapefruit juice (see INTERACTIONS). Patients with Child-Pugh B and C (liver cirrhosis). Pregnancy and lactation (see PREGNANCY AND LACTATION).

Liver effects: Persistent elevations (> 3 times the upper limit of normal (ULN) occurring on 2 or more occasions) in serum transaminases occurred in 0,7 % of patients who received ASPAVOR in clinical trials. The incidence of these abnormalities was 0,2 %, 0,2 %, 0,6 % and 2,3 % for 10, 20, 40 and 80 mg respectively. It is recommended that liver function tests be performed before the initiation of treatment with ASPAVOR and repeated as clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with ASPAVOR, promptly interrupt therapy. If an alternate aetiology is not found, do not restart ASPAVOR. ASPAVOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of ASPAVOR (see CONTRAINDICATIONS).

Skeletal muscle: Rhabdomyolysis with or without renal impairment has been reported with the use of ASPAVOR. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Myalgia has been reported in patients treated with ASPAVOR (see SIDE EFFECTS). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values greater than 10 times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. ASPAVOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with ASPAVOR is increased with concurrent administration of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin, colchicine, the hepatitis C protease inhibitor telaprevir, boceprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, atazanavir plus ritonavir and fosamprenavir plus ritonavir and cytochrome P450 inhibitors. Medical practitioners considering combined therapy with ASPAVOR and fibric acid derivatives, erythromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, atazanavir plus ritonavir, immunosuppressive medicines, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either medicine. Muscle-related adverse events have been reported with concomitant ASPAVOR and fusidic acid. Temporary suspension of ASPAVOR may be appropriate during fusidic acid therapy (see INTERACTIONS). ASPAVOR therapy should be withdrawn in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Protease inhibitors: Co-administration of ASPAVOR and protease inhibitors was associated with increased plasma concentrations of ASPAVOR.

Haemorrhagic stroke: In a post-hoc analysis of a clinical study, patients without coronary heart disease (CHD) who had a stroke or transient ischaemic attack (TIA) within the preceding 6 months who were initiated on atorvastatin 80 mg revealed a higher incidence of haemorrhagic stroke compared to placebo. Patients with haemorrhagic stroke on entry appeared to be at increased risk for recurrent haemorrhagic stroke.

Endocrine function: Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including ASPAVOR.

Lactose intolerance: ASPAVOR tablets contain lactose. ASPAVOR should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

The risk of myopathy during treatment with ASPAVOR is increased with concurrent administration of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, niacin (nicotinic acid) or cytochrome P450 3A4 inhibitors (macrolide antibiotics e.g. erythromycin, and azole antifungals e.g. clotrimazole) (see WARNINGS AND SPECIAL PRECAUTIONS u2013 Skeletal muscle). Inhibitors of cytochrome P450 3A4: ASPAVOR is metabolised by cytochrome P450 3A4. Concomitant administration of ASPAVOR with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of ASPAVOR. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4 (see WARNINGS AND SPECIAL PRECAUTIONS).

Transporter inhibitors: Inhibitors of the OATP1B1 (e.g. ciclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of ASPAVOR 10 mg and ciclosporin 5,2 mg/kg/day resulted in an 8,7-fold increase in exposure to atorvastatin.

Erythromycin/clarithromycin: In healthy individuals, plasma concentrations of ASPAVOR increased approximately 40 % with co-administration of ASPAVOR and erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS AND SPECIAL PRECAUTIONS u2013 Skeletal muscle).

Combination of protease inhibitors: Plasma concentrations of atorvastatin increased with concomitant administration of ASPAVOR with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of ASPAVOR alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of ASPAVOR should be avoided. Concomitant administration of ASPAVOR 10 mg single dose with tipranavir 500 mg twice daily plus ritonavir 200 mg twice daily for seven days, resulted in a 9,4-fold increase in atorvastatin AUC and 8,6-fold increase in atorvastatin C max. ASPAVOR did not result in a change in pharmacokinetics of tipranavir plus ritonavir. Concomitant administration of ASPAVOR 20 mg single dose with telaprevir 750 mg every eight hours, for 10 days, resulted in a 7,9-fold increase in atorvastatin AUC and 10,6-fold increase in atorvastatin C max. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing ASPAVOR and the lowest dose necessary should be used. Concomitant administration of ASPAVOR 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5,9-fold increase in atorvastatin AUC. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, atazanavir plus ritonavir, the dose of ASPAVOR should not exceed 20 mg and should be used with caution. Concomitant administration of ASPAVOR 40 mg once a day for 4 days with saquinavir 400 mg twice daily plus ritonavir 400 mg twice daily for 15 days resulted in a 3,9-fold increase in atorvastatin AUC and 4,3-fold increase in atorvastatin C max. The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Concomitant administration of ASPAVOR 10 mg once a day for 4 days with darunavir 300 mg twice daily plus ritonavir 100 mg twice daily for 9 days resulted in a 3,4-fold increase in atorvastatin AUC and 2,3-fold increase in atorvastatin C max. Concomitant administration of ASPAVOR 10 mg once a day for 4 days with fosamprenavir 1 400 mg twice a day for 14 days resulted in a 2,3-fold increase in atorvastatin AUC and 4,0-fold increase in atorvastatin C max. ASPAVOR resulted in a 1,27-fold decrease in fosamprenavir. Concomitant administration of ASPAVOR 10 mg once a day for 4 days with fosamprenavir 700 mg twice a day plus ritonavir 100 mg twice a day for 14 days resulted in a 2,5-fold increase in atorvastatin AUC and 2,8-fold increase in atorvastatin C max. ASPAVOR did not result in a change in pharmacokinetics of fosamprenavir plus ritonavir. In patients taking nelfinavir, the dose of ASPAVOR should not exceed 40 mg daily. Concomitant administration of ASPAVOR 10 mg once a day for 28 days with nelfinavir 1250 mg twice a day for 14 days resulted in a 74 % increase in atorvastatin AUC and 2,2-fold increase in atorvastatin C max. Concomitant administration of ASPAVOR 40 mg single dose with boceprevir 800 mg three times a day for 7 days resulted in a 2,3-fold increase in atorvastatin AUC and 2,66-fold increase in atorvastatin C max (see WARNINGS AND SPECIAL PRECAUTIONS u2013 Skeletal muscle). Diltiazem hydrochloride: Co-administration of ASPAVOR with diltiazem was associated with an increase in AUC of 51 % of ASPAVOR (see CONTRAINDICATIONS). Cimetidine: Atorvastatin plasma concentrations and LDL-C reduction were not altered by co-administration of cimetidine. Itraconazole: Co-administration of ASPAVOR 40 mg, single dose and itraconazole 200 mg, once daily, was associated with a 3,3-fold increase in AUC and a 20 % increase in C max. Grapefruit juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of ASPAVOR by 2,5 to 3,3-fold and the combination should be avoided (see CONTRAINDICATIONS). Inducers of cytochrome P450 3A4: Concomitant administration of ASPAVOR with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin) can lead to variable reductions in plasma concentrations of ASPAVOR. Due to the dual interaction mechanism of rifampicin, simultaneous co-administration of ASPAVOR with rifampicin is not recommended, as delayed administration of ASPAVOR after administration of rifampicin has been associated with a significant reduction in ASPAVOR plasma concentrations. Antacids: Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides with ASPAVOR decreased plasma concentrations of atorvastatin approximately 35 %; however, LDL-C reduction was not altered. Antipyrine: Because ASPAVOR does not affect the pharmacokinetics of antipyrine, interactions with other medicines metabolised via the same cytochrome isozymes are not expected. Colestipol: Plasma concentrations of atorvastatin decreased approximately 25 % when colestipol and ASPAVOR were co-administered. However, LDL-C reduction was greater when ASPAVOR and colestipol were co-administered than when either medicine was given alone. Cholestyramine: No data are available. Digoxin: Co-administration of multiple doses of ASPAVOR and digoxin increased steady-state plasma digoxin concentrations by approximately 20 %. Patients taking digoxin should be monitored appropriately (see WARNINGS AND SPECIAL PRECAUTIONS). Azithromycin: Co-administration of ASPAVOR (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of ASPAVOR. Oral contraceptives: Co-administration of ASPAVOR and an oral contraceptive increased AUC values of norethindrone and ethinyl estradiol approximately 30 % and 20 %, respectively. These increases should be considered when selecting an oral contraceptive for a woman taking ASPAVOR. Warfarin: ASPAVOR had no clinically significant effect on prothrombin/INR time when administered to patients receiving combined ASPAVOR and warfarin therapy for two weeks. Nevertheless, patients receiving ASPAVOR should be closely monitored when ASPAVOR is combined with warfarin therapy. Colchicine: Although interaction studies with ASPAVOR and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine. Amlodipine: Atorvastatin pharmacokinetics were not altered by the co-administration of atorvastatin 80 mg and amlodipine 10 mg at steady-state. Fusidic acid: Although interaction studies with ASPAVOR and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored and temporary suspension of ASPAVOR treatment may be appropriate. Other concomitant therapy: In clinical studies, ASPAVOR was used concomitantly with antihypertensive agents and oestrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.

ASPAVOR is contraindicated in pregnancy, in mothers breastfeeding their infants and in women of childbearing potential not using adequate contraceptive measures. ASPAVOR should be administered to women of childbearing age only when such patients are using adequate contraception and have been informed of the potential hazards to the foetus. An interval of one month should be allowed from stopping ASPAVOR treatment to conception in the event of planning a pregnancy.

ASPAVOR has no or negligible influence on the ability to drive and use machines.

Adverse events have been categorised as follows: Very common: u2265 1/10 (u2265 10 %), Common: u2265 1/100 and < 1/10 (u2265 1 % and < 10 %), Uncommon: u2265 1/1 000 and < 1/100 (u2265 0,1 % and < 1 %), Rare: u2265 1/10 000 and < 1/1 000 (u2265 0,01 % and < 0,1 %), Very rare: < 1/10 000 (< 0,01 %).

Adverse events in placebo-controlled studies (% of patients)

System Organ Class Adverse event Placebo N = 270 Atorvastatin 10 mg N = 863 Atorvastatin 20 mg N = 36 Atorvastatin 40 mg N = 79 Atorvastatin 80 mg N = 94 Infections and infestations Infection Flu syndrome 10,0 1,9 10,3 2,2 2,8 0,0 10,1 2,5 7,4 3,2 Nervous system disorders Headache 7,0 5,4 16,7 2,5 6,4 Injury and poisoning Accidental injury 3,7 4,2 0,0 1,3 3,2 Gastrointestinal disorders Abdominal pain Constipation Diarrhoea Dyspepsia Flatulence 0,7 1,8 1,5 4,1 3,3 2,8 2,1 2,7 2,3 2,1 0,0 0,0 0,0 2,8 2,8 3,8 2,5 3,8 1,3 1,3 2,1 1,1 5,3 2,1 1,1

Musculoskeletal and connective tissue disorders Back pain Arthralgia Myalgia 3,0 1,5 1,1 2,8 2,0 3,2 0,0 0,0 5,6 3,8 5,1 1,3 1,1 0,0 0,0 Immune system disorders Allergic reaction 2,6 0,9 2,8 1,3 0,0 General disorders and administration site conditions Asthenia 1,9 2,2 0,0 3,8 0,0 Respiratory, thoracic and mediastinal disorders Sinusitis Pharyngitis 2,6 1,5 2,8 2,5 0,0 0,0 2,5 1,3 6,4 2,1 Skin and subcutaneous tissue disorders Rash 0.7 3,9 2,8 3,8 1,1

The following additional adverse events have been reported in atorvastatin clinical trials:

System Organ Class Frequency Side effects Blood and lymphatic system disorders Uncommon Thrombocytopenia Ear and labyrinth disorders Uncommon Tinnitus Gastrointestinal disorders Common Nausea, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence Uncommon Vomiting Rare Pancreatitis General disorders and administration site conditions Common Asthenia, chest pain Uncommon Malaise Rare Peripheral oedema Very rare Fatigue Hepatobiliary disorders Rare Hepatitis, cholestatic jaundice Immune system disorders Common Allergic reaction (including anaphylaxis) Injury and poisoning Uncommon Tendon rupture Metabolism and nutrition disorders Uncommon Hypoglycaemia, hyperglycaemia, anorexia, weight gain Nervous system disorders Common Hypoaesthesia, paraesthesia, dizziness, headache Uncommon Peripheral neuropathy, amnesia, dysgeusia Musculoskeletal and connective tissue disorders Common Myalgia, arthralgia, back pain Rare Myositis, muscle cramps Very rare Rhabdomyolysis, myopathy Psychiatric disorders Common Insomnia Reproductive system and breast disorders Uncommon Impotence Skin and subcutaneous tissue disorders Common Pruritus, rash Uncommon Alopecia, urticaria Rare Bullous rashes Very rare Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Paediatric patients: Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections.

There is no specific treatment for ASPAVOR overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive medicine binding to plasma proteins, haemodialysis is not expected to significantly enhance ASPAVOR clearance.