Lipogen 10/20/40/80 mg Film coated tablets

(a) Hypercholesterolaemia

LIPOGEN is indicated:

• As an adjunct to diet for reduction of elevated total-cholesterol, LDL-cholesterol, apolipoprotein-B, and triglyceride levels in patients with primary hypercholesterolaemia (heterozygous familial) and mixed dyslipidaemia (Fredrickson Types IIa and IIb);
• 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.

(b) Paediatric Patients (10-17 years of age)

LIPOGEN 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/u2113 (190 mg/du2113) or
• LDL-C remains u2265 4,04 mmol/u2113 (160 mg/du2113) 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.

(c) 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, atorvastatin is indicated to:

• reduce the risk of ischaemic cardiovascular and cerebrovascular diseases.

Secondary Prevention

LIPOGEN is indicated in the prevention of cardiovascular events in patients with clinically evident coronary heart disease and increased cholesterol levels. Therapy with LIPOGEN should be a component of multiple-risk-factor intervention in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolaemia. LIPOGEN should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate. Prior to initiating therapy with atorvastatin, secondary causes for hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C and TG.

Posology

Patients should be on standard cholesterol-lowering diets prior to initiation of treatment with LIPOGEN and they should remain on such diets during treatment with LIPOGEN. The usual LIPOGEN starting dose is 10 mg once daily. Doses need to be individualised based on the patientu2019s baseline LDL-C levels, the goal of therapy and the patientu2019s response to therapy. Dosages should only be adjusted after an interval of 4 weeks or more. The indication will determine the maximum recommended dose (see below). LIPOGEN can be taken any time of the day with or without food.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia:

Most patients are controlled on LIPOGEN 10 (10 mg) once daily. Although a therapeutic response is evident within 2 weeks of initiation of therapy, it usually takes 4 weeks to achieve maximum response. The response is sustained during chronic therapy.

Heterozygous familial hypercholesterolaemia in paediatric patients (> 10-17 years of age): Treatment should be initiated with LIPOGEN 10 mg daily. The maximum recommended dose is 20 mg/day.

Homozygous familial hypercholesterolaemia in adults: In a compassionate-use, uncontrolled trial in which 29 patients with homozygous familial hypercholesterolaemia participated, most patients responded to a 80 mg atorvastatin dose, with a mean reduction in LDL-C of 20 % (range 7 % - 53 %). However, some patients experienced an increase in LDL-C.

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

Special populations

Dosage in patients with renal insufficiency: No dose adjustment is required in patients with renal disease, since renal disease does not influence the plasma concentrations nor the lipid effects of LIPOGEN.

Dosage in patients with hepatic dysfunction: Although the therapeutic response to LIPOGEN is not affected, serum levels of atorvastatin are greatly increased in patients with moderate to severe hepatic dysfunction. Patients with chronic alcoholic liver disease demonstrate markedly increased plasma concentrations of LIPOGEN. In patients with Child-Pugh A disease there is a 4-fold increase in C max and AUC, while C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease. Caution with dosage is therefore required in patients who consume substantial quantities of alcohol and/or have a history of hepatic disease (see sections 4.3 and 4.4).

Method of administration

Oral use. LIPOGEN can be taken any time of the day, with or without food.

LIPOGEN is contra-indicated in:

• Patients with hypersensitivity to atorvastatin or to any component of LIPOGEN listed in section 6.1
• Patients with active liver disease or persistent elevations of serum transaminases exceeding three times the upper limit of normal.
• During pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6)
• Patients who concomitantly use rifampicin, diltiazem and grapefruit juice.
• Patients with Child-Pugh B and C liver cirrhosis.
• Patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir

Liver effects: Statins like LIPOGEN have been associated with biochemical abnormalities of liver function. Persistent elevations [> 3 times the upper limit of normal (ULN) which occurred on 2 or more occasions] in serum transaminases occurred at incidences of 0,2 %, 0,2 %, 0,6 % and 2,3 % for 10, 20, 40 and 80 mg atorvastatin, respectively. Upon dose reduction, interruption of treatment, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Jaundice has been reported in patients treated with atorvastatin, as in LIPOGEN. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin as in LIPOGEN.

It is recommended that patients undergo liver functions tests before commencement of treatment, following each increase in dosage, and periodically thereafter. Changes in liver enzyme values mostly commence in the first 4 months of treatment with LIPOGEN. Patients who develop increases in transaminase levels require monitoring until the abnormalities have resolved. It is recommended that LIPOGEN be withdrawn if increases in ALT or AST of > 3 times ULN persist. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with LIPOGEN, promptly interrupt therapy. If an alternate aetiology is not found, do not restart LIPOGEN.

LIPOGEN should be administered with caution to patients who consume substantial quantities of alcohol and/or have a history of liver disease. Use of LIPOGEN is contra-indicated in patients with active liver disease or unexplained persistent transaminase elevations.

Haemorrhagic stroke / use in patients with recent stroke or transient ischaemic attack (TIA): Post-hoc analysis of a clinical study indicated that patients without coronary heart disease (CHD) who had a stroke or transient ischaemic attack (TIA) within the preceding 6 months of starting atorvastatin, as in LIPOGEN had a higher incidence of haemorrhagic stroke compared to patients who received placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1).

Skeletal muscle: LIPOGEN, like other HMG-CoA reductase inhibitors may affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, 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. There have been reports of rhabdomyolysis with or without renal impairment in patients who took HMG-CoA reductase inhibitors, such as LIPOGEN. Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin, as in LIPOGEN and with other statins.

A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Before the treatment 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
• Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and special populations including genetic subpopulations (see section 5.2)

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.

Creatine kinase measurement: Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.

Whilst on treatment u2013 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 u2264 5 x ULN, treatment discontinuation should be considered.

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

LIPOGEN must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected. A diagnosis of myopathy should be considered in any patient who presents with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to promptly report any of the following symptoms: unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. If markedly elevated CPK levels occur or if myopathy is diagnosed or suspected, treatment with LIPOGEN should be discontinued.

Effect of co-administered medicinal products on atorvastatin

Co-administration of LIPOGEN with immunosuppressive medicines, fibric acid derivatives, niacin (nicotinic acid) in lipid-modifying doses, or cytochrome P450 3A4 inhibitors (ciclosporin, macrolide antibiotics, e.g. clarithromycin or erythromycin and azole antifungals, and HIV protease inhibitors) increases the risk of myopathy (see section 4.4).

Inhibitors of cytochrome P450 3A4: Since LIPOGEN is metabolised by cytochrome P450 3A4 (CYP3A4), co-administration of LIPOGEN with cytochrome P450 3A4 inhibitors can cause increases in LIPOGEN plasma concentrations. The variability of effect on cytochrome P450 3A4 determines the extent of interaction and potentiation of effects (see section 4.4). Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin. Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicines with LIPOGEN cannot be avoided lower starting and maximum doses of LIPOGEN should be considered and appropriate clinical monitoring of the patient is recommended.

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with LIPOGEN may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of LIPOGEN should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.

Erythromycin / clarithromycin: In healthy individuals, LIPOGEN plasma concentrations increased approximately 40 % with concurrent administration of erythromycin, a known inhibitor of cytochrome P450 3A4. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the LIPOGEN dose exceeds 20 mg (see section 4.4).

Combination of protease inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin as in LIPOGEN with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Co-administration of atorvastatin (40 mg once daily) with ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) resulted in a 3-fold increase in atorvastatin AUC. Co-administration of atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5,9 fold increase in atorvastatin AUC (see section 4.4). Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LIPOGEN should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LIPOGEN and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of LIPOGEN should not exceed 20 mg and should be used with caution (see section 4.4). In patients taking the HIV protease nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of LIPOGEN should not exceed 40 mg and close clinical monitoring is recommended.

Diltiazem hydrochloride: Concurrent administration of LIPOGEN with diltiazem is associated with a 51 % increase in the AUC of LIPOGEN (see section 4.3).

Cimetidine: Co-administration of LIPOGEN and cimetidine does not alter atorvastatin plasma concentrations or LDL-C reductions.

Grapefruit juice: One or more components of grapefruit juice inhibit CYP 3A4 and can cause increases in plasma concentrations of LIPOGEN by a factor of 2,5 to 3,5. This combination should therefore be avoided (see section 4.3).

Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the LIPOGEN dose exceeds 20 mg.

Inducers of cytochrome P450 3A4: Co-administration of LIPOGEN with medicines that induce cytochrome P450 3A4 (e.g. efavirenz, rifampicin, St. John's Wort) can cause variable reductions in plasma concentrations of LIPOGEN. Due to the dual interaction mechanism of rifampicin (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of LIPOGEN with rifampicin is not recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampicin on atorvastatin concentrations in hepatocytes is however unknown.

The concomitant administration of LIPOGEN and rifampicin is contra-indicated.

Antacid: Concurrent administration of oral antacid suspensions that contain magnesium and aluminium hydroxides with LIPOGEN will reduce plasma concentrations of atorvastatin by approximately 35 %. However, this does not alter the extent of LDL-C reduction.

Antipyrine: Because LIPOGEN does not affect the pharmacokinetics of antipyrine, interactions with other medicines metabolised via the same cytochrome isozymes are not expected.

Colestipol: Concomitant administration of colestipol and LIPOGEN will reduce LIPOGEN plasma concentrations with approximately 25 %. However, the reduction in LDL-C is greater when LIPOGEN and colestipol is given concurrently than when either medicine is administered alone.

Digoxin: Concurrent administration of multiple doses of LIPOGEN and digoxin can increase steady-state digoxin plasma concentrations by approximately 20 %. Patients receiving digoxin need to be monitored appropriately (see section 4.4).

Azithromycin: Concurrent administration of LIPOGEN (10 mg once daily) and azithromycin (500 mg once daily) does not change the plasma concentrations of atorvastatin.

Oral contraceptives: When LIPOGEN is co-administered with an oral contraceptive, increases in AUC values of norethindrone and ethinyl oestradiol of approximately 30 % and 20 %, respectively, may occur. These increases should be taken into account when an oral contraceptive is selected for a woman on LIPOGEN.

Warfarin: Prothrombin time/INR should be determined before starting LIPOGEN in patients taking anticoagulants such as warfarin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time/INR occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on anticoagulant therapy. If the dose of LIPOGEN is changed or discontinued, the same procedure should be repeated. Patients receiving LIPOGEN should be closely monitored when LIPOGEN is combined with warfarin therapy.

Amlodipine: Co-administration of LIPOGEN 80 mg and amlodipine 10 mg does not alter LIPOGEN pharmacokinetics at steady state.

Other concomitant therapy: No evidence of clinically significant adverse interactions have been reported when atorvastatin, such as contained in LIPOGEN was used concomitantly with antihypertensive medicines and oestrogen replacement therapy. However, interaction studies with specific medicines have not been performed.

Ciclosporin / transport protein inhibitors: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 / transport proteins (e.g. ciclosporin) can increase the bioavailability of atorvastatin. The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and ciclosporin 5,2 mg/kg/day compared to that of atorvastatin alone. The co-administration of LIPOGEN with ciclosporin should be avoided.

Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of LIPOGEN with gemfibrozil should be avoided (see section 4.4).

Other fibrates / fibric acid derivatives: The use of fibrates alone is occasionally associated with muscle related events, including myopathy / rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and LIPOGEN. If concomitant administration cannot be avoided, the lowest dose of LIPOGEN to achieve the therapeutic objective should be used and the patients should be appropriately monitored.

Ezetimibe: The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and LIPOGEN. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid: Interaction studies with LIPOGEN and fusidic acid have not been conducted. Muscle related events, including rhabdomyolysis, have been reported with atorvastatin as in LIPOGEN and fusidic acid when given concurrently. The mechanism of this interaction is not known. The concurrent use of LIPOGEN and fusidic acid is not recommended, and therefore, patients should be closely monitored and temporary suspension of LIPOGEN treatment may be appropriate.

Niacin: The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; a reduction in LIPOGEN dosage should be considered in this setting.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing LIPOGEN with colchicine.

Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

LIPOGEN is contra-indicated in pregnancy and lactation as well as in women of childbearing potential who are not making use of adequate contraception. LIPOGEN 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. If a pregnancy is being planned, an interval of one month should be allowed from discontinuing LIPOGEN treatment to conception.

Breastfeeding

Women who are breastfeeding should be advised to not use LIPOGEN. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.

Fertility

It is reported that atorvastatin had no effect on male or female fertility.

LIPOGEN has negligible influence on the ability to drive and use machines. However, LIPOGEN may cause dizziness and blurred vision that can impair a patientu2019s ability to drive or use machinery.

MedRA System organ class

Frequency

Adverse Effects

Infections and infestations

Frequent

Nasopharyngitis.

Blood and lymphatic system disorders

Less frequent: Thrombocytopenia.

Immune system disorders

Frequent

Allergic reactions.

Less frequent: Anaphylaxis, angioedema.

Metabolism and nutrition disorders

Frequent

Hyperglycaemia, HbA1c glycosylated haemoglobin increases

Less frequent: Hypoglycaemia, weight gain, anorexia.

Unknown frequency

Diabetes mellitus

Psychiatric disorders

Less frequent

Nightmare, insomnia.

Unknown frequency: Depression, cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).

Nervous system disorders

Frequent

Headache.

Less frequent

Dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia, peripheral neuropathy, haemorrhagic stroke (see section 4.4)

Eye disorders

Less frequent

Blurred vision, visual disturbance

Ear and labyrinth disorders

Less frequent

Tinnitus, hearing loss

Respiratory, thoracic and mediastinal disorders

Frequent

Pharyngolaryngeal pain, epistaxis.

Unknown frequency

Interstitial lung disease (see section 4.4 Special warnings and precautions for use)

Gastro-intestinal disorders

Frequent

Constipation, flatulence, dyspepsia, nausea, diarrhoea

Less frequent

Vomiting, upper and lower abdominal pain, eructation, pancreatitis

Unknown frequency

Abdominal discomfort.

Hepatobiliary disorders

Less frequent

Hepatitis, cholestasis, jaundice, hepatic failure.

Skin and subcutaneous tissue disorders

Less frequent

Urticaria, skin rash, pruritus, alopecia, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Frequent

Myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.

Less frequent

Neck pain, muscle fatigue, myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture

Unknown frequency

Musculoskeletal pain.

Renal and urinary disorders

Unknown frequency

Urinary tract infection

Reproductive system and breast disorders

Less frequent

Gynaecomastia

Unknown frequency

Sexual dysfunction

General disorders and administration site conditions

Less frequent

Malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Frequent

Abnormal liver function test, increased blood creatine kinase

Less frequent

Positive white blood cells urine.

Frequency unknown: Increased blood alkaline phosphatase, increase hepatic enzyme, elevated hepatic/serum transaminases (including increase alanine aminotransferase), elevated serum creatine kinase (CK) levels (see section 4.4).

Description of selected adverse reactions

Paediatric patients (ages 10-17 years)

The most frequent adverse reactions are infections. Other frequent adverse events reported in children are headache, abdominal pain, increased alanine aminotransferase, increased blood creatine phosphokinase. Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is limited experience with respect to long-term safety in the paediatric population.

There is no specific treatment for overdosage with LIPOGEN. Should an overdose occur, symptomatic and supportive measures should be instituted as required. Liver function tests should be performed and serum CK levels should be monitored. Since atorvastatin is extensively bound to plasma proteins, haemodialysis is not expected to significantly contribute to LIPOGEN clearance.