Alipto tablets

a) Hypercholesterolaemia

ALIPTO is indicated:

• As an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglyceride levels in patients with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) and combined (mixed) hyperlipidaemia (corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other non-pharmacological measures is inadequate.
• To reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if there are no treatments available.

b) Paediatric Patients (10 u2013 17 years old)

ALIPTO is indicated as an adjunct to diet to reduce total-C, LDL-C, and apolipoprotein B levels in boys and postmenarchal girls between 10 to 17 years old, with heterozygous familial hypercholesterolaemia if after an adequate trial of diet therapy the following findings are present:

• 1) LDL- C remains u2265 190 mg/du2113 (4,98 mmol/u2113) or
• 2) LDL- C remains u2265 160 mg/du2113 (4,04 mmol/u2113) 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, ALIPTO is indicated to reduce the risk of ischaemic cardiovascular and cerebrovascular diseases.

Secondary Prevention

ALIPTO is indicated in the prevention of cardiovascular events in patients with clinically evident coronary heart disease and increased cholesterol levels. Therapy with lipid-lowering agents should be a component of multiple-risk-factor intervention in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolaemia. Lipid-altering agents 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 ALIPTO, secondary causes for hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other medicine therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG.

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

Primary hypercholesterolaemia and combined hyperlipidaemia

The majority of patients are controlled with 10 mg ALIPTO once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Heterozygous familial hypercholesterolaemia in paediatric patients (> 10 u2013 17 years old)

Patients should be started with 10 mg ALIPTO 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 ALIPTO, with a greater than 15 % reduction in LDL-C (18 % - 45 %).

Prevention of cardiovascular complications

The dosage range is 10 to 80 mg once daily.

Special populations

Dosage in patients with renal insufficiency

Renal disease has no influence on the plasma concentrations or on the lipid effects of ALIPTO; thus, no adjustment of dose is required.

Dosage in patients with hepatic dysfunction

In patients with moderate to severe hepatic dysfunction, the therapeutic response to ALIPTO 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. Cmax and AUC are each 4-fold greater in patients with Child-Pugh A disease. Cmax and AUC are each 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 section 4.3 and 4.4).

Method of administration

Oral use.

• Hypersensitivity to atorvastatin or to any of the ingredients of ALIPTO.
• Active liver disease or unexplained persistent increase of serum transaminases exceeding 3 times the upper limit of normal (see section 4.4).
• Concomitant use with rifampicin, diltiazem and grapefruit juice.
• Patients with Child-Pugh B and C (liver cirrhosis).
• Pregnancy and lactation.

Liver effects: It is recommended that liver function tests should be performed before initiating treatment and periodically thereafter. Furthermore, patients who develop any signs or symptoms suggestive of liver injury should also have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in transaminases (ALT or AST) of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of ALIPTO is recommended. ALIPTO 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 contra-indications to the use of ALIPTO.

Muscle Effects: ALIPTO may affect the skeletal muscle and cause myalgia (generalised muscle pain), myositis (inflammation of muscle tissue), and myopathy (muscle aching or muscle weakness) that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine phosphokinase (CPK) values greater than 10 times the upper limit of normal. ALIPTO should be discontinued if CPK increases significantly or if myopathy is diagnosed. The risk of myopathy during treatment with ALIPTO is increased with concomitant use of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin, and cytochrome P450 inhibitors (see section 4.5). Risk of myasthenia gravis and ocular myasthenia with statin use. ALIPTO 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). ALIPTO should be used with caution in patients with renal impairment as the risk of myopathy is increased.

Before the treatment ALIPTO should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatine kinase (CK) level should be measured before starting 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
• in elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.
• situations where an increase in plasma levels may occur, such as interactions and special populations including genetic subpopulations.

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 re-measured within 5 to 7 days later to confirm the results.

Whilst on treatment

• 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 ALIPTO or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
• ALIPTO must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Protease inhibitors

Co-administration of ALIPTO and protease inhibitors increases plasma concentrations of ALIPTO.

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.

Increase in glycosylated haemoglobin (HbAIB) and fasting serum glucose levels have been reported with statin use.

Products containing mannitol may have a laxative effect or cause diarrhoea.

ALIPTO 10/ 20/ 40: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium-freeu2019.

ALIPTO 80: This medicinal product contains 23,44 mg sodium per tablet equivalent to 1,17 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The most serious consequence of interactions with ALIPTO is the development of myopathy or rhabdomyolysis. Medicines that cause myopathy when given alone increase the risk of myopathy with ALIPTO; these medicines include fibric acid derivatives (fibrates or gemfibrozil), and nicotinic acid. The risk of myopathy is also increased by medicines that increase the plasma concentrations of ALIPTO, by inhibiting their metabolism or by inhibiting their uptake into the liver.

Inhibitors of cytochrome P450 3A4: ALIPTO is metabolised by the cytochrome P450 isoenzyme CYP3A4 and interactions may occur with medicines that inhibit this enzyme, including immunosuppressants (ciclosporin), itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV-protease inhibitors, nefazodone, danazol, amiodarone, and verapamil. There may also be a similar interaction with grapefruit juice. Such combinations should be used with caution, if at all, and dose reduction may be revised. Rhabdomyolysis may be reported when atorvastatin is given with the non-nucleoside reverse transcriptase inhibitor delavirdine. Rhabdomyolysis and hepatitis have also been reported in patients receiving atorvastatin with diltiazem.

Inducers of cytochrome P450 3A4: Concomitant administration of ALIPTO with inducers of cytochrome P450 isoenzyme CYP3A4 (e.g. efavirenz, rifampicin, St. Johnu2019s Wort) can lead to variable reductions in the plasma concentrations of ALIPTO. Due to the dual interaction mechanism of rifampicin, simultaneous co-administration of ALIPTO with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in ALIPTO plasma concentrations.

Antacids: Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides decreases plasma concentrations of ALIPTO approximately 35 %, however, LDL-C reduction is not altered.

Colestipol: Plasma concentrations of ALIPTO decreased approximately 25 % when colestipol and ALIPTO were co-administered. However, LDL-C reduction was greater when ALIPTO and colestipol were co-administered than when either medicine was given alone.

Digoxin: Co-administration of multiple doses of ALIPTO and digoxin increased steady-state plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately.

Oral contraceptives: Co-administration of ALIPTO with an oral contraceptive produces increases in plasma concentrations of norethindrone and ethinyl oestradiol.

Warfarin: Prothrombin time should be determined before starting ALIPTO in patients taking warfarin or other oral anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on warfarin or other oral anticoagulants. If the dose of ALIPTO is changed or discontinued, the same procedure should be repeated.

Ticagleror: Co-administration of ALIPTO and ticagrelor increased atorvastatin acid C max by 23 % and AUC by 36 %. Similar increases in AUC and C max were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.

ALIPTO is contraindicated in pregnancy, during breastfeeding and in women of child-bearing potential (see section 4.3). Women of child-bearing potential should use appropriate contraceptive measures during treatment. An interval of one month should be allowed from stopping ALIPTO treatment to conception in the event of planning a pregnancy. Treatment with ALIPTO should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.

The product causes some serious or frequent side effects such dizziness, headache, confusion and memory loss, which may impact the ability to drive or operate machines. Patients should be advised not to drive or use machines until they know how ALIPTO affects them.

Blood and lymphatic system disorders

Less frequent Thrombocytopenia

Ear and labyrinth disorders

Less frequent Tinnitus, hearing loss

Eye disorders

Less frequent Blurred vision, visual disturbances

Frequency unknown Ocular myasthenia

Gastrointestinal disorders

Frequent Nausea, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence

Less frequent Vomiting, eructation, pancreatitis

General disorders and administration site conditions

Frequent Asthenia, chest pain

Less frequent Malaise, peripheral oedema, fatigue, pyrexia

Hepatobiliary disorders

Less frequent Hepatitis, cholestatic jaundice, hepatic failure

Immune system disorders

Frequent Allergic reactions (including anaphylaxis), angioedema

Injury, poisoning and procedural complications

Less frequent Tendon rupture

Metabolism and nutrition disorders

Less frequent Hypoglycaemia, hyperglycaemia, anorexia, weight gain

Nervous system disorders

Frequent Hypoaesthesia, paraesthesia, dizziness, headache

Less frequent Peripheral neuropathy, amnesia, dysgeusia

Frequency unknown Myasthenia gravis

Musculoskeletal and connective tissue disorders

Frequent Myalgia, arthralgia, back pain

Less frequent Myositis, muscle cramps, rhabdomyolysis, myopathy, neck pain, muscle fatigue, tendonopathy, sometimes complicated by rupture

Psychiatric Disorders

Less frequent Nightmare, insomnia, memory loss, forgetfulness, confusion

Reproductive system and breast disorders

Less frequent Impotence, gynaecomastia

Skin and subcutaneous tissue disorders

Frequent Pruritus, rash

Less frequent Alopecia, urticaria, bullous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Infections and infestations

Frequent Nasopharyngitis

Investigations

Frequent Abnormal liver function test, increased blood creatine kinase

Less frequent Positive white blood cells urine

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of ALIPTO is important. It allows continued monitoring of the benefit/risk balance of ALIPTO. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Report all side effects to Unimed Healthcare (Pty) Ltd. By reporting side-effects, you can help provide more information on the safety of ALIPTO.

Symptoms

There is no specific treatment available for ALIPTO overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.