Dezzolip 10/20/40/80 10mg/20mg/40mg/80mg Film coated tablet

a) Hypercholesterolaemia

DEZZOLIP 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)

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

Secondary Prevention

DEZZOLIP 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 DEZZOLIP, 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 DEZZOLIP and should continue on this diet during treatment with DEZZOLIP. 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 DEZZOLIP 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 DEZZOLIP 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 DEZZOLIP, 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.

Dosage in patients with renal insufficiency

Renal disease has no influence on the plasma concentrations or on the lipid effects of DEZZOLIP; 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 DEZZOLIP 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 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 4.3 and 4.4).

• Hypersensitivity to atorvastatin or to any of the ingredients of DEZZOLIP.
• Active liver disease or unexplained persistent increase of serum transaminases exceeding 3 times the upper limit of normal (See 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 DEZZOLIP is recommended.

DEZZOLIP 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 DEZZOLIP.

Skeletal Muscle: DEZZOLIP 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. DEZZOLIP should be discontinued if CPK increases significantly or if myopathy is diagnosed.

The risk of myopathy during treatment with DEZZOLIP is increased with concomitant use of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin, and cytochrome P450 inhibitors (See 4.5).

DEZZOLIP 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).

DEZZOLIP should be used with caution in patients with renal impairment as the risk of myopathy is increased.

Before the treatment DEZZOLIP 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 DEZZOLIP or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
• DEZZOLIP 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 DEZZOLIP and protease inhibitors increases plasma concentrations of DEZZOLIP.

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.

The most serious consequence of interactions with DEZZOLIP is the development of myopathy or rhabdomyolysis. Medicines that cause myopathy when given alone increase the risk of myopathy with DEZZOLIP; 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 DEZZOLIP, by inhibiting their metabolism or by inhibiting their uptake into the liver.

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

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

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

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

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

Warfarin: Prothrombin time should be determined before starting DEZZOLIP 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 DEZZOLIP is changed or discontinued, the same procedure should be repeated.

DEZZOLIP is contraindicated in pregnancy, during breastfeeding and in women of child-bearing potential (See 4.3). Women of child-bearing potential should use appropriate contraceptive measures during treatment. An interval of one month should be allowed from stopping DEZZOLIP treatment to conception in the event of planning a pregnancy.

Treatment with DEZZOLIP should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.

DEZZOLIP has negligible influence on the ability to drive and use machines.

Infections and infestations

Frequent: Nasopharyngitis

Blood and lymphatic system disorders

Less frequent: Thrombocytopenia

Immune system disorders

Frequent: Allergic reactions (including anaphylaxis), angioedema

Metabolism and nutrition disorders

Less frequent: Hypoglycaemia, hyperglycaemia, anorexia, weight gain

Psychiatric disorders

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

Nervous system disorders

Frequent: Hypoaesthesia, paraesthesia, dizziness, headache

Less frequent: Peripheral neuropathy, amnesia, dysgeusia

Eye disorders

Less frequent: Blurred vision, visual disturbances

Ear and labyrinth disorders

Less frequent: Tinnitus, hearing loss

Gastrointestinal disorders

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

Less frequent: Vomiting, eructation, pancreatitis

Hepato-biliary disorders

Less frequent: Hepatitis, cholestatic jaundice, hepatic failure

Skin and subcutaneous tissue disorders

Frequent: Pruritus, rash

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

Musculoskeletal, connective tissue and bone disorders

Frequent: Myalgia, arthralgia, back pain

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

Reproductive system and breast disorders

Less frequent: Impotence, gynaecomastia

General disorders and administrative site conditions

Frequent: Asthenia, chest pain

Less frequent: Malaise, peripheral oedema, fatigue, pyrexia

Investigations

Frequent: Abnormal liver function test, increased blood creatine kinase

Less frequent: Positive white blood cells urine

Injury and poisoning

Less frequent: Tendon rupture

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of DEZZOLIP is important. It allows continued monitoring of the benefit/risk balance of DEZZOLIP. 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 Unicorn Pharmaceuticals (Pty) Ltd at [email protected] By reporting side-effects, you can help provide more information on the safety of DEZZOLIP.

Symptoms

There is no specific treatment available for DEZZOLIP 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.