INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PRANALIP ™ 10 mg TABLETS
PRANALIP ™ 20 mg TABLETS
PRANALIP ™ 40 mg TABLETS

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

PRANALIP ™ 10 mg TABLETS
PRANALIP ™ 20 mg TABLETS
PRANALIP ™ 40 mg TABLETS

COMPOSITION
Each PRANALIP 10 mg tablet contains Pravastatin sodium 10 mg
Each PRANALIP 20 mg tablet contains Pravastatin sodium 20 mg
Each PRANALIP 40 mg tablet contains Pravastatin sodium 40 mg

PHARMACOLOGICAL CLASSIFICATION
A 7.5 Serum cholesterol reducers

PHARMACOLOGICAL ACTION
Pravastatin is a cholesterol-lowering agent derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, pravastatin, an inactive lactone, is hydrolysed to the corresponding beta-hydroxyacid, the active form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate - limiting step in the biosynthesis of cholesterol. As a result, pravastatin, reduces total plasma cholesterol, low - density lipoprotein (LDL)- and very low- density lipoprotein(VLDL) –cholesterol concentrations. Apolipoprotein B is also decreased. In addition, pravastatin moderately increases high - density lipoprotein (HDL)-cholesterol and variably reduces plasma triglycerides.
Pharmacokinetics:
There is an extensive first-pass extraction by the liver, with oral bioavailability of the active medicine or metabolites being less than 5%. More than 95% of pravastatin and its beta- hydroxy metabolite are bound to plasma proteins. Following an oral dose, peak plasma concentrations of pravastatin are seen in 1 - 2 hours. Pravastatin is excreted primarily via the liver, and less than 13% of its metabolites are excreted in the urine.

INDICATIONS:
HYPERCHOLESTEROLAEMIA
PRANALIP is indicated, in combination with diet, to decrease elevated serum total cholesterol and LDL-cholesterol in patients with:
Primary hypercholesterolaemia,
Heterozygous familial hypercholesterolaemia, or
Mixed hyperlipidaemia,
when response to diet or other nonpharmacological measures alone are adequate.
CORONARY HEART DISEASE (PREVENTION)
PRANALIP is indicated in patients with coronary heart disease hypercholesterolaemia unresponsive to diet, to:
Reduce the risk of total mortality, by reducing coronary death,
Reduce the risk of non- fatal myocardial infarction,
Reduce the risk of undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) and
Slow the progression of coronary atherosclerosis.

CONTRA-INDICATIONS
Hypersensitivity to PRANALIP, other HMG-CoA reductase inhibitors or any of the ingredients
Acute or chronic liver disease
Unexplained persistent elevations of serum transaminases.
Pregnancy and lactation (see warnings).
Porphyria: Safety has not been established.

WARNINGS:
The active metabolite of PRANALIP is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child - bearing potential.
Use in paediatric patients is not recommended, as safety and efficacy have not been established.

INTERACTIONS
Myopathy caused by medicine interactions:
Concomitant administration of medicines that inhibit cytochrome P450 isoenzyme CYP3A4 may result in high plasma levels of PRANALIP, thus increasing the risk of myopathy, and is not recommended. Medicines that inhibit cytochrome P450 isoenzyme CYP3A4 include cyclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone.
The risk of myopathy is increased when other medicines that cause myopathy, such as fibrates and niacin, are given with PRANALIP. A maximum dose of 10 mg PRANALIP daily is recommended in patients taking cyclosporin, fibrates or lipid lowering doses of niacin (nicotinic).
Digoxin:
PRANALIPmay cause increases in digoxin levels.
Coumarin-derivatives (e.g Warfarin):
A possible increase in the anticoagulant effect of the coumarin anticoagulants may occur. Patients taking coumarin anticoagulant should have their INR determined before starting PRANALIP therapy. The INR should be monitored frequently enough in the early stages of therapy until stabilised. Once a stable INR has been documented, INR can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. When there is a dose adjustment of PRANALIP, this procedure should be repeated.
Bile acid sequestrants.
PRANALIPshould be taken 1 hour before or 4 hours after cholestyramine.
Concurrent use may decrease the bioavailability of PRANALIP.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation have not been established.
The active metabolite of PRANALIP is fetotoxic and teratogenic in rats, and it should therefore not be used in female patients of child- bearing potential.

DOSAGE AND DIRECTIONS FOR USE
The patient must follow a cholesterol-lowering diet before initiation of, and while on PRANALIP therapy.
HYPERCHOLESTEROLAEMIA:
Adults: Initial dose: 10 mg daily as a single dose in the evening.
The dose of PRANALIP should be reduced if LDL- cholesterol levels fall below 1,94 mmol/L or total plasma cholesterol levels fall below 3,6 mmol/L.
CORONARY HEART DESEASE:
Adults: Initial dose: 20 mg/day as a single dose in the evening.

Dosage Adjustments
If required, the dose should be adjusted at intervals of not less than 4 weeks, up to a maximum of 80 mg daily as a single dose in the evening.
PRANALIP can be taken with meals or on an empty stomach.

DOSAGE IN RENAL INSUFFICIENCY:
PRANALIP does not undergo significant renal excretion, therefore modification of dose should not be necessary in patients with mild to moderate renal insufficiency.
In patients with severe renal insufficiency PRANALIP therapy should be closely monitored and doses above 10 mg/day should be implemented with caution.

CONCOMITANT THERAPY:
PRANALIP effective alone or in combination with bile acid sequestrants. When both medicines are prescribed, PRANALIP should be given 1 hour before or 4 hours after cholestyramine administration (See Interactions).
A maximum daily dose of 10 mg PRANALIP is recommended in patients taking cyclosporin, fibrates or niacin concomitantly ( See Interactions).

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects:
Gastro-intestinal:
Constipation, diarrhoea, nausea, vomiting, flatulence, dyspepsia, abdominal pain, cramps and pancreatitis.
Haematological:
Anaemia, neutropenia.
Skin and appendages:
Skin rash, alopecia.
Musculoskeletal:
Frequent: Myalgia, muscle cramps.
Less frequent: Myopathy, myositis, rhabdomyolysis presenting as muscle pain with elevated creatine phosphoskinase and myoglobinuria leading to renal failure.
Central nervous system:
Headache, dizziness, fatigue, paraesthesia, peripheral neuropathy.
Hypersensitivity reactions:
Less frequent: Reactions may include angiodema, lupus - like syndrome, polymyalgia, rheumatica, vasculitis, thrombocytopenia, increased erythrocytes sedimentation rate, eosinophilia, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, malaise and dyspnoea.
Other:
Mass gain has been reported.

LABORATORY TEST FINDINGS:
Marked and persistent increases of serum transaminases and elevated alkaline phosphatase and gamma - glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatinine kinase (CK) levels, derived from skeletal muscle, have been reported (See Special precautions).

Special precautions:
PRANALIP should be used with caution in patients who:
Consume substantial amounts of alcohol and/or who have a history of liver disease
May be predisposed to developing renal failure secondary to rhabdomyolysis such as in those with severe acute infection, hypotension, severe metabolic endocrine or electrolyte disorders, uncontrolled seizures, major surgery or trauma. There is an increased risk of developing renal failure if rhabdomyolysis occurs.
Have severe renal impairment

Hepatic Effects:
Liver function tests, including serum transaminase determinations are recommended prior to initiation of PRANALIP therapy and periodically until one year after the last elevation in dose. PRANALIP should be discontinued if the rise in transaminase levels is persistent and /or increases to three times or more the upper limit of normal (ULN)

Myopathy
Reducing the risk of myopathy:
1. General measures:
Patients starting therapy with PRANALIP should be advised of the risk of myopathy and should report, promptly, unexplained muscle pain, tenderness or weakness. A creatinine kinase (CK) level above 10 times the Upper Limit of Normal (ULN) in a patient, with unexplained symptoms, indicates myopathy. PRANALIP should be discontinued if myopathy is diagnosed or suspected.
2. Measures to reduce the risk of myopathy caused by medicine interactions.
The benefits and risks of using PRANALIP concomitantly with immunosuppressants, fibrates or lipid- lowering doses of niacin should be carefully considered, and the dose of PRANALIP generally not exceed 10 mg/day. Concomitant administration with cyclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone, is not recommended.
In patients receiving cyclosporine, PRANALIP should be temporarily discontinued if systemic azole derivative - antifungal therapy is required.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS AND SPECIAL PRECAUTIONS)
Treatment of overdose:
General measures should be adopted and liver function should be monitored. Treatment is symptomatic and supportive.

IDENTIFICATION

PRANALIP 10 mg	A yellow, oval convex, side wall scored tablet encoded P 10
PRANALIP 20 mg	A yellow, oval convex, side wall scored tablet encoded P 20
PRANALIP 40 mg	A yellow, oval convex, side wall scored tablet encoded P 40

PRESENTATION

PRANALIP 10 mg	Polyethylene container containing 30 tablets and a dessicant insert
PRANALIP 20 mg	Polyethylene container containing 30 tablets and a dessicant insert
PRANALIP 40 mg	Polyethylene container containing 30 tablets and a dessicant insert

STORAGE
Store at room temperature not exceeding 25°C.
Keep tightly closed. Protect from moisture and light.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBERS

PRANALIP 10 mg	37/7.5/0638
PRANALIP 20 mg	37/7.5/0639
PRANALIP 40 mg	37/7.5/0640

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
HEXAL Pharma (SA) Pty LTD
46 Mahogany Road
Mahogany Ridge
Pinetown
3610

DATE OF PUBLICATION OF PACKAGE INSERT
June 2005

New addition to this site: June 2005
Source: Pharmaceutical Industry
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