Consumer medicine information

Pravastatin Sandoz

Pravastatin sodium

BRAND INFORMATION

Brand name

Pravastatin Sandoz

Active ingredient

Pravastatin sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pravastatin Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Pravastatin Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT PRAVASTATIN SANDOZ IS USED FOR

This medicine is used to lower high blood cholesterol levels (doctors call this hypercholesterolaemia).

It is also used in people who have had a heart attack or an episode of unstable angina, even when their cholesterol levels are normal.

It is also used to treat heterozygous familial hypercholesterolaemia in children and adolescent patients aged 8 years and older as an adjunct to diet and lifestyle changes.

It contains the active ingredient pravastatin sodium. Pravastatin sodium belongs to a group of medicines called HMG-CoA reductase inhibitors.

It works by reducing the level of cholesterol in your blood and helps to protect you in other ways from heart attack or stroke.

It is more effective if it is taken with a diet low in fat.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

BEFORE YOU TAKE PRAVASTATIN SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • pravastatin sodium, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.
  • any other similar medicines, especially if they are in the same drug class as Pravastatin Sandoz (HMG-CoA reductase inhibitor).
    Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.

Do not take this medicine if you have or have had problems with your liver.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • liver problems. Your doctor will do a blood test to make sure you have no problems with your liver.
  • muscle pain from other medicines used to treat high cholesterol
  • breathing discomfort, persistent cough, fatigue, weight loss and fever
  • suffer from hormonal disorders
  • suffer from central nervous system vascular lesions
  • suffer from allergies
  • suffer from homozygous familial hypercholesterolaemia (a doctor will have told you this)
  • have increased triglycerides in your blood (a doctor will have told you this also)
  • suffer from muscle disease (including pain, tenderness or weakness).

Tell your doctor if you plan on becoming pregnant or will be breastfeeding while you are using Pravastatin Sandoz. You doctor can discuss with you the risks and benefits involved.

Tell your doctor if you drink alcohol regularly.

If you have not told your doctor about any of the above, tell him/her before you start taking Pravastatin Sandoz.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Pravastatin Sandoz may interfere with each other. These include:

  • any other medicine to lower cholesterol, such as gemfibrozil, cholestyramine or colestipol
  • ciclosporin, a medicine used to suppress the immune system
  • ketoconazole, a medicine used to treat fungal infections
  • spironolactone, a medicine used to treat high blood pressure
  • cimetidine, a medicine used to treat ulcers
  • gemfibrozil
  • cholestyramine and colestipol
  • antacids
  • macrolides
  • propanol
  • bile acid sequestrants
  • digoxin
  • warfarin or other coumarin anticoagulants.

These medicines may be affected by Pravastatin Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

It generally does not interfere with your ability to drive or operate machinery. However some people may experience dizziness, so you should be sure how you react to Pravastatin Sandoz before you drive a car, or operate machinery.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE PRAVASTATIN SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Adults - The usual dose is 10 to 80 mg per day for lowering cholesterol and 40mg for reducing the risk of a stroke or heart attack.

If you have kidney or liver problems, or if you are over 65 years old, the starting dose is 10mg.

Children (8 to 13 years old) with heterozygous familial hypercholesterolaemia - The usual dose is 20mg once daily.

Adolescents (14 to 18 years old) with heterozygous familial hypercholesterolaemia - The usual dose is 40mg once daily.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Pravastatin Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the tablets with a glass of water or another liquid. The tablets can be broken in half. If you need to break Pravastatin Sandoz, hold the tablet with both hands and snap along the break line.

Pravastatin Sandoz can be taken with or without food.

When to take Pravastatin Sandoz

Take your medicine once a day in the evening before bedtime.

Taking it at the same time each day will have the best effect. It will also help you to remember when to take it.

How long to take Pravastatin Sandoz

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Pravastatin Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING PRAVASTATIN SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Pravastatin Sandoz.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests (such as checking your cholesterol levels) from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Pravastatin Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Pravastatin Sandoz affects you. This medicine generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Pravastatin Sandoz may cause dizziness in some people. If you have any of those symptoms, do not drive, operate machinery or do anything else that could be dangerous.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Pravastatin Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • upset stomach, nausea, diarrhoea, wind
  • constipation
  • headache
  • dizziness
  • blurred vision
  • fatigue
  • sleep disturbance
  • sexual dysfunction
  • depression.

Tell your doctor as soon as possible if you notice any of the following:

  • unexplained muscle pain, muscle tenderness or weakness, muscle cramps
  • chest pain, feeling of tightness, pressure or heaviness in the chest.

The above lists include the most common side effects of the medicine.

Tell your doctor immediately if you notice any of the following:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • joint pain
  • skin rash or itchiness
  • sensitivity to light
  • fever, generally feeling unwell.

These are the symptoms of an hypersensitivity reaction.

In few cases, statins have been reported to induce de novo or aggravate preexisting myasthenia gravis or ocular myasthenia.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING PRAVASTATIN SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Pravastatin Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Pravastatin Sandoz comes in four types of tablets:

Pravastatin Sandoz 10 mg - light brown, oval tablet, scored on both sides and marked with "P10".

Pravastatin Sandoz 20 mg - light brown, oval tablet, scored on both sides and marked with "P20".

Pravastatin Sandoz 40 mg - light brown, oval tablet, scored on both sides and marked with "P40".

Pravastatin Sandoz 80 mg - light brown, oval tablet, marked with "HLP80".

Available in blister packs of 30 tablets.

Not all strengths may be marketed.

Ingredients

Active ingredient:

  • Pravastatin Sandoz 10 mg - 10 mg pravastatin sodium
  • Pravastatin Sandoz 20 mg - 20 mg pravastatin sodium
  • Pravastatin Sandoz 40 mg - 40 mg pravastatin sodium
  • Pravastatin Sandoz 80 mg - 80 mg pravastatin sodium

Inactive ingredients:

  • microcrystalline cellulose
  • lactose monohydrate
  • dibasic sodium phosphate
  • croscarmellose sodium
  • sodium lauryl sulphate
  • povidone
  • iron oxide red CI77491
  • colloidal anhydrous silica
  • magnesium stearate.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was revised in January 2024.

Australian Register Numbers

Pravastatin Sandoz 10 mg tablets: AUST R 152451

Pravastatin Sandoz 20 mg tablets: AUST R 152458

Pravastatin Sandoz 40 mg tablets: AUST R 152450

Pravastatin Sandoz 80 mg tablets: AUST R 152452

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Pravastatin Sandoz

Active ingredient

Pravastatin sodium

Schedule

S4

 

1 Name of Medicine

Pravastatin sodium.

2 Qualitative and Quantitative Composition

Each Pravastatin Sandoz 10 mg tablets contains 10 mg pravastatin sodium.
Each Pravastatin Sandoz 20 mg tablets contains 20 mg pravastatin sodium.
Each Pravastatin Sandoz 40 mg tablets contains 40 mg pravastatin sodium.
Each Pravastatin Sandoz 80 mg tablets contains 80 mg pravastatin sodium.
Not all strengths may be marketed in Australia.

Excipient with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pravastatin Sandoz 10 mg tablet is a light brown, mottled, oval tablet, scored on both sides and debossed "P 10" on one side.
Pravastatin Sandoz 20 mg tablet is a light brown, mottled, oval tablet, scored on both sides and debossed "P 20" on one side.
Pravastatin Sandoz 40 mg tablet is a light brown, mottled, oval tablet, scored on both sides and debossed "P 40" on one side.
Pravastatin Sandoz 80 mg tablet is a light brown, mottled, oval tablet, debossed "HLP 80" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

As an adjunct to diet for the treatment of hypercholesterolaemia. Prior to initiating therapy with pravastatin, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, and alcoholism) should be identified and treated.
Patients with previous myocardial infarction including those who have normal (4.0 to 5.5 mmol/L) serum cholesterol levels.
Patients with unstable angina pectoris (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
As an adjunct to diet and lifestyle modification for the treatment of heterozygous familial hypercholesterolaemia in children and adolescent patients aged 8 years and older (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

Prior to initiating Pravastatin Sandoz (pravastatin sodium), the patient should be placed on a standard cholesterol lowering diet (American Heart Association (AHA) Phase 1 or NCEP Step 1) for a maximum of three to six months, depending upon the severity of the lipid elevation. Dietary therapy should be continued during treatment.

Adult patients.

The recommended starting dose is 10 to 20 mg once daily at bedtime. In primary hypercholesterolaemic patients with significant renal or hepatic dysfunction, and in the elderly, a starting dose of 10 mg daily at bedtime is recommended. For maximum effect Pravastatin Sandoz should be taken at bedtime on an empty stomach.
Since the maximal effect of a given dose is seen within four weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient's response to therapy and established treatment guidelines. The recommended dosage range is 10 to 80 mg administered once a day at bedtime.
Pravastatin Sandoz may be given in divided doses.
For the prevention of coronary heart disease in patients with hypercholesterolaemia the dose is 40 mg per day as a single dose. The same dose is recommended for secondary prevention of myocardial infarction (MI) in patients with average (normal) serum cholesterol.

Paediatric patients.

Children (ages 8 to 13 years inclusive).

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (ages 14 to 18 years).

The recommended dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.
Children and adolescents treated with pravastatin should be re-evaluated in adulthood and appropriate changes made to their cholesterol lowering regimen to achieve adult goals for low density lipoprotein cholesterol (LDL-C).

Ciclosporin.

In patients taking ciclosporin, with or without other immunosuppressive drugs, concomitantly with pravastatin, therapy should be initiated with 10 mg/day and titration to higher doses should be performed with caution.

Concomitant therapy.

Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
As for other HMG-CoA reductase inhibitors, combination of pravastatin with fibrates is not recommended and should be generally avoided.
Pravastatin must not be co-administered with fusidic acid.
Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin or pravastatin alone. No adverse effects unique to the combination or in addition to those previously reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure) have been reported when another 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or lipid lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The efficacy and safety of pravastatin 80 mg in combination with other lipid-lowering agents have not been investigated.

4.3 Contraindications

Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminase elevation exceeding 3 times the upper limit of normal (ULN) in liver function tests (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia. Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to a pregnant woman. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy.
Safety in pregnant women has not been established. Although pravastatin was not teratogenic in rats at doses as high as 1,000 mg/kg daily nor in rabbits at doses of up to 50 mg/kg daily, pravastatin should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking pravastatin, it should be discontinued and the patient advised again as to the potential hazards to the foetus.

Women of childbearing potential.

Pravastatin should not be administered to women of childbearing age unless using effective contraception and are highly unlikely to conceive, and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued and the patient again advised of the potential hazard to the foetus.
Concomitant use of fusidic acid (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

General.

Pravastatin may elevate creatine phosphokinase and transaminase levels (see Section 4.8 Adverse Effects (Undesirable Effects)). This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.

Homozygous familial hypercholesterolaemia.

Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolaemia. In this group of patients, it has been reported that HMG-CoA reductase inhibitors are less effective because the patients lack functional low density lipoprotein (LDL) receptors.

Hypertriglyceridemia.

Pravastatin has only a moderate triglyceride lowering effect and it is not indicated where hypertriglyceridemia is the abnormality of most concern (i.e. hypertriglyceridemia types I, IV and V).

Severe hypercholesterolemia.

Higher doses (≥ 40 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of pravastatin. Caution should be exercised in such patients who are also significantly renally impaired or elderly.

Thyroid function.

Serum thyroxine was studied in 661 patients who were administered pravastatin in five controlled clinical trials. From observations of up to two years in duration, no clear association was found between pravastatin use and changes in thyroxine levels.

Skeletal muscle.

Myalgia, myopathy and rhabdomyolysis have been reported with the use of HMG-CoA reductase inhibitors. Although there is no muscular contraindication to the prescription of a statin, certain predisposing factors may increase the risk of muscle toxicity and therefore justify a careful evaluation of the benefit/risk and special clinical monitoring (see below). Uncomplicated myalgia has been reported in pravastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than ten times the upper limit of normal (ULN), was reported to be possibly due to pravastatin in < 0.1% of patients in clinical trials. During therapy with lovastatin, another HMG-CoA reductase inhibitor, either alone or in combination with gemfibrozil, markedly elevated CPK values have been seen in conjunction with a myositis syndrome.
Very rarely (in about 1 case over 100,000 patient-years), rhabdomyolysis occurs, with or without secondary renal insufficiency. Rhabdomyolysis is an acute potentially fatal condition of skeletal muscle, which may develop at any time during treatment and is characterised by massive muscle destruction associated with major increase in CK (usually > 30 or 40 x ULN) leading to myoglobinuria. Rhabdomyolysis resulting in renal failure has also been observed during concomitant therapy with lovastatin and the immunosuppressive agent, ciclosporin. Although myalgia has been associated with pravastatin therapy, the myositis syndrome, as seen with lovastatin, has not so far been reported with pravastatin.
However, myopathy should be considered in any patients with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness (particularly if associated with malaise or fever). In such cases CK levels should be measured (see below). Statin therapy should be temporarily interrupted when CK levels are > 5 x ULN or when there are severe clinical symptoms. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is suspected or diagnosed. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy. CPK levels should be checked at 6 to 12 month intervals in paediatric patients.
The risk of myopathy with statins appears to be exposure-dependent and therefore may vary with individual drugs (due to lipophilicity and pharmacokinetic differences), including their dosage and potential for drug interactions. An increase in the incidence of myopathy has been described in patients receiving other statins in combination with inhibitors of cytochrome P450 metabolism. This may result from pharmacokinetic interactions that have not been documented for pravastatin.
The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with fibrates, ciclosporin, erythromycin or niacin. The use of fibrates alone is occasionally associated with myopathy. In a limited size clinical trial of combined therapy with pravastatin (40 mg/day) and gemfibrozil (1200 mg/day) myopathy was not reported, although a trend towards CPK elevations and musculoskeletal symptoms was seen.
There have been reports of rhabdomyolysis (including some fatalities) in patients receiving pravastatin and fusidic acid in combination.
As for other HMG-CoA reductase inhibitors, combination of pravastatin with fibrates is not recommended and should generally be avoided. Pravastatin must not be co-administered with fusidic acid.
Myopathy has not been observed in 3 post-transplant clinical trials which had involved a total of 100 patients (76 cardiac and 24 renal). Some patients have been treated for up to 2 years with pravastatin (10 to 40 mg) and ciclosporin, with or without other immunosuppressants. In a separate lipid lowering trial involving 158 patients, no myopathy has been reported with pravastatin in combination with niacin.
Pravastatin must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Pravastatin therapy may be re-introduced seven days after the last dose of fusidic acid.
Routine monitoring of CK is recommended at 6 to 12-month intervals in paediatric patients on statin therapy. In adult, asymptomatic adult patients on statin therapy, routine monitoring of CK or other muscle enzyme levels is not recommended. However, measurement of CK is recommended before starting statin therapy in patients with special predisposing factors, and in patients developing muscular symptoms during statin therapy, as described below. If CK levels are significantly elevated at baseline (> 5 x ULN), CK levels should be re-measured about 5 to 7 days later to confirm the results. When measured, CK levels should be interpreted in the context of other potential factors that can cause transient muscle damage, such as strenuous exercise or muscle trauma.

Before treatment initiation.

Caution should be used in patients with predisposing factors such as renal impairment, hypothyroidism, previous history of muscular toxicity with a statin or fibrate, personal or familial history of hereditary muscular disorders, or alcohol abuse.
In these cases, CK levels should be measured prior to initiation of therapy. CK measurement should also be considered before starting treatment in persons over 70 years of age especially in the presence of other predisposing factors in this population. If CK levels are significantly elevated (> 5 x ULN) at baseline, treatment should not be started and the results should be remeasured after 5-7 days. The baseline CK levels may also be useful as a reference in the event of a later increase during statin therapy.

During treatment.

Patients should be advised to report promptly unexplained muscle pain, tenderness, weakness or cramps. In these cases, CK levels should be measured. If a markedly elevated (> 5 x ULN) CK level is detected, statin therapy must be interrupted. Treatment discontinuation should also be considered if the muscular symptoms are severe and cause daily discomfort, even if the CK increase remains ≤ 5 x ULN. If symptoms resolve and CK levels return to normal, then reintroduction of statin therapy may be considered at the lowest dose and with close monitoring. If a hereditary muscular disease is suspected in such patients, restarting statin therapy is not recommended.

Immune-mediated necrotizing myopathy.

There have been rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatinine kinase, which persists despite discontinuation of statin treatment, muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.

Type 2 diabetes mellitus.

There is sufficient evidence to support an association between statin use and new-onset type 2 diabetes mellitus; however, the risk appears to be mainly in patients already at increased risk of developing diabetes. Risk factors for the development of diabetes include raised fasting glucose, history of hypertension, raised triglycerides and raised body mass. Patients at risk should be monitored both clinically and biochemically according to national guidelines.
There is insufficient evidence to confirm or exclude an increased risk for any individual statin or a dose-response relationship. The cardiovascular benefits of a statin therapy continue to outweigh the risk of diabetes.

Endocrine function.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol levels, and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. The effects of HMG-CoA reductase inhibitors on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown.
In one long-term study investigating the endocrine function in hypercholesterolemic patients, pravastatin treatment had no effect upon basal and stimulated cortisol levels, as well as on aldosterone secretion. Although no change was reported in the testicular function, conflicting results were observed in the analysis of sperm motility after administration of pravastatin.
In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p < 0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥ 50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g. ketoconazole, spironolactone, and cimetidine) that may diminish the levels of activity of steroid hormones.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including pravastatin (see Type 2 diabetes mellitus).
In a placebo-controlled study of 214 paediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18 years) for two years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol (girls) or testosterone (boys)) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes or Tanner score relative to placebo.

Central nervous system toxicity.

CNS vascular lesions, characterised by perivascular haemorrhage and oedema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day, a dose that produced a plasma drug level about 50 times higher than the mean drug level in humans taking 40 mg/day. Similar CNS vascular lesions have been observed with several other drugs in this class.
A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibres) in clinically normal dogs in a dose dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg dose.

Hypersensitivity.

With lovastatin an apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, thrombocytopenia, leukopenia, haemolytic anaemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever and malaise. Although to date hypersensitivity syndrome has not been described as such, in a few instances eosinophilia and skin eruptions appear to be associated with pravastatin treatment. If hypersensitivity is suspected pravastatin should be discontinued. Patients should be advised to report promptly any signs of hypersensitivity such as angioedema, urticaria, photosensitivity, polyarthralgia, fever and malaise.

Interstitial lung disease.

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in hepatic impairment.

HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. As with other lipid-lowering agents, including non-absorbable bile acid-binding resins, marked persistent increases (> 3 x ULN) in serum transaminases were seen in 1.3% of patients treated with pravastatin in the US for an average period of 18 months. In clinical trials, these elevations were usually not associated with clinical signs and symptoms of liver disease and usually declined to pre-treatment levels upon discontinuation of therapy. Only two patients had marked persistent abnormalities possibly attributable to therapy.
The significance of these changes, which usually appear during the first few months of treatment initiation, is not known. In the majority of patients treated with pravastatin in clinical trials, these increased values declined to pre-treatment levels despite continuation of therapy at the same dose. These biochemical findings are usually asymptomatic although worldwide experience indicates that anorexia, weakness and/or abdominal pain may also be present in rare patients.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy. If an alternate etiology is not found, do not restart pravastatin.
As with other lipid-lowering agents, liver function tests should be performed periodically. Special attention should be given to patients who develop increased transaminase levels and those on higher doses of pravastatin. Liver function tests should be repeated to confirm an elevation and subsequently monitored at more frequent intervals. If increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal or exceed 3 x ULN and persist, therapy should be discontinued.
Caution should be exercised when pravastatin is administered to patients with a history of liver disease or heavy alcohol ingestion. Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect.

Use in renal impairment.

A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,908). A small increase was seen in mean AUC values and half-life (1.5) for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Given this small sample size, the dosage administered, and the degree of individual variability, patients with renal impairment who are receiving pravastatin should be closely monitored and as precautionary measure, the lowest dose should be used in these patients.

Use in the elderly.

Pharmacokinetic evaluation of pravastatin in patients over the age of 65 years indicates an increased AUC. There were no reported increases in the incidence of adverse effects in these or other studies involving patients in that age group, however elderly patients may be more susceptible to myopathy. As a precautionary measure, the lowest dose should be administered initially.

Paediatric use.

The safety and effectiveness of pravastatin in children and adolescents with heterozygous familial hypercholesterolaemia from 8 - 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that observed in adults with influenza and headache commonly reported in both treatment groups (see Section 4.8 Adverse Effects (Undesirable Effects), Paediatric use). Doses greater than 40 mg have not been studied in this population. For dosing information, see Section 4.2 Dose and Method of Administration, Adult patients, Paediatric patients.
Double blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

Lactose.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Myasthenia gravis/ocular myasthenia.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Pravastatin should be discontinued in case these conditions occur. Recurrences when the same or a different statin was (re-) administered have been reported.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, pravastatin treatment should be discontinued throughout the duration of the fusidic acid treatment.

Gemfibrozil, fenofibrates and fibric acid derivatives.

In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax and Tmax for the pravastatin metabolite SQ 31,906. Combination therapy with pravastatin and gemfibrozil is generally not recommended.
The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse events, including rhabdomyolysis, have been reported when fibrates are coadministered with other statins, particularly in subjects with pre-existing renal insufficiency. Although e.g. gemfibrozil does not statistically affect the bioavailability of pravastatin, an association with concomitant use of pravastatin cannot be excluded. Therefore, the combined use of pravastatin and fibrates (e.g. gemfibrozil, fenofibrate) should generally be avoided. If this combination is considered necessary, careful clinical and CK monitoring of patients on such regimen is required.
Based on postmarketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle). Therefore, combined drug therapy should be approached with caution.

Cholestyramine/colestipol.

When pravastatin was administered one hour before or four hours after cholestyramine or one hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. Concomitant administration resulted in an approximately 40 - 50% decrease in the mean AUC of pravastatin (see Section 4.2 Dose and Method of Administration).

Ciclosporin.

In a single dose study, pravastatin levels were found to be increased in cardiac patients receiving ciclosporin. In a second multi-dose study in renal transplant patients receiving ciclosporin, pravastatin levels were higher than those seen in healthy volunteer studies. This does not appear to be a metabolic interaction involving P450 3A4.

Digoxin.

Coadministration of digoxin with HMG-CoA reductase inhibitors has been shown to increase the steady state digoxin concentrations. The potential effects of coadministration of digoxin and pravastatin sodium are not known. As a precautionary measure, patients taking digoxin should be closely monitored.

Warfarin.

With concomitant administration, pravastatin did not alter the plasma protein-binding of warfarin. Chronic dosing of the two drugs did not produce any changes in the anticoagulant status.

Antipyrine.

Clearance by the cytochrome P450 system was unaltered by concomitant administration of pravastatin. Since pravastatin does not appear to induce hepatic drug-metabolising enzymes, it is not expected that any significant interaction of pravastatin with other drugs (e.g. phenytoin, quinidine) metabolised by the cytochrome P450 system will occur.

Antacids.

On average, antacids reduce the bioavailability of pravastatin. This change is not statistically significant, and the clinical significance is not known.

Cimetidine.

Cimetidine increases the bioavailability of pravastatin. This change is not statistically significant, and the clinical significance of these interactions is not known.

Macrolides.

Macrolides have the potential to increase statin exposure while used in combination. Pravastatin should be used cautiously with macrolide antibiotics due to potential increased risk of myopathies. In one of the two interaction studies with pravastatin and erythromycin a statistically significant increase in pravastatin AUC and Cmax was observed. In a similar study with clarithromycin a statistically significant increase in AUC and Cmax was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.

Propranolol.

Coadministration of propranolol and pravastatin reduced the AUC values.

Colchicine.

Due to the increased risk of myopathy/rhabdomyolysis, clinical and biological monitoring is advised, especially when starting association between pravastatin and colchicine.

Nicotinic acid.

The risk of muscle toxicity is increased when statins are administered concomitantly with nicotinic acid. In one study, Chinese patients taking nicotinic acid plus laropiprant concomitantly with simvastatin were reported to have a higher incidence of myopathy and rhabdomyolysis compared to Caucasians.

Rifampicin.

Caution should be exercised when combining pravastatin to rifampicin if both are given at the same time.

Coumarin anticoagulants.

Pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin.

Vitamin K antagonists.

As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of pravastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of pravastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is needed.

Bile acid sequestrants.

Preliminary evidence suggests that the cholesterol-lowering effects of pravastatin sodium and the bile acid sequestrants, cholestyramine/colestipol are additive. When pravastatin was administered one hour before or four hours after cholestyramine or one hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. Concomitant administration resulted in decrease in the mean AUC of pravastatin.

Other drugs.

Unlike simvastatin and atorvastatin, pravastatin is not significantly metabolised in vivo by cytochrome P450 3A4. Therefore, plasma concentrations of pravastatin are not significantly elevated when cytochrome P450 3A4 is inhibited by agents such as diltiazem and itraconazole.
In interaction studies with aspirin, gemfibrozil, nicotinic acid or probucol, no statistically significant differences in bioavailability were seen when pravastatin was administered. In other interaction studies, antacids (one hour prior to pravastatin) reduced and cimetidine increased the bioavailability of pravastatin; these changes were not statistically significant.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of pravastatin with systematic fusidic acid. Coadministration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary pravastatin treatment should be discontinued throughout the duration of the fusidic acid treatment.
Also see Section 4.4 Special Warnings and Precautions for Use.
During clinical trials, no noticeable drug interactions were reported when pravastatin was added to diuretics, antihypertensives, digitalis, angiotensin converting enzyme inhibitors, calcium channel blockers, beta-blockers or nitroglycerins.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a study in rats with a daily dose up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.
The clinical significance of these findings is not clear.
(Category D)
[Category D] - Drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Accompanying texts should be consulted for further details.
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 cases where pregnant women took HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy, serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant women is exposed to a HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to HMG-CoA reductase inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor, she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist (see Section 4.3 Contraindications).
 A negligible amount of pravastatin is excreted in human breast milk. Because of the potential for adverse reactions in breastfeeding infants, if the mother is being treated with pravastatin, breastfeeding should be discontinued.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Pravastatin is generally well tolerated. Adverse events, both clinical and laboratory are usually mild and transient. In all clinical studies (controlled and uncontrolled), approximately 2% of patients were discontinued from treatment due to adverse experiences attributable to pravastatin.
The safety and tolerability of pravastatin at a dose of 80 mg in two controlled trials, with a mean exposure of 8.6 months were similar to that of pravastatin at lower doses. However, musculoskeletal adverse events, gastrointestinal adverse events and CK elevations are slightly more common with an 80 mg dose.
In seven randomised double blind, placebo-controlled trials involving over 21,500 patients treated with pravastatin 40 mg (N = 10,784) or placebo (N = 10,719), the safety and tolerability in the pravastatin group was comparable to that of the placebo group. Over 19,000 patients were followed for a median of 4.8 to 5.9 years, while the remaining patients were followed for two years or more.
Clinical adverse events probably or possibly related, or of uncertain relationship to therapy, occurring in at least 0.5% of patients treated with pravastatin or placebo in these long-term morbidity/mortality trials are shown in Table 1.

Lens.

In 820 patients treated with pravastatin for periods up to a year or more, there was no evidence that pravastatin was associated with cataract formation. In placebo-controlled studies, 294 patients (92 on placebo/control, 202 on pravastatin) were evaluated using the Lens Opacity Classification System (a sophisticated method of lens assessment) at six months and one year following the initiation of treatment. When compared with the baseline evaluation, the final examination revealed the results in Table 2.
There was no statistically significant difference in the change in lens opacity between the control and pravastatin treatment groups during this time interval.
Comparative data indicate that pravastatin is 100-fold less potent than both lovastatin and simvastatin (other HMG-CoA reductase inhibitors) in inhibiting cholesterol biosynthesis in rat lens and 40-fold less potent than lovastatin in inhibiting cholesterol biosynthesis in rabbit lens. Furthermore, unlike lovastatin and simvastatin, cataracts have not been observed in animal studies (beagle dogs) when chronic oral doses of pravastatin were administered for two years.
In three large placebo-controlled trials, West of Scotland Study (WOS), Cholesterol and Recurrent Events Study (CARE) and the Long-Term Intervention with pravastatin in Ischaemic Disease Study (LIPID) (see Section 5.1 Pharmacodynamic Properties, Clinical trials), involving a total of 19,786 patients treated with pravastatin (N = 9,895) or placebo (N = 9,873), the safety and tolerability profile in the pravastatin group was comparable to that of the placebo group over the median 4.8-5.9 years of follow up.
The following effects have been reported with drugs in this class (not all the effects listed below have necessarily been associated with pravastatin therapy).

Skeletal.

Myopathy, rhabdomyolysis, arthralgia.
Rhabdomyolysis (examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria elevated serum CK, acute renal failure, cardiac arrhythmia. Rhabdomyolysis may be fatal. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

Neurological.

Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, vertigo, memory loss, paraesthesia, peripheral neuropathy, peripheral nerve palsy.

Hypersensitivity reactions.

An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, haemolytic anaemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnoea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal.

Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.

Skin.

Alopecia, pruritus. A variety of skin changes (e.g. nodules, discolouration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.

Reproductive.

Gynecomastia, loss of libido, erectile dysfunction, sexual dysfunction.

Eye.

Progression of cataracts (lens opacities), ophthalmoplegia.

Psychiatric.

Anxiety, depression, sleep disturbances including insomnia and nightmares.

Respiratory.

Exceptional cases of interstitial lung disease, especially with long-term therapy.

Laboratory test abnormalities.

Increases in serum transaminase (ALT, AST), CPK, alkaline phosphatase, bilirubin and thyroid function abnormalities have been observed (see Section 4.4 Special Warnings and Precautions for Use).
Transient asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anaemia, thrombocytopenia and leukopenia have been reported with HMG-CoA reductase inhibitors.

Postmarketing.

In addition to the above the following adverse events have been reported during postmarketing experience of pravastatin:

Nervous system disorders.

Very rare: peripheral polyneuropathy, in particular if used for long period of time, paresthesia.
Frequency not known: myasthenia gravis.

Eye disorders.

Frequency not known: ocular myasthenia.

Immune system disorders.

Very rare: hypersensitivity reactions (anaphylaxis, angioedema, lupus erythematous-like syndrome).

Gastrointestinal disorders.

Very rare: pancreatitis.

Hepatobiliary disorders.

Very rare: jaundice, hepatitis, fulminant hepatic necrosis.
Unknown: fatal and non-fatal hepatic failure.

Musculoskeletal and connective tissue disorders.

Very rare: rhabdomyolysis, which can be associated with acute renal failure secondary to myoglobinuria, myopathy (see Section 4.4 Special Warnings and Precautions for Use), myositis, polymyositis.
Frequency not known: immune-mediated necrotizing myopathy (see Section 4.4 Special Warnings and Precautions for Use). Isolated cases of tendon disorders, sometimes complicated by rupture.

Class effects.

Nightmares, memory loss, depression, exceptional cases of interstitial lung disease, especially with long-term therapy (see Section 4.4 Special Warnings and Precautions for Use).

Endocrine disorders.

Diabetes mellitus: frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m2 of hypertension).

Paediatric use.

In a two year double blind placebo-controlled study involving 100 boys and 114 girls with HeFH, there were no serious adverse events or discontinuations for adverse events attributable to pravastatin. Pravastatin was generally well tolerated in paediatric patients and the adverse reaction profile was similar to that observed in adults. The incidence of headache was 23.6% vs 15.7%; musculoskeletal pain 16.0% vs 7.4%; CPK elevations greater than four times the pre-treatment level 3.8 vs 2.8% and dizziness 5.7% vs 0%, in pravastatin treated patients vs. placebo treated patients, respectively. (See Section 5.1 Pharmacodynamic Properties, Clinical trials, Paediatric study; Section 4.4 Special Warnings and Precautions for Use, Paediatric use.)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There has been limited experience with over dosage of pravastatin. To date there are two reported cases, both of which were asymptomatic and not associated with clinical laboratory test abnormalities. Of these two cases, one occurred in a clinical trial patient who ingested pravastatin 3 g; the other ingested pravastatin 280 mg as marketed tablets. Both cases also involved overdose of concomitant medications.

Treatment.

Should overdose occur, treat symptomatically and institute supportive measures as required.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pravastatin is one of a new class of lipid lowering compounds, the HMG-CoA reductase inhibitors that reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalysing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.
Pravastatin produces its lipid-lowering effect in two ways. Firstly, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it affects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of LDL receptors on cell surfaces and enhanced receptor mediated catabolism and clearance of circulating LDL. Secondly, pravastatin inhibits LDL production by inhibiting hepatic synthesis of very low density lipoprotein (VLDL), the LDL precursor.
Clinical and pathological studies have shown that elevated levels of total cholesterol (total-C), LDL-C and apolipoprotein B (a membrane transport complex for LDL) promote human atherosclerosis. Similarly, decreased levels of high density lipoprotein (HDL) cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level of HDL-C. In multicentre clinical trials, those pharmacological and/or non-pharmacological interventions that lowered Total-C and LDL-C and increased HDL-C reduced the rate of cardiovascular events (both fatal and non-fatal myocardial infarctions) and improved survival. In both normal volunteers and patients with hypercholesterolaemia, treatment with pravastatin reduced Total-C, LDL-C, apolipoprotein B, VLDL-C and triglycerides (TG) while increasing HDL-C and apolipoprotein A.
The effects of HMG-CoA reductase inhibitors on lipoprotein A, fibrinogen and certain other independent biochemical risk markers for coronary heart disease are unknown.
Pravastatin is a hydrophilic HMG-CoA reductase inhibitor.

Clinical trials.

Hypercholesterolaemia.

In controlled trials in patients with moderate hypercholesterolaemia, with or without atherosclerotic cardiovascular disease, pravastatin monotherapy reduced the progression of atherosclerosis and cardiovascular events (e.g. fatal and non-fatal myocardial infarction) or death.
Pravastatin is highly effective in reducing Total-C and LDL-C in patients with heterozygous familial, familial combined and non-familial (non-FH) forms of hypercholesterolaemia. A therapeutic response is seen within one week, and the maximum response usually is achieved within four weeks. This response is maintained during extended periods of therapy.
A single daily dose administered in the evening is as effective as the same total daily dose given twice a day. Once daily administration in the evening appears to be marginally more effective than once daily administration in the morning, perhaps because hepatic cholesterol is synthesised mainly at night.
In multicentre, double blind, placebo-controlled studies of patients with primary hypercholesterolaemia, treatment with pravastatin significantly decreased Total-C, LDL-C, and Total-C/HDL-C and LDL-C/HDL-C ratios, decreased VLDL-C and plasma TG levels, and increased HDL-C. Whether administered once or twice daily, a clear dose-response relationship (i.e. lipid lowering) was seen by one to two weeks following the initiation of treatment (see Table 3).
In a pooled analysis of two multicenter, double blind, placebo-controlled studies in patients with primary hypercholesterolaemia, treatment with pravastatin at a daily dose of 80 mg increased HDL-C and significantly decreased Total-C, LDL-C, and TG from baseline after 6 weeks. The efficacy results of the individual studies were consistent with the pooled data. Mean percent changes from baseline after 6 weeks of treatment were: Total-C (-27%), LDL-C (-37%), HDL-C (+3%) and TG (-19%), with placebo-subtracted changes for LDL-C and TG of -36% and -20% respectively.
Pravastatin, in combination with diet, has been shown to reduce the incidence of cardiovascular events (e.g. fatal and non-fatal myocardial infarction). The mechanism responsible for the beneficial effects of pravastatin in hypercholesterolaemic patients is not known.

Atherosclerosis.

In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolaemia (baseline LDL-C range 3.4 to 4.9 mmol/L). In this double blind, multicentre, controlled clinical trial in which 408 patients were randomised, angiograms were evaluated at baseline and at three years in 264 patients. No statistically significant difference between pravastatin and placebo was seen for the primary endpoint (per-patient change in mean coronary artery diameter), or for one of two secondary endpoints (change in percent lumen diameter stenosis). For the other secondary endpoint (change in minimum lumen diameter), statistically significant slowing of disease was seen in the pravastatin treatment group (p = 0.02). Although the trial was not designed to assess clinical coronary events, for myocardial infarction (fatal and non-fatal) the event rate was reduced in the pravastatin group by a statistically significant margin (10.5% for placebo versus 4.2% for pravastatin, p = 0.0498).
In another three year, double blind, placebo-controlled, randomized trial in patients with mild to moderate hyperlipidemia, the Pravastatin, Lipids and Atherosclerosis in the Carotids (PLAC II) study, the effect of pravastatin therapy on carotid atherosclerosis was assessed by B-mode ultrasound. No statistically significant differences were seen in the carotid bifurcation, internal carotid artery, or all segments combined (the primary endpoint); pravastatin did reduce the increase in wall thickness in the common carotid artery (p = 0.02). Although the study was not designed to assess cardiovascular events or mortality, the event rates were reduced in the pravastatin treatment group by statistically significant margins for two combined endpoints: non-fatal or fatal myocardial infarction (13.3% for placebo versus 2.7% for pravastatin, p = 0.018) and non-fatal myocardial infarction or all deaths (17.1% for placebo versus 6.7% for pravastatin, p = 0.049).
Analysis of pooled events from PLAC I and PLAC II showed that treatment with pravastatin was associated with a 67% reduction in the event rate of fatal and non-fatal myocardial infarction (11.4% for placebo versus 3.8% for pravastatin, p = 0.003) and 55% for the combined endpoint of non-fatal myocardial infarction or death from any cause (13.8% for placebo versus 6.2% for pravastatin, p = 0.009). Divergence in the cumulative event rate curves began at one year and was statistically significant at two years.
In consideration of the results of PLAC I and PLAC II, it is important to be aware of the limitations of angiography in defining the extent and site of atherosclerosis plaque. Acute coronary events tend to occur not at the site of severe stenosis, but at lesser stenoses which are lipid rich and more prone to rupture. In addition, angiographic changes are not properly validated endpoints to measure morbidity and/or mortality in patients with atherosclerotic coronary artery disease associated with hypercholesterolaemia.

Prevention of coronary heart disease.

Pravastatin is effective in reducing the risk of coronary heart disease (CHD) death (fatal myocardial infarction and sudden death) and non-fatal myocardial infarction and improving survival in hypercholesterolaemic male patients without previous myocardial infarction.
The West of Scotland Study (WOS) was a randomised, double blind, placebo-controlled trial among 6,595 male patients (45 to 64 years) with moderate to severe hypercholesterolaemia (LDL-C = 4 to 6.6 mmol/L), a total fasting cholesterol > 6.5 mmol/L, and without previous myocardial infarction. Patients were treated with standard care, including dietary advice, and either pravastatin 40 mg (n = 3,302) or placebo (n = 3,293) each evening for a median duration of 4.8 years. The study was designed to assess the effect of pravastatin on fatal and non-fatal coronary heart disease. Significant results (p < 0.05) are given in Table 4.
The effect on the combined endpoint of coronary heart disease death or non-fatal myocardial infarction was evident as early as six months after beginning pravastatin therapy.
There was no statistically significant difference between treatment groups in non-cardiovascular mortality, including cancer death (see Table 5 and Figure 1).

Myocardial infarction and unstable angina pectoris.

Pravastatin is effective in reducing the risk of a fatal coronary event and non-fatal myocardial infarction in patients with a previous myocardial infarction and average (normal) serum cholesterol, who are > 65 years of age and whose serum LDL cholesterol is > 3.36 mmol/L. Pravastatin is effective in reducing the frequency of stroke in patients with a previous myocardial infarction and average (normal) serum cholesterol. Pravastatin is also effective in reducing the risk of total mortality, coronary heart disease death, and recurrent coronary events (including myocardial infarction) in patients with unstable angina pectoris.
In the Cholesterol and Recurrent Events (CARE) study the effect of pravastatin on coronary heart disease death and non-fatal myocardial infarction was assessed in 4,159 men and women with average (normal) serum cholesterol levels (baseline mean Total-C = 209 mg/dL) (5.4 mmol/L), and who had experienced a myocardial infarction in the preceding 3 to 20 months. Patients in this double blind, placebo-controlled study participated for an average of 4.9 years. Treatment with pravastatin significantly reduced the rate of a recurrent coronary event (either CHD death or non-fatal myocardial infarction) by 24% (p = 0.003). This risk reduction was statistically significant in those patients aged 65 years of age or older, and in those who demonstrated a serum LDL cholesterol of > 3.36 mmol/L. The reduction in risk for this combined endpoint was significant for both men and women. The risk of undergoing revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 27% (p < 0.001) in the pravastatin treated patients. Pravastatin also significantly reduced the risk for stroke by 32% (p = 0.032), and stroke or transient ischemic attack (TIA) combined by 26% (p = 0.025). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. The comparison of the primary, secondary and tertiary endpoints for the study are summarised in Table 6.
In the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, the effect of pravastatin 40 mg daily was assessed in 9,014 men and women with normal to elevated serum cholesterol levels (baseline total C = 4.0 to 7.0 mmol/L; mean total C = 5.66 mmol/L; mean total C/HDL C ratio = 5.9), and who had experienced either a myocardial infarction or had been hospitalised for unstable angina pectoris in the preceding 3 to 36 months. Patients with a wide range of baseline levels of triglycerides were included (≤ 5.0 mmol/L) and enrolment was not restricted by baseline levels of HDL cholesterol. At baseline, 82% of patients were receiving aspirin, 76% were receiving antihypertensive medication, and 41% had undergone myocardial revascularisation. Patients in this multicentre, double blind, placebo-controlled study participated for a mean of 5.6 years (median = 5.9 years). Treatment with pravastatin significantly reduced the risk for CHD death by 24% (p = 0.0004). The risk for coronary events (either CHD death or non-fatal myocardial infarction) was significantly reduced by 24% (p < 0.0001) in the pravastatin treated patients. The risk for fatal or non-fatal myocardial infarction was reduced by 29% (p < 0.0001). Pravastatin reduced both the risk for total mortality by 23% (p < 0.0001) and cardiovascular mortality by 25% (p < 0.0001). The risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 20% (p < 0.0001) in the pravastatin treated patients. Pravastatin also significantly reduced the risk for stroke by 19% (p = 0.0477). Treatment with pravastatin significantly reduced the number of days of hospitalisation per 100 person-years of follow-up by 15% (p < 0.001). The prespecified subgroup (age, sex, hypertensive, diabetics, smokers, lipid subgroups) analyses were conducted using the combined endpoint of CHD and non-fatal myocardial infarction. The study was not powered to examine results within each subgroup but formal testing for heterogeneity of treatment effect was undertaken across each of the subgroups and no significant heterogeneity was found (p ≥ 0.08), i.e. a consistent treatment effect was seen with pravastatin therapy across all patient subgroups and event parameters. Among patients who qualified with a history of myocardial infarction, pravastatin significantly reduced the risk for total mortality by 25% (p = 0.0016); for CHD mortality by 23% (p = 0.004); for CHD events by 22% (p = 0.002) and for fatal or non-fatal myocardial infarction by 25% (p = 0.0008). Among patients who qualified with a history of hospitalisation for unstable angina pectoris, pravastatin significantly reduced the risk for total mortality by 26% (p = 0.0035); for CHD mortality by 26% (p = 0.0358); for CHD events by 29% (p = 0.0001) and for fatal or non-fatal myocardial infarction by 37% (p = 0.0003). The results of the LIPID study are shown in Table 7.

Solid organ transplantation.

The safety and efficacy of pravastatin treatment in patients receiving immunosuppressive therapy following kidney and cardiac transplantation were assessed in two prospective randomised controlled trials. Patients were treated concurrently with either 20 mg or 40 mg pravastatin and a standard immunosuppressive regimen of ciclosporin and prednisone. Cardiac transplant patients also received azathioprine as part of their immunosuppressive regimen. Plasma lipid levels were reduced in patients who received pravastatin. In the patients who received pravastatin in these trials (n = 71) no significant increases in creatinine phosphokinase or hepatic transaminases were observed and there were no cases of myositis and rhabdomyolysis. However, there are limited data available on the incidence of these adverse events in transplant patients and physicians should consider the risk of myositis and rhabdomyolysis when prescribing pravastatin therapy for hyperlipidaemia in transplant patients.

Paediatric study.

A double blind placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolaemia (HeFH), aged 8 to 18 years was conducted for two (2) years. The children (aged 8 to 13 years) were randomised to placebo (n = 63) or pravastatin 20 mg daily (n = 65) and the adolescents (aged 14 to 18 years) were randomised to placebo (n = 45) or pravastatin 40 mg daily (n = 41). Inclusion in the study required an LDL-C level > 95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolaemia. The mean baseline LDL-C value was 239 mg/dL (6.2 mmol/L) and 237 mg/dL (6.1 mmol/L) in the pravastatin (range: 151 to 405 mg/dL, 3.9 to 10.5 mmol/L) and placebo (range: 154 to 375 mg/dL, 4.0 to 9.7 mmol/L) groups, respectively. The mean baseline total cholesterol and apolipoprotein B levels in the pravastatin group were: 302 mg/dL (7.8 mmol/L) and 141 mg/dL (1.4 g/L), respectively; mean baseline total cholesterol and apolipoprotein B levels in the placebo group were: 299 mg/dL (7.7 mmol/L) and 140 mg/dL (1.4 g/L), respectively.
The treatment criteria for Heterozygous Familial Hypercholesterolaemia in children and adolescent patients aged 8 years and older are:
LDL-C consistently greater than 95th percentile for age and gender.
An adequate trial of a lipid lowering diet.
One parent with a clinical or molecular diagnosis of familial hypercholesterolaemia.
Pravastatin significantly decreased plasma levels of LDL-C, total-C and apolipoprotein B in both children and adolescents (see Table 8). The effect of pravastatin treatment in the two age groups was similar.
The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Pravastatin is administered orally in the active form. It is rapidly absorbed, with peak plasma levels attained 1 to 1.5 hours following ingestion. Based on urinary recovery of radio-labelled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%.
Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66), which is its primary site of action, and the primary site of cholesterol synthesis and of LDL-C clearance. Since it is excreted in the bile, plasma levels are of limited value in predicting therapeutic effectiveness. Pravastatin plasma concentrations (including area under the concentration time curve (AUC), peak (Cmax) and steady-state minimum (Cssmin)) are directly proportional to the administered dose. Steady-state AUCs, Cmax and Cssmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin tablets. Approximately 50% of the circulating drug is bound to plasma proteins.
The plasma elimination half-life (t1/2) of pravastatin (oral) is between 1.5 and 2 hours. Approximately 20% of a radio-labelled oral dose is excreted in urine and 70% in the faeces. After intravenous administration of radio-labelled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e. biliary excretion and biotransformation).
Accumulation of drug and/or metabolites may occur in patients with renal or hepatic insufficiency, although, as there are dual routes of elimination, the potential exists for compensatory excretion by the alternate route. The major metabolite of pravastatin is the 3-alpha-hydroxy isomer. This metabolite has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound.
After two weeks of once daily oral administration of pravastatin 20 mg, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) nanogram.hour/mL for children (8 to 11 years, n = 14) and adolescents (12 to 16 years, n = 10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 nanogram/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability.
A bioavailability study comparing pravastatin sodium 40 mg tablets with the originator product gave mean Cmax for pravastatin of 69.6 mg/mL and 62.6 mg/mL, respectively. The Cmax point estimate was 111.2 and the 90% confidence interval was between 103.2-119.7. Mean AUC∞ point estimate was 107.6 and the 90% confidence interval was between 100.5-115.1.
The plasma elimination half-life (t1/2) was 2.83 h and Tmax was 0.84 h.

5.3 Preclinical Safety Data

Genotoxicity.

In six genetic toxicology studies performed with pravastatin, there was no evidence of mutagenic potential at the chromosomal or gene level.

Carcinogenicity.

In a two-year oral study of rats, a statistically significant increase in the incidence of hepatocellular carcinomas was observed in male rats given pravastatin 100 mg/kg/day. This change was not seen in male rats given 40 mg/kg or less, or in female rats at doses up to 100 mg/kg/day. Increased incidences of hepatocellular carcinomas were also observed in male and female mice dosed with pravastatin at 250 and 500 mg/kg/day, but not at 100 mg/kg/day or less. An increased incidence of pulmonary adenomas was seen in female mice dosed at 250 mg/kg/day. The AUC value for the serum concentration of pravastatin at the no effect dose level of 100 mg/kg/day in mice was 2 times higher than that in humans receiving pravastatin 80 mg/day.
The hepatocarcinogenic effect of pravastatin in rats is associated with proliferation of hepatic peroxisomes. Other HMG-CoA reductase inhibitors (simvastatin and lovastatin) also induce hepatic peroxisome proliferation and hepatocellular carcinomas in rats and mice. The clinical significance of these findings is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, dibasic sodium phosphate, croscarmellose sodium, sodium lauryl sulfate, povidone, iron oxide red CI77491, colloidal anhydrous silica, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light and moisture.

6.5 Nature and Contents of Container

Available in Al/Al blister packs of 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Pravastatin sodium is an odourless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (> 300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform and ether.

Chemical structure.

The chemical name of pravastatin sodium is sodium (3R,5R)-7-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy-1-naphthyl]]-3,5-dihydroxyheptanoic acid. Its empirical formula is C23H35NaO7 (MW: 446.52) and its chemical structure is:

CAS number.

81131-70-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes