Consumer medicine information

Pravachol

Pravastatin sodium

BRAND INFORMATION

Brand name

Pravachol

Active ingredient

Pravastatin sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pravachol.

What is in this Leaflet

The information in this leaflet will answer some of the questions you may have about PRAVACHOL. This leaflet does not tell you everything about the medicine.

Your doctor and pharmacist have been provided with full information and can answer any questions you may have.

This leaflet is no substitute for talking with your doctor or pharmacist. You should follow all advice from your doctor when being treated with this medicine.

Ask your doctor or pharmacist if you have any concerns about taking this medicine.

You should read this leaflet carefully before starting PRAVACHOL and keep it in a safe place to refer to later.

What is it used for

PRAVACHOL is used to treat people who have had a heart attack or an episode of unstable angina, or who have high blood cholesterol levels. In these people PRAVACHOL can reduce the risk of further heart disease, reduce the possibility of needing a bypass operation, or reduce the risk of having a stroke.

It lowers high blood cholesterol levels (Doctors call this hypercholesterolaemia). It is also used if your cholesterol levels are normal if you have had a heart attack or an episode of unstable angina.

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

If you have had a heart attack, an episode of unstable angina or you have too much cholesterol in your blood, then you have an increased risk of a blood clot forming in your blood vessels and causing a blockage. Blood vessels that become blocked in this way can lead to further heart disease, angina or stroke.

PRAVACHOL may be used to lower lipids in heart or kidney transplant patients, who are also being given immunosuppressive medicine.

It is used to treat long-term (chronic) conditions so it is important that you take your PRAVACHOL every day.

It is not addictive or habit forming.

It is only available upon prescription from your doctor.

How does it work

PRAVACHOL tablets contain pravastatin sodium, a drug that reduces 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.

Before I take it

Before taking PRAVACHOL, you should be aware of the following:

You should not take it

  • if you are or may become pregnant
  • if you are breast feeding
  • if you have ever had an allergic reaction to pravastatin sodium or any other ingredient listed at the end of this leaflet
  • if you have ever had liver disease
  • if you have had muscle pain from any other medicine used to treat high cholesterol

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

Before you take it

You must tell your doctor if:

  • you are taking other medicines or treatment
  • you drink alcohol regularly
  • you have ever had liver problems
  • you have a problem with your kidneys
  • you are or may become pregnant
  • you are breastfeeding
  • you suffer from hormonal disorders
  • you suffer from central nervous system vascular lesions
  • you suffer from allergies
  • you suffer from homozygous familial hypercholesterolaemia, (a doctor will have told you this)
  • you have increased triglycerides in your blood (a doctor will have told you this also)
  • you suffer from muscle disease (including pain, tenderness or weakness).

Taking other medicines

Some medicines can affect the way PRAVACHOL works.

You should always tell your doctor about any other medicines you take, even those bought without a doctor's prescription.

It is especially important that you tell your doctor if you are taking any of the following:

  • any other medicine to lower cholesterol
  • cyclosporin
  • ketoconazole
  • spironolactone
  • cimetidine
  • gemfibrozil
  • cholestyramine and colestipol
  • antacids
  • Macrolides
  • Propanol
  • Bile acid sequestrants
  • Digoxin
  • Warfarin or other Coumarin anticoagulants

Please discuss any of these with your doctor if you need to take any of them.

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 PRAVACHOL before you drive a car, or operate machinery.

How to take it

How much to take

PRAVACHOL should only be used as directed by your doctor. Your doctor will decide on the dose, this will depend on many factors including your cholesterol level. The dose for lowering cholesterol is 10 – 80mg, and is 40mg for reducing the possibility of a stroke or heart attack.

The recommended dose is 20 mg once daily for children 8 – 13 years of age and 40 mg once daily in adolescents 14 – 18 years of age, with heterozygous familial hypercholesterolaemia.

How to take it

Take PRAVACHOL once a day in the evening before bed-time.

For best results, take PRAVACHOL on an empty stomach (ie. two or more hours after your last meal).

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

If you forget to take it

If you forget to take a dose of PRAVACHOL, take the next dose normally at your usual time.

Side Effects

All medicines, including PRAVACHOL, can sometimes cause unwanted effects. This is not an exhaustive list.

The most common side effects are:

  • upset stomach
  • nausea
  • diarrhoea
  • wind
  • constipation
  • headache
  • dizziness.

Tell your doctor as soon as possible if you have any of these side effects or any other problem while taking PRAVACHOL.

Your doctor may arrange blood tests.

You must tell your doctor immediately, or go to the hospital, if you suffer any of the following:

  • unexplained muscle pain
  • tenderness
  • weakness.

It is also possible to suffer from an allergic reaction to PRAVACHOL, so tell your doctor if you develop a skin rash or itchiness, fever, joint pain or shortness of breath.

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

If you take too much (Overdose)

Call your doctor immediately if you or someone else has taken too much PRAVACHOL.

If your doctor is not available call your nearest hospital or a Poisons Information Centre on 13 11 26.

Storage

Store PRAVACHOL in a cool dry place, and keep the tablets in the blister until it is time to take them.

Store PRAVACHOL below 25°C, and protect from light and moisture.

The expiry date is printed on the pack. Do not take it after the expiry date or if the tablets have changed in appearance colour or taste.

Ask your pharmacist about disposal of unused tablets.

Keep all medicines out of reach of children.

Product description

What it looks like

Pravachol 10mg tablet - engraved ‘10’. AUST R 68706

Pravachol 20mg tablet - engraved ‘20’. AUST R 68704

Pravachol 40mg tablet - engraved ‘40’. AUST R 58075

Pravachol 80mg tablet - engraved ‘80’. AUST R 101491

Pravachol tablets are yellow capsule shaped tablets supplied in blister packs containing 30 tablets per pack.

Active ingredients

Pravachol 10mg tablets - 10mg pravastatin sodium

Pravachol 20mg tablets - 20mg pravastatin sodium

Pravachol 40mg tablets - 40mg pravastatin sodium

Pravachol 80mg tablets - 80mg pravastatin sodium

Inactive ingredients

PRAVACHOL tablets also contain lactose, povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, magnesium oxide and iron oxide-yellow.

Contains sugars as lactose.

Sponsor & Distributor

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne Victoria 3121

This leaflet was revised in October 2023.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Pravachol

Active ingredient

Pravastatin sodium

Schedule

S4

 

1 Name of Medicine

Pravastatin sodium.

2 Qualitative and Quantitative Composition

Pravachol 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 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalysing the early rate limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.
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.
Pravachol tablets are available in 10 mg, 20 mg, 40 mg and 80 mg.

Excipients of known effect.

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

3 Pharmaceutical Form

Pravachol is available as yellow capsule shaped biconvex tablets containing 10 mg, 20 mg, 40 mg or 80 mg pravastatin sodium. The 10 mg tablet (8.8 x 4.4 mm) is engraved "10" on one side, the 20 mg tablet (11.0 x 5.5 mm) is engraved "20" on one side, the 40 mg tablet (14.0 x 7.0 mm) is engraved "40" on one side, the 80 mg tablet (17.6 x 8.8 mm) is engraved "80" on one side. The tablets are supplied in blister packs containing 30 tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

1. 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, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.
2. Pravachol is indicated in patients with previous myocardial infarction including those who have normal (4.0-5.5 mmol/L) serum cholesterol levels.
3. Pravachol is indicated in patients with unstable angina pectoris (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
4. Pravachol is indicated 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

Prior to initiating Pravachol (pravastatin sodium), the patient should be placed on a standard cholesterol-lowering diet (AHA Phase 1 or NCEP Step 1) for a maximum of 3 to 6 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 Pravachol 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.
Pravachol 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 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 8-13 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 LDL-C.

Ciclosporin.

In patients taking ciclosporin, with or without other immunosuppressive drugs, concomitantly with pravastatin, therapy should be initiated with 10 mg per 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.
Pravachol 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-cholesterol than that achieved with lovastatin or pravastatin alone. No adverse reactions 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 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.
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.

Use in pregnancy.

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 1000 mg/kg daily nor in rabbits at doses of up to 50 mg/kg daily, Pravachol 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 the woman becomes pregnant while taking Pravachol, it should be discontinued and the patient advised again as to the potential hazards to the foetus.

Women of childbearing potential.

Pravachol should not be administered to women of childbearing age unless on an 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.
Pravachol must not be co-administered with 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 LDL receptors.
Therapy is not suitable when hypercholesterolaemia is due to elevated HDL-cholesterol.
As for other HMG-CoA reductase inhibitors, combination of pravastatin with fibrates is not recommended.

Hypertriglyceridemia.

Pravachol has only a moderate triglyceride lowering effect and it is not indicated where hypertriglyceridaemia is the abnormality of most concern (i.e. hypertriglyceridaemia 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 muscular 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 10 times the upper limit of normal, 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, muscle cramps 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 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. Although there is no muscular contraindication to the prescription of a statin, certain predisposing factors that include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment may increase the risk of muscular toxicity and therefore justify a careful evaluation of the benefit/risk and special clinical monitoring. CK measurement is indicated before starting statin therapy in these patients.
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 Pravachol.
The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either fibrates, ciclosporin, erythromycin, clarithromycin and other macrolides or niacin. The use of fibrates alone is occasionally associated with myopathy. The combined use of a statin and fibrates should generally be avoided. 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. Pravachol 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 (10-40 mg) and ciclosporin and either 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.
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 re-measured 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.
Pravachol must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Pravachol therapy may be reintroduced seven days after the last dose of fusidic acid.
Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin co-administered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 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 postmenopausal 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 premenopausal 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 gonadotrophin 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 gonadotrophin stimulation did not change significantly after therapy in these patients. 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, 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.

CNS toxicity.

CNS vascular lesions, characterized by perivascular haemorrhage and edema 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 Pravachol treatment. If hypersensitivity is suspected Pravachol should be discontinued. Patients should be advised to report promptly any signs of hypersensitivity such as angioedema, urticaria, photosensitivity, polyarthralgia, fever or 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, nonproductive 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 (greater than three times the upper limit of normal) 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 pretreatment 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 post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Pravachol. 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 Pravachol.
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 three times the upper limit of normal 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 3x-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 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 Pravachol 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 and Paediatric patients.
In children before puberty, the benefit/risk of treatment should be carefully evaluated by physicians before treatment initiation.
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 co-administered 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 post-marketing 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 multidose study in renal transplant patients receiving ciclosporin, pravastatin levels were higher than those seen in healthy volunteer studies. Clinical and biochemical monitoring of patients receiving this combination is recommended (see Section 4.2 Dose and Method of Administration). 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) metabolized 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 is not known.

Macrolides.

Macrolides have the potential to increase statin exposure while used in combination. Pravastatin should be used cautiously with macrolide antibiotics (e.g. erythromycin, clarithromycin, roxithromycin) 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.

Co-administration 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.

Lenalidomide.

There is an increased risk of rhabdomyolysis when statins are combined to lenalidomide. A reinforced clinical and biological monitoring is warranted notably during the first weeks of treatment.

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 Pravachol was administered. In other interaction studies, antacids (one hour prior to Pravachol) 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 Pravachol with systemic fusidic acid. Co-administration 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, Pravachol 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 Pravachol was added to: diuretics, antihypertensives, digitalis, angiotensin converting enzyme inhibitors, calcium channel blocker, 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)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformation 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.
Special caution is recommended in adolescent females of childbearing potential to ensure proper understanding of the potential risk associated with pravastatin therapy during pregnancy. If a patient plans to become pregnant or becomes pregnant, the doctor has to be informed immediately and pravastatin should be discontinued because of the potential risk to the foetus (see Section 4.3 Contraindications).
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 woman 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 nursing infants, if the mother is being treated with Pravachol, nursing 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)

Pravachol 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 Pravachol.
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 4.8-5.9 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 Pravachol for periods up to a year or more, there was no evidence that Pravachol was associated with cataract formation. In placebo-controlled studies, 294 patients (92 on placebo/ control), 202 on Pravachol 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) involving a total of 19,786 patients treated with pravastatin (N = 9895) or placebo (N = 9873), 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 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 creatine kinase, 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 extraocular movement, facial paresis), tremor, vertigo, memory loss, paraesthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, insomnia, depression.
Uncommon: dizziness, headache, sleep disturbance, insomnia.
Not known: myasthenia gravis.

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.
Uncommon: dyspepsia/heartburn, abdominal pain, nausea/vomiting, constipation, diarrhoea, flatulence.

Skin.

Alopecia, pruritus. A variety of skin changes (e.g. nodules, discolouration, dryness of skin/ mucous membranes, changes to hair/ nails) have been reported.
Uncommon: pruritus, rash, urticaria, scalp/hair abnormality (including alopecia).

Renal and urinary.

Uncommon: abnormal urination (including dysuria, frequency, nocturia).

Reproductive.

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

Eye.

Progression of cataracts (lens opacities), ophthalmoplegia.
Uncommon: vision disturbance (including blurred vision and diplopia.
Not known: ocular myasthenia.

General.

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

Laboratory test abnormalities.

Elevated transaminases, alkaline phosphatase and bilirubin; thyroid function abnormalities.
Increases in serum transaminase (ALT, AST) values and CPK 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 leucopenia have been reported with HMG-CoA reductase inhibitors.

Events of special clinical interest.

Skeletal muscle.

Effects on the skeletal muscle, e.g. musculoskeletal pain including arthralgia, muscle cramps, myalgia, muscle weakness and elevated CK levels have been reported in clinical trials. The rate of myalgia and muscle weakness and the incidence of CK level > 3 x ULN and > 10 x ULN in CARE, WOSCOPS and LIPID was similar to placebo (see Section 4.4 Special Warnings and Precautions for Use).

Liver effects.

Elevations of serum transaminases have been reported. In the three long-term, placebo-controlled clinical trials CARE, WOSCOPS and LIPID, marked abnormalities of ALT and AST (> 3 x ULN) occurred at similar frequency in both treatment groups.

Post marketing.

In addition to the above the following adverse events have been reported during post marketing 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), muscle rupture. Isolated cases of tendon disorders, sometimes complicated by rupture.

Skin and subcutaneous tissue disorders.

Rare: photosensitivity reaction.
Very rare: dermatomyositis.
Unknown: rash including - lichenoid rash.

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 (2) 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 pretreatment 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 this medicinal product is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

There has been limited experience with overdosage 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 3 g pravastatin; the other ingested 280 mg pravastatin, 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 Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pravachol produces its lipid-lowering effect in two ways. First, 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. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor.
Clinical and pathologic studies have shown that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (a membrane transport complex for LDL) promote human atherosclerosis. Similarly, decreased levels of 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 pharmacologic and/or nonpharmacologic interventions that lowered total-C and LDL-C and increased HDL-C reduced the rate of cardiovascular events (both fatal and nonfatal myocardial infarctions) and improved survival. In both normal volunteers and patients with hypercholesterolaemia, treatment with Pravachol reduced total-C, LDL-C, apolipoprotein B, VLDL-C and TG while increasing HDL-C and apolipoprotein A.
The effects of HMG-CoA reductase inhibitors on Lp(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 MI) or death.
Pravachol is highly effective in reducing total-C and LDL-C in patients with heterozygous familial, familial combined and nonfamilial (non-FH) forms of hypercholesterolaemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 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 1 to 2 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 hypercholesterolemia, 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.
Pravachol, 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 Pravachol 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 = 3.4-4.9 mmol/L). In this double-blind, multicentre, controlled clinical trial in which 408 patients were randomized, 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 nonfatal) 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 3-year, double-blind, placebo-controlled, randomized trial in patients with mild to moderate hyperlipidaemia, 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: nonfatal or fatal myocardial infarction (13.3% placebo versus 2.7% for pravastatin, p = 0.018) and nonfatal 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 nonfatal myocardial infarction or death from any cause (13.8% 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 2 years.
In consideration of the results of Pravastatin Limitation of Atherosclerosis in Coronary and Carotid Arteries Trials (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.

Pravachol is effective in reducing the risk of coronary heart disease (CHD) death (fatal MI and sudden death) plus non-fatal MI 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 6595 male patients (45-64 years) with moderate to severe hypercholesterolaemia (LDL-C = 4-6.6 mmol/L), a total fasting cholesterol > 6.5 mmol/L, and without a previous MI. Patients were treated with standard care, including dietary advice, and either pravastatin 40 mg (n = 3302) or placebo (n = 3293) 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 (CHD). Significant results (p < 0.05) are given in Table 4.
The effect on the combined endpoint of coronary heart disease death or nonfatal myocardial infarction was evident as early as six months after beginning pravastatin therapy.
There was no statistically significant difference between treatment groups in noncardiovascular mortality, including cancer death (see Table 5 and Figure 1).

Myocardial infarction and unstable angina pectoris.

Pravachol is effective in reducing the risk of a fatal coronary event and non-fatal MI 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. Pravachol is effective in reducing the frequency of stroke in patients with a previous myocardial infarction and average (normal) serum cholesterol. Pravachol is also effective in reducing the risk of total mortality, CHD 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 nonfatal MI was assessed in 4159 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 3-20 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 nonfatal MI) 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 the 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 9014 men and women with normal to elevated serum cholesterol levels (baseline total-C = 4.0-7.0 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 3-36 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 nonfatal MI) was significantly reduced by 24% (p < 0.0001) in the pravastatin treated patients. The risk for fatal or nonfatal 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, hypertensives, diabetics, smokers, lipid subgroups) analyses were conducted using the combined endpoint of CHD and nonfatal MI. 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 nonfatal MI 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 nonfatal MI by 37% (p = 0.0003). See 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 is 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 8-18 years was conducted for two (2) years. The children (aged 8-13 years) were randomised to placebo (n = 63) or 20 mg of pravastatin daily (n = 65) and the adolescents (aged 14-18 years) were randomised to placebo (n = 45) or 40 mg of pravastatin 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: 151-405 mg/dL, 3.9-10.5 mmol/L) and placebo (range: 154-375 mg/dL, 4.0-9.7 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; and 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

Pravachol 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 radiolabelled 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 (Cmin)) are directly proportional to the administered dose. Steady-state AUCs, Cmax and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of Pravachol 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 radiolabelled oral dose is excreted in urine and 70% in the faeces. After intravenous administration of radiolabelled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by nonrenal 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 3α-hydroxy isomer. This metabolite has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound.
After 2 weeks of once daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) nanogram.hr/mL for children (8-11 years, n = 14) and adolescents (12-16 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.

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 2-year oral study of rats, a statistically significant increase in the incidence of hepatocellular carcinomas was observed in male rats given 100 mg/kg daily of pravastatin. 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 daily. Increased incidences of hepatocellular carcinomas were also observed in male and female mice dosed with pravastatin at 250 and 500 mg/kg daily, 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 80 mg pravastatin per 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

Pravachol tablets contain the following inactive ingredients: lactose, povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, magnesium oxide and iron oxide - yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.

6.5 Nature and Contents of Container

Pravachol 10 mg.

3, 30 and 100 tablet blister packs (Al/Al)*.

Pravachol 20 mg.

3, 30 and 100 tablet blister packs (Al/Al)*.

Pravachol 40 mg.

3, 5, 7 and 30 tablet blister packs (Al/Al)*.

Pravachol 80 mg.

30 tablet blister packs (Al/Al)*.
* Not all the presentations are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Pravastatin sodium is designated chemically as:
(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, sodium salt, and has the following structure:

CAS number.

81131-70-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes