Consumer medicine information

Cholstat

Pravastatin sodium

BRAND INFORMATION

Brand name

Cholstat

Active ingredient

Pravastatin sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cholstat.

What is in this leaflet

This leaflet answers some common questions about Cholstat.

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

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

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

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

What Cholstat is used for

Cholstat is used to:

  • lower high cholesterol levels
  • lower cholesterol in heart or kidney transplant patients, who are also being given immunosuppressive medicine.
  • reduce the risk of further heart disease
  • reduce the risk of having a stroke help people with unstable angina pectoris (chest pain).
  • treat heterozygous familial hypercholesterolaemia in children and adolescent patients aged 8 years and older as an added measure to diet and lifestyle changes.
    Cholesterol is present in many foods and is also made in your body by the liver. If your body does not balance the amount of cholesterol it needs with the amount of cholesterol eaten, then your cholesterol becomes too high.

High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

When you have high levels of cholesterol it may 'stick' to the inside of your blood vessels instead of being carried to the parts of the body where it is needed. Over time, this can form hard areas [called plaques] on the walls of your blood vessels, making it more difficult for the blood to flow. This blocking of your blood vessels can lead to heart disease (such as heart attack and angina), and stroke.

There are different types of cholesterol, called LDL and HDL. LDL cholesterol is the 'bad' cholesterol that can block your blood vessels. HDL cholesterol is the 'good' cholesterol that is thought to remove the 'bad' cholesterol from the blood vessels.

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

Cholstat is available only with a doctor's prescription.

There is no evidence that Cholstat is addictive.

Before you take Cholstat

When you must not take it

Do not take Cholstat if you are allergic to medicines containing pravastatin sodium, any other medicine used to reduce the level of cholesterol in your blood or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives; swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take Cholstat if you have:

  • liver problems
  • muscle pains caused by any other medicine used to treat high cholesterol or triglycerides (fats).

Do not take Cholstat if you are pregnant or planning to become pregnant. Cholstat can harm your developing baby if you take it during pregnancy. Women who are able to conceive, should not take Cholstat unless using effective contraception (e.g., the birth control pill).

Do not take Cholstat if you are breastfeeding. Cholstat passes into breast milk and can harm your baby.

Do not take Cholstat if the expiry date (EXP.) printed on the pack has passed. If you take the tablets after the expiry date, they may not work as well.

Do not take Cholstat if the packaging shows signs of tampering or the tablets do not look quite right.

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 are allergic to any other medicines, foods, dyes or preservatives.

Let your doctor know if you are drinking alcohol while taking Cholstat.

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

  • liver problems
  • kidney problems
  • diabetes
  • under-active thyroid
  • suffer from central nervous system vascular lesions
  • hormonal disorders
  • increased triglycerides in blood
  • homozygous familial hypercholesterolaemia
  • increased triglycerides in your blood
  • suffer from muscle disease (including pain, tenderness or weakness)

Your doctor may want to take special care if you have or had any of these conditions.

Tell your doctor if you drink alcohol regularly.

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you start taking Cholstat.

Taking other medicines

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

Some medicines may be affected by Cholstat, or may affect how well it works. These include:

  • any other medicine to lower cholesterol
  • gemfibrozil (Jezil, Lopid)
  • colestyramine (Questran lite) and colestipol (Colestid Granules)
  • ciclosporin (Neoral, Sandimmun)
  • ketoconazole (Nizoral)
  • spirolactone (Spiractin)
  • cimetidine (Magicul, Tagamet)
  • nicotinic acid (No Doz Plus +)
  • erythromycin (Eryc)
  • antacids.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

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

How to take Cholstat

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

If you do not understand the instructions on the pack, ask your doctor or pharmacist.

How to take it

Swallow the tablets with a glass of water.

Cholstat tablets should not be divided.

How much to take

The usual starting dose for lowering cholesterol is 10 mg to 20 mg at night, and varied ultimately between 10 mg to 80 mg once a day.

The dose for reducing the possibility of a stroke or heart attack is 40 mg per day.

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

However, the dose varies from patient to patient. Also, people over 65 may require a lower than usual dose. Therefore, your doctor will decide on the right dose for you after taking into consideration a number of factors including your cholesterol level and any other medicines that you are taking.

When to take it

Take Cholstat once a day in the evening before bed-time. For the best result, take Cholstat on an empty stomach (e.g., 3 hours after your dinner).

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

How long to take it for

Keep taking Cholstat for as long as your doctor recommends. To properly control your condition, take Cholstat every day. Treatment with Cholstat is usually long term, even lifelong.

If you forget to take it

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

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

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

If you take too much (overdose)

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

While you are taking Cholstat

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking Cholstat.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Cholstat.

Use effective contraception (e.g., birth control pill) while you are taking Cholstat.

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

If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking Cholstat.

If you notice that you are getting muscle pain, tenderness or weakness for no reason, tell your doctor as soon as you can.

If you have to have any blood tests tell your doctor that you are taking Cholstat. Cholstat may affect the results of some tests.

Visit your doctor regularly so they can check on your progress. Your doctor may want to do some blood tests to check your liver.

Things you must not do

Do not stop taking Cholstat, without checking with your doctor.

Do not use Cholstat to treat any other conditions unless your doctor tells you to.

Do not give Cholstat 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 Cholstat affects you. Cholstat generally does not interfere with your ability to drive. However some people do experience dizziness. If this does occur to you, 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 Cholstat.

Like all other medicines, Cholstat may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • skin rash, itching or hives
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

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

  • unexplained muscle pain, cramping tenderness and/or weakness
  • joint pain.

The above list includes serious side effects which may require medical attention. Serious side effects are rare.

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

  • nausea, vomiting
  • upset stomach, wind, constipation, diarrhoea.
  • headache, dizziness
  • vision disturbance, ringing in the ears
  • nervousness, sleep disturbance
  • tiredness
  • passing urine too often.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some patients. Some changes can only be found when your doctor does tests from time to time to check your progress.

After taking Cholstat

Storage

Keep Cholstat 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.

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

Do not store Cholstat or any other medicine in the bathroom or near a sink.

Do not leave Cholstat in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking Cholstat, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Cholstat comes in 3 strengths of tablets:

  • Cholstat 10 - white to off-white, capsule shaped, biconvex tablets with "G G" on one side and "PR 10" on the other side
  • Cholstat 20 - white to off-white, capsule shaped, biconvex tablets with "G G" on one side and "PR 20" on the other side
  • Cholstat 40 - white to off-white, capsule shaped, biconvex tablets with "G" on one side and "PR 40" on the other side.

Each pack contains 10 or 30 tablets.

Ingredients

The active ingredient in Cholstat is pravastatin sodium.

Each Cholstat 10 tablet contains 10 mg of pravastatin sodium.

Each Cholstat 20 tablet contains 20 mg of pravastatin sodium.

Each Cholstat 40 tablet contains 40 mg of pravastatin sodium.

The tablets also contains:

  • aluminium magnesium silicate
  • croscarmellose sodium
  • povidone
  • microcrystalline cellulose
  • talc
  • lactose monohydrate
  • magnesium stearate.

The tablets are gluten free.

Manufacturer/Supplier

Cholstat is supplied by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au
Medical Information
Phone: 1800 028 365

Australian registration numbers:

Cholstat 10 - AUST R 98486

Cholstat 20 - AUST R 98488

Cholstat 40 - AUST R 98489

This leaflet was prepared on 26 November 2019

Cholstat_cmi\Nov19/00

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Cholstat

Active ingredient

Pravastatin sodium

Schedule

S4

 

1 Name of Medicine

Cholstat (pravastatin sodium).

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 freely soluble in methanol and water (> 300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform and ether.
(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.

Molecular formula.

C23H35NaO7.

Molecular weight.

446.52.

Chemical structure.


CAS number.

The Chemical Abstracts Service (CAS) Registry Number of the medicine. 81131-70-6.

2 Qualitative and Quantitative Composition

Pravastatin belongs to a 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.
Each tablet contains 10 mg, 20 mg or 40 mg of pravastatin sodium as the active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

Cholstat 10: Pravastatin 10 mg tablets, white to off-white, capsule shaped, biconvex tablets with "G/G" on one side and "PR 10" on the other side.
Cholstat 20: Pravastatin 20 mg tablets; white to off-white, capsule shaped, biconvex tablets with "G/G" on one side and "PR 20" on the other side.
Cholstat 40: Pravastatin 40 mg tablets; white to off-white, capsules shaped, biconvex tablets with "G" on one side and "PR 40" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pravastatin 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 low density lipoprotein (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 very low density lipoprotein (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 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 nonpharmacological 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 pravastatin reduced total-C, LDL-C, apolipoprotein B, VLDL-C and triglycerides (TG) while increasing high density lipoprotein cholesterol (HDL-C) and apolipoprotein A.
The effects of HMG-CoA reductase inhibitors on lipoprotein A (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 nonfatal MI) or death.
Pravastatin 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 synthesized 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 multicentre, 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 nonfatal 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 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, randomised 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 nonfatal 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% 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.

Pravastatin is effective in reducing the risk of coronary heart disease (CHD) death (fatal MI and sudden death) plus nonfatal MI and improving survival in hypercholesterolemic 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 to 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 = 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 nonfatal 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.

Pravastatin is effective in reducing the risk of a fatal coronary event and nonfatal 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. 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, 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 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 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 Ischemic 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 3-36 months. Patients with a wide range of baseline levels of triglycerides were included (≤ 5.0 mmol/L) and baseline levels of HDL cholesterol did not restrict enrolment. 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 end point 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 immunosuppresive regimen of ciclosporin and prednisone. Cardiac transplant patients also received azathioprine as part of their immunosuppresive 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 to 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; and
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

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 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 administered dose. Steady-state AUCs, Cmax and Cmin 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 3.5 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 AUC were 80.7 (CV 44%) and 44.8 (CV 89%) nanogram.hour/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 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.

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

4.3 Contraindications

Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations in liver function tests.
(Category D)
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 the 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 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.
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 transminase 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.

Hypertrigylceridemia.

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).

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. 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. Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also very rarely 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. 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 during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either fibrates, ciclosporin, erythromycin or nicotinic acid. 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 (1,200 mg/day) myopathy was not reported, although a trend towards CPK elevations and musculoskeletal symptoms was seen. The combined use of pravastatin and fibrates should generally be avoided.
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 mg to 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 nicotinic acid.
Pravastatin must not be coadministered 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 reintroduced seven days after the last dose of fusidic acid.

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. 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 premenopausal 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, cimetidine) that may diminish the levels of activity of steroid hormones.
Increase in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including pravastatin.
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, 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), erythrocytes sedimentation rate (ESR) increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever and malaise. Although to date hypersensitivity syndrome has not been described as such, in 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, 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.

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.

Use in hepatic impairment.

HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. As with other lipid lowering agents, 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 U.S. for an average period of 18 months. In clinical trials these elevations were not associated with clinical signs and symptoms of liver disease and usually declined to pretreatment 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.
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 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.

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. 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 patients). 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.

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

Gemfibrozil.

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.

Colestyramine/ colestipol.

When pravastatin was administered one hour before or four hours after colestyramine 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 to 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. This does not appear to be a metabolic interaction involving cytochrome P450 3A4.

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.

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) reduce and cimetidine increase 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 systemic 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 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 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 a 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 breastfeeding infants, if the mother is being treated with pravastatin, breastfeeding should be discontinued.

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 4.8-5.9 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 following as shown 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), Long-Term Intervention with Pravastatin in Ischaemic Disease (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 to 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 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.

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, dyspnea, 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.

Eye.

Progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory abnormalities.

Elevated transaminases, alkaline phosphatise and bilirubin, and thyroid function abnormalities.

Sleep disturbances including insomnia and nightmares.


Depression.


Sexual dysfunction.


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


Laboratory test abnormalities.

Increase 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 leukopenia have been reported with HMG-CoA reductase inhibitors.

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, 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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Prior to initiating Cholstat (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 hypercholesterolemic 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 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 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.

Pravastatin has been administered concurrently with colestyramine, 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. (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.
Pravastatin tablets should not be broken in half.

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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cholstat tablets contain the following inactive ingredients: aluminium magnesium silicate, lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and talc.
See Section 2 Qualitative and Quantitative Composition.

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.

6.5 Nature and Contents of Container

Container type: Al/Al.
Pack sizes: 10's, 30's, 100's.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

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

Summary Table of Changes