Pravastatin Mylan 10mg, 20mg & 40mg Tablets

4.2 Posology and method of administration

Paediatric population (8 - 18 years of age) with heterozygous familial hypercholesterolaemia
The recommended dose range is 10 – 20 mg once daily between 8 and 13 years of age as doses greater than 20 mg have not been studied in this population and 10 – 40 mg daily between 14 and 18 years of age (for children and adolescent females of childbearing potential, see section 4.6; for results of the study see section 5.1). There is no clinical data in children younger than 8 years old.

4.4 Special warnings and precautions for use

Muscle disorders
As with others HMG-CoA Reductase inhibitors (statins), pravastatin has been associated with the onset of myalgia, myopathy and very rarely, rhabdomyolysis. Myopathy must be considered in any patient under statin therapy presenting with unexplained muscle symptoms such as pain or tenderness, muscle weakness, or muscle cramps. In such cases creatine kinase (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. 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.

The risk of myopathy with statins appears to be exposure-dependent and therefore may vary with individual active substances (due to lipophilicity and pharmacokinetic differences), including their dosage and potential for interactions with medicinal products. 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 (see below).

The risk and severity of muscular disorders during statin therapy is increased by the co-administration of interacting medicinal productsmedicines, such as cyclosporine, 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. The co-administration of statins and nicotinic acid should be used with caution. An increase in the incidence of myopathy has also been described in patients receiving other statins in combination with inhibitors of cytochrome P450 metabolism. This may result from pharmacokinetic interactions that have not been documented for pravastatin (see section 4.5). When associated with statin therapy, muscle symptoms usually resolve following discontinuation of statin therapy.

Statins such asincluding pravastatin Pravastatin 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. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

4.5 Interaction with other medicinal products and other forms of interaction

Colestyramine/Colestipol
Concomitant administration resulted in approximately 40 to 50 % decrease in the bioavailability of pravastatin. There was no clinically significant decrease in bioavailability or therapeutic effect when pravastatin was administered one hour before or four hours after cholestyramine or one hour before colestipol (see section 4.2).

Ciclosporin
Concomitant administration of pravastatin and ciclosporin leads to an approximately 4-fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended (see section 4.2).

Macrolides
Macrolides have the potential to increase stain 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 two interaction studies with pravastatin and erythromycin a statistically significant increase in pravastatin AUC (70 %) and Cmax (121 %) was observed. In a similar study with clarithromycin a statistically significant increase in AUC (110 %) and Cmax (127 %) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.

Products metabolised by cytochrome P450

Pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system. This is why products that are metabolised by, or inhibitors of, the cytochrome P450 system can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as have been seen with other statins.  The absence of a significant pharmacokinetic interaction with pravastatin has been specifically demonstrated for several products, particularly those that are substrates/inhibitors of CYP3A4 e.g. diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors (e.g. fluconazole).

 

In one of two interaction studies with pravastatin and erythromycin a statistically significant increase in pravastatin AUC (70 %) and C_max (121 %) was observed.  In a similar study with clarithromycin a statistically significant increase in AUC (110 %) and C_max (127 %) was observed.  Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.

4.8     Undesirable effects

Gastrointestinal disorders and administration site conditions:

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

Gastrointestinal disorders and administration site conditions:

Very rare: pancreatitis.

 

Hepatobiliary disorders:

Very rare: jaundice, hepatitis, fulminant hepatic necrosis.

 

Skin and subcutaneous tissue disorders:

Rare: photosensitivity reaction

Not knownNot knownVery rare: dermatomyositis.

 

Musculoskeletal and connective tissue disorders:

Very rare: rhabdomyolysis, which can be associated with acute renal failure secondary to myoglobinuria, myopathy (see section 4.4) myositis, polymyositis.

Not known: Immune-mediated necrotising myopathy (see section 4.4)

 

Isolated cases of tendon Uncommon: Tendon disorders, especially tendonitis, sometimes complicated by rupture.

 

The following adverse events have been reported with some statins:
-      Nightmares
-      Memory loss
-      Depression
-      Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)
-      Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose at 5.6 mmol/L, BMI >30kg/m², raised triglycerides, history of hypertension).

Musculoskeletal disorders:
Not known: Immune-mediated necrotising myopathy (see section 4.4) 

5.3     Preclinical safety data

In mice, a 2-year carcinogenicity study with pravastatin demonstrates at doses of 250 and 500 mg/kg/day (≥> 310 times the maximum human mg/kg dose), statistically significant increase in the incidence of hepatocellular carcinomas in males and females, and lung adenomas in females only.  In rats a 2-year carcinogenicity study demonstrates at a dose of 100 mg/kg/day (125 times the maximum human mg/kg/dose) a statistically significant increase in the incidence of hepatocellular carcinomas in males only.

When administered to juvenile rats (postnatal days [PND] 4 through 80), 5 to 45 mg/kg/day, thinning of the corpus callosum was observed at serum pravastatin levels approximately ≥ 1 times (AUC) the maximum paediatric and adolescent dose of 40 mg. At pravastatin levels approximately ≥ 2 times (AUC) the 40 mg human dose, neurobehavioural changes were observed (enhanced startle response and increased errors in watermaze learning). No thinning of the corpus callosum was observed in rats dosed with pravastatin (≥ 250 mg /kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. The cause and significance of the corpus callosum thinning and neurobehavioural effects in juvenile rats are unknown.

 

Altered sperm endpoints and reduced fertility were observed in males at 335 times (AUC) the human dose. The no-observed-effect-levels for reproductive endpoints were 1 (male) and 2 (female) times (AUC) the 40 mg human dose.

 

4.2 Posology and method of administration

Posology
Prior to initiating Pravastatin Mylan Tablets, secondary causes of hypercholesterolaemia should be excluded and patients should be placed on a standard lipid-lowering diet that should be continued during treatment.

Pravastatin Mylan Tablets are administered orally once daily preferably in the evening with or without food.

Paediatric population Children and adolescents (8 - 18 years of age) with heterozygous familial hypercholesterolaemia
The recommended dose range is 10 – 20 mg once daily between 8 and 13 years of age as doses greater than 20 mg have not been studied in this population and 10 – 40 mg daily between 14 and 18 years of age (for children and adolescent females of childbearing potential, see section 4.6; for results of the study see section 5.1).

Concomitant therapy
The lipid lowering effects of Pravastatin Mylan Tablets on total cholesterol and LDL-cholesterol are enhanced when combined with a bile acid-binding resin (e.g. cholestyramine, colestipol). Pravastatin Mylan Tablets should be given either one hour before or at least four hours after the resin (see section 4.5).

For patients taking ciclosporine cyclosporine with or without other immunosuppressive medicinal products, treatment should begin with 20 mg of pravastatin sodium once daily and titration to 40 mg should be performed with caution (see section 4.5).

Method of administration
Pravastatin Mylan Tablets are administered orally once daily preferably in the evening with or without food.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Active liver disease including unexplained persistent elevations of serum transaminase elevation exceeding 3 x the upper limit of normal (ULN) (see section 4.4)
- Pregnancy and lactation breast-feeding (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

CiclosporinCyclosporin
Concomitant administration of pravastatin and ciclosporin cyclosporin leads to an approximately 4fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. Clinical and biochemical monitoring of patients receiving this combination is recommended (see section 4.2).

Warfarin and other oral anticoagulants
Bioavailability parameters at steady state for pravastatin were not altered following administration with warfarin. Chronic dosing of the two products did not produce any changes in the anticoagulant action of 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.

4.6 Fertility, Ppregnancy and lactation

Pregnancy
Pravastatin is contraindicated during pregnancy and should be administered to women of childbearing potential only when these patients are unlikely to conceive and have been informed of the potential risk. 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 must be discontinued because of the potential risk to the foetus (see section 4.3).

LactationBreast-feeding
A small amount of pravastatin is excreted in human breast milk; therefore pravastatin is contraindicated during breastfeeding (see section 4.3).

4.8 Undesirable effects

Gastrointestinal disorders and administration site conditions:
Uncommon: dyspepsia/heartburn, abdominal pain, nausea/vomiting, constipation, diarrhoea, flatulence.

Nervous system disorders:
Very rare: peripheral polyneuropathy, in particular if used for long period of time, paresthesia.

Immune system disorders:
Very rare: hypersensitivity reactions: anaphylaxis, angioedema, lupus erythematouslike syndrome.

Nervous system disorders:
Very rare: peripheral polyneuropathy, in particular if used for long period of time, paraesthesia.

Skin and subcutaneous tissue disorders:
Not known: dermatomyositis.

Musculoskeletal and connective tissue disorders:
Very rare: rhabdomyolysis, which can be associated with acute renal failure secondary to myoglobinuria, myopathy (see section 4.4) myositis, polymyositis.
Not known: Immune-mediated necrotising necrotizing myopathy (see section 4.4)

The following adverse events have been reported with some statins:
- Nightmares
- Memory loss
- Depression
- Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)
- Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ at 5.6 mmol/L, BMI >30kg/m2, raised triglycerides, history of hypertension).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Serum lLipid reducing modifying agents,/cholesterol and triglyceride reducers/ HMG-CoA reductase inhibitors, ATC code: C10AA03.

Clinical efficacy and safety:
Primary prevention:
The "West of Scotland Coronary Prevention Study (WOSCOPS)" was a randomised, double-blind, placebo-controlled trial among 6595 male patients aged from 45 to 64 years with moderate to severe hypercholesterolaemia (LDL-C: 155-232 mg/dl [4.0-6.0 mmol/l]) and with no history of myocardial infarction, treated for an average duration of 4,8 years with either a 40 mg daily dose of pravastatin or placebo as an adjunct to diet.

Heart and kidney transplantation:
The efficacy of pravastatin in patients receiving an immunosuppressant treatment following:
- heart transplant was assessed in one prospective, randomised, controlled study (n=97). Patients were treated concurrently with either pravastatin sodium (20-40 mg) or not, and a standard immunosuppressive regimen of ciclosporincyclosporine, prednisone and azathioprine. Treatment with pravastatin significantly reduced the rate of cardiac rejection with haemodynamic compromise at one year, improved one-year survival (p=0.025), and lowered the risk of coronary vasculopathy in the transplant as determined by angiography and autopsy (p=0.049).
- renal transplant was assessed in one prospective not controlled, not randomised study (n=48) of 4 months duration. Patients were treated concurrently with either pravastatin sodium (20 mg) or not, and a standard immunosuppressive regimen of ciclosporincyclosporin, and prednisone. In patients following kidney transplantation, pravastatin significantly reduced both the incidence of multiple rejection episodes and the incidence of biopsy-proved acute rejection episodes, and the use of pulse injections of both prednisolone and Muromonab-CD3.

Paediatric populationChildren and adolescents (8 - 18 years of age):
A double-blind placebo-controlled study in 214 paediatric patients with heterozygous familial hypercholesterolaemia was conducted over 2 years. Children (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).

5.2 Pharmacokinetic properties

Metabolism Biotransformation and elimination:
Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate or an inhibitor of P-glycoprotein but rather a substrate of other transport proteins. Following oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces. Plasma elimination half-life of oral pravastatin is 1.5 to 2 hours.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrateMonohydrate
Dihydroxy aluminium sodium carbonateAluminium Sodium Carbonate
Sodium stearyl fumarateStearyl Fumarate

10 mg and 40 mg Tablets only:
Iron oxide red Oxide Red (E172)

20 mg Tablets only:
Iron oxide yellow Oxide Yellow (E172)

 

4.4 Special warnings and precautions for use

The risk and severity of muscular disorders during statin therapy is increased by the co-administration of interacting medicinal products. The use of fibrates alone is occasionally associated with myopathy. The combined use of a statin and fibrates should generally be avoided. The co-administration of statins and nicotinic acid should be used with caution. An increase in the incidence of myopathy has also been described in patients receiving other statins in combination with inhibitors of cytochrome P450 metabolism. This may result from pharmacokinetic interactions that have not been documented for pravastatin (see section 4.5). When associated with statin therapy, muscle symptoms usually resolve following discontinuation of statin therapy.

Pravastatin 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. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

 

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Pravastatin sodium and fusidic acid should only be considered on a case by case basis and under close medical supervision.

 

 

The concurrent use of pravastatin and fusidic acid is not recommended, therefore, temporary suspension of pravastatin may be considered during fusidic acid therapy (see section 4.5).

 

4.5 Interaction with other medicinal products and other forms of interaction

Fibrates

The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle

related adverse events, including rhabdomyolysis, have been reported when fibrates are coadministered

with other statins. These adverse events with pravastatin can not be excluded; therefore

the combined use of pravastatin and fibrates (e.g. gemfibrozil, fenofibrate) should generally be

avoided (see section 4.4). If this combination is considered necessary, careful clinical and CK

monitoring of patients on such regimen is required.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. 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 (see section 4.4).

 

 

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.

 

Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of pravastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Additional text / text changes highlighted in RED

3. PHARMACEUTICAL FORM

Tablets

Pravastatin Mylan 10 mg tablets: Light pink colour, mottled, round, flat, bevelled tablets (6 mm) debossed with “10” on one side and plain on the other.
Pravastatin Mylan 20 mg tablets: Light yellow colour, mottled, round tablet (8 mm) debossed with “20” on one side and break line on the other side. The tablet can be divided into equal halves. 
Pravastatin Mylan 40 mg tablets: Light pink colour, mottled, round tablet (10 mm) debossed with “40” on one side and break line on the other side. The tablet can be divided into equal halves.


4.4 Special warnings and precautions for use

During treatment
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.


4.8 Undesirable effects

The frequencies of adverse events are ranked according to the following: very common (> 1/10); common (> 1/100, <1/10); uncommon (> 1/1000, <1/100); rare (> 1/10000, <1/1000); very rare (<1/10000) ; not known (cannot be estimated from the available data).

Musculoskeletal and connective tissue disorders:
Very rare: rhabdomyolysis, which can be associated with acute renal failure secondary to myoglobinuria, myopathy (see section 4.4) myositis, polymyositis.
Not known: Immune-mediated necrotizing myopathy (see section 4.4)

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971 FREE; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.


10. DATE OF REVISION OF THE TEXT

June 2015



(internal reference: UK/H/2810/IB/010 (PR 576467) & UK/H/2810/R/001 (PR 445446))

Shelf life increased from 2 years to 3 years$0$0$0$0$0$0$0(Internal Ref: UK/H/2810/IB/007)$0

4.4 Special warnings and precautions for use

The following text added:

Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

4.8 Undesirable effects

The following side effect was added:

The following adverse events have been reported with some statins:

- Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

10. DATE OF REVISION OF THE TEXT

Date changed to November 2012



(internal ref: UK/H/2810/IB/004)

None provided