Pravastatin/ Fenofibrate

Registered South African indications:

• Mixed hyperlipidaemia in patients at high cardiovascular risk (as an adjunct to diet and other non-pharmacological treatment)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (CrCl <60ml/min)
• Severe hepatic impairment
  - Biliary cirrhosis
  - Active liver disease
  - Unexplained persistent elevations in liver function tests (including serum transaminase elevation) exceeding 3 fold the upper limit of normal (ULN)
• Children and adolescents (<18 years)
• Known photo allergy or photo toxic reaction during treatment with fibrates or ketoprofen
• Gallbladder disease
• Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia
• Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmed creatine phosphokinase elevation above 5 times the ULN under previous statin treatment
• Coadministration with fusidic acid

Cautions

• Moderate hepatic impairment
  - History of liver disease
• Elderly (>70 years)
• Hypothyroidism
• Personal history of muscular toxicity with a statin or fibrate
• Personal or familial history of hereditary muscular disorders
• Alcohol abuse
• Hereditary muscular disease
• Prolonged use  
• History of pulmonary embolism
• Diabetes mellitus
• High risk for diabetes, including risk factors such as:
  - Fasting glucose of 5,6-6,9 mmol/L
  - BMI >30kg/m² 
  - Raised triglycerides
  - Hypertension
• Hereditary galactose intolerance
• Lapp lactase deficiency
• Glucose galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Mixed hyperlipidaemia in patients at high cardiovascular risk (as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction)) 
- To reduce triglycerides and increase HDL-C when LDL-C levels are adequately controlled while on treatment with pravastatin 40mg monotherapy

Pravastatin/ fenofibrate
40/ 160 (mg)

• Oral (cap): 40/160mg, dly, at night with food

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Prior to initiating pravastatin/ fenofibrate, secondary causes of combined dyslipidaemia should be excluded and patients should be placed on a standard cholesterol and triglycerides-lowering diet which should be continued during treatment

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Dietary restrictions instituted before therapy should be continued. Response to therapy should be monitored by determination of serum lipid values

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Rapid reduction of serum lipid levels usually follows pravastatin/ fenofibrate treatment, but treatment should be discontinued if an adequate response has not been achieved within three months

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Since it is less well absorbed from an empty stomach, pravastatin/ fenofibrate should always be taken with food

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The pharmacokinetic properties of pravastatin/ fenofibrate are not identical to the coadministration of the existing monotherapies when taken with fat-meal or in fasting state

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• Women of child-bearing potential must use highly effective contraception while taking pravastatin/ fenofibrate
• Special caution is recommended in women of child-bearing 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 medical practitioner has to be informed immediately and the pravastatin/ fenofibrate combination (pravastatin) should be discontinued because of the potential risk to the foetus

Breastfeeding

• Contraindicated
• Mothers on pravastatin/ fenofibrate should not breastfeed their infants
• Pravastatin sodium: Pravastatin is excreted in human breast milk, therefore pravastatin is contraindicated for use in mothers who are breastfeeding their infants
• Fenofibrate: Fenofibrate is excreted in milk and therefore is contraindicated for use in mothers who are breastfeeding their infants. There are no data on the excretion of fenofibrate and/or its metabolites into human breast milk

Renal Impairment

• Mild (CrCl ≥60ml/min): No dose adjustment recommended
• Moderate to severe (CrCl <60ml/min): Contraindicated

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate: Caution; no dose adjustment recommended
  Use is not recommended
• Severe: Contraindicated

Elderly

• Caution; no dose adjustment recommended
  Treatment initiation should be decided after renal function has been evaluated
  Limited safety data is available in patients >75 years of age. Exercise care

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Sleep disturbances
  - Insomnia
  - Nightmares
• Dizziness
• Headache
• Paraesthesia
• Fatigue

Cardiovascular Disorders

• Palpitations

Gastrointestinal Disorders

• Abdominal distention
• Abdominal pain
• Upper abdominal pain
• Constipation
• Diarrhoea
• Dry mouth
• Dyspepsia
• Eructation
• Flatulence
• Nausea and vomiting
• Abdominal discomfort
• Pancreatitis

Hepatobiliary Disorders

• Increased transaminases
• Hepatic pain
• Increased gamma-glutamyl transferase
• Biliary tract stone or sludge formation
• Obstruction of bile duct

Genitourinary Disorders

• Increased blood creatinine
• Decreased creatinine clearance
• Increased creatinine clearance
• Renal failure

Endocrine and Metabolic Disorders

• Aggravated diabetes mellitus
• Obesity
• Increased blood cholesterol
• Increased blood triglycerides
• Increased low-density lipoprotein
• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Increased blood creatine phosphokinase
• Muscle spasms
• Musculoskeletal pain
• Myalgia
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Influenza-like illness

Additional information on the individual active ingredients of the combination

Central Nervous System Disorders

• Peripheral polyneuropathy
• Fatigue
• Nightmares (statins)
• Memory loss (statins)
• Depression (statins)

Cardiovascular Disorders

• Thromboembolism
  - Pulmonary embolism
  - Deep vein thrombosis

Respiratory Disorders

• Interstitial pneumopathies
• Interstitial lung disease (long term use) (statins)
  - Dyspnoea
  - Non-productive cough
  - Fatigue
  - Weight loss
  - Fever

Hepatobiliary Disorders

• Cholelithiasis
• Jaundice
• Complications of cholelithiasis
  - Cholecystitis
  - Cholangitis
  - Biliary colic
• Fulminant hepatic necrosis

Genitourinary Disorders

• Abnormal urination
  - Abnormal frequency
  - Dysuria
  - Nocturia
• Increased blood urea
• Sexual dysfunction

Endocrine and Metabolic Disorders

• Diabetes mellitus (dependent on the presence or absence of risk factors) (statins)

Musculoskeletal Disorders

• Myositis
• Muscular weakness
• Rhabdomyolysis associated with
  - Acute renal failure secondary to myoglobinuria
  - Myopathy
• Polymyositis
• Tendon disorders (sometimes complicated by rupture)
• Immune-mediated necrotising myopathy

Skin and Subcutaneous Tissue Disorders

• Rash
• Scalp/hair abnormality
  - Alopecia
• Photosensitivity reactions

Immune, Blood and Lymphatic System Disorders

• Decreased haemoglobin
• Decreased white blood cell count

Sensory Disorders

• Visual disturbance
  - Blurred vision
  - Diplopia
• Vertigo

Pravastatin

• Fusidic acid
• Bile acid resin
• Cholestyramine
• Colestipol
• Ciclosporin
• Agents metabolised by cytochrome P450
• Diltiazem
• Verapamil
• Itraconazole
• Ketoconazole
• Protease inhibitors
• CYP2C9 inhibitors
• Fluconazole
• Macrolide antibiotics
• Erythromycin
• Clarithromycin

Other interactions

• Grapefruit juice

Fenofibrate

• Bile acid resin
• Cholestyramine
• Colestipol
• Oral anticoagulants
• Ciclosporin

• Lipid levels
• Renal function
• Creatine phosphokinase levels
• Hepatic function

Additional observations

• Signs and symptoms of muscle toxicity

Before treatment initiation 

• Creatine phosphokinase (CK) levels should be measured prior to initiation of therapy
• The baseline CK levels may also be useful as a reference in the event of a later increase during the combination therapy
• When measured, CK levels should be interpreted in the context of other potential factors that can cause transient muscle damage, such as strenuous exercise or muscle trauma and repeated if necessary
• If CK levels are significantly elevated >5 times the ULN at baseline, the test should be repeated after 5 - 7 days
• If confirmed, the treatment should definitively not be initiated 

During treatment 

• Routine monitoring of CK is recommended every 3 months during the first 12 months of treatment with pravastatin/ fenofibrate and then at time intervals as determined by the treating medical practitioner, but not less than annually
• Patients should be advised to promptly report unexplained muscle pain, tenderness, weakness or cramps. In these cases, CK levels should be measured
• If a markedly elevated >5 times the ULN CK level is detected and confirmed, pravastatin/ fenofibrate therapy must be discontinued
• Treatment discontinuation should also be considered if the muscular symptoms are severe and cause daily discomfort (whatever the CK levels). If a hereditary muscular disease is suspected in such patients, restarting pravastatin/ fenofibrate therapy is not recommended
• There have been reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins such as pravastatin
• IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment

Pravastatin/ fenofibrate contains fenofibrate and pravastatin, which have different modes of action and show additive effects in terms of reduction of serum lipid. Pravastatin is more effective in reducing LDL-C and total cholesterol, but presents only modest effects on TG and HDL-C, while fenofibrate is very effective in decreasing TG and increasing HDL-C.

Fenofibrate
Fenofibrate is a fibric acid derivative whose lipid-modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα). Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDL cholesterol levels are frequently increased. LDL and VLDL triglycerides are reduced. The overall effect is a decrease in the ratio of low and very low-density lipoproteins to high-density lipoproteins. Fenofibrate has a uricosuric effect, increasing urinary secretion of uric acid by two-fold.

Pravastatin
Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalysing the early rate-limiting step in cholesterol biosynthesis, and produces its lipid-lowering effect in two ways. Firstly, with the reversible and specific competitive inhibition of HMG-CoA reductase, it affects modest reduction in the synthesis of intracellular cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL-cholesterol. Secondly, pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLD-cholesterol, the LDL-cholesterol precursor. In both healthy subjects and patients with hypercholesterolaemia, pravastatin lowers the following lipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides, while HDL-cholesterol and apolipoprotein A are elevated.

COMBINATION PREPARATION

Pravastatin 40mg/ Fenofibrate 160mg

Capsule (40mg/ 160mg)

• Pravafen (Austell Laboratories) originator