Source: Marketing Authorisation Holder Revision Year: 2020 Publisher: Activo Health (Pty) Ltd. Block B, Arena Office Park, 272 West Avenue, Centurion, 0157
Serum transaminase values may be increased, usually to less than 3 times the upper limit of normal, in slightly less than 1 to 2% of patients receiving HMG-CoA reductase inhibitors for at least 1 year.
Marked increases to more than 3 times the upper limit of normal have occurred.
Determinations are recommended prior to initiation of therapy, following each dosage increase, and subsequently when clinically indicated. LESTAVOR should be discontinued if the rise in transaminase levels is persistent and/or increases to three times the upper limit of normal (ULN) or more.
LESTAVOR should be used with caution in patients who consume substantial amounts of alcohol and/or who have a history of liver disease.
Renal impairment has no influence on plasma concentrations; therefore dose adjustment is not needed. (See also rhabdomyolysis under “Skeletal muscle” below).
LESTAVOR may cause myopathy and rhabdomyolysis, especially at higher doses, and it should be used with caution in patients at risk of rhabdomyolysis, and particularly in patients taking medicines, such as cytochrome P450 inhibitors (see INTERACTIONS), that increase plasma concentrations of the HMG-CoA reductase inhibitor, LESTAVOR.
Rhabdomyolysis with or without renal impairment has been reported with the use of HMG-CoA reductase inhibitors such as LESTAVOR. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for the skeletal muscle adverse events.
Patients starting treatment with LESTAVOR should be advised of the risk of myopathy and should promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever. A creatine kinase (CK) level above 10 times the Upper Limit of Normal (ULN) in a patient, with unexplained symptoms, indicate myopathy. LESTAVOR should be discontinued if creatine phosphokinase increases significantly or if myopathy is diagnosed.
The benefits of using LESTAVOR concomitantly with immunosuppressants, fibrates or lipid-lowering doses of niacin should be carefully considered. Concomitant administration with ciclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone is not recommended. In patients receiving ciclosporin, LESTAVOR should be temporarily discontinued.
Patients without coronary heart disease who had a stroke or transient ischaemic attack (TIA) within the preceding months who were initiated on atorvastatin 80 mg revealed a higher incidence of haemorrhagic stroke compared to placebo. Patients with haemorrhagic stroke on entry appeared to be at risk for recurrent haemorrhagic stroke.
Use in paediatric patients is not recommended, as safety and efficacy have not been established.
Atorvastatin is metabolised by cytochrome P450 3A4. Concomitant administration of LESTAVOR with inhibitors of cytochrome P450 3A4 can lead to an increase in plasma concentrations of atorvastatin.
Medicines that inhibit cytochrome P450 isoenzyme CYP3A4 include: ciclosporin, itraconazole, ketoconazole, erythromycin/clarithromycin (see Macrolides below), HIV-protease inhibitors, amiodarone, verapamil and nefazodone. There is a similar interaction with grapefruit juice (contra-indicated); see Grapefruit juice below.
Erythromycin/clarithromycin: In healthy individuals plasma concentrations of atorvastatin increased approximately 40% with co-administration of erythromycin, a known inhibitor of CYP 3A4. Azithromycin: Co-administration of atorvastatin 10 mg and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Co-administration of grapefruit juice and atorvastatin may increase the concentration of atorvastatin, as in LESTAVOR, by 2,5 to 3,3 fold. Therefore the combination should be avoided (see CONTRA-INDICATIONS).
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4, such as efavirenz and rifampicin can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual mechanism of rifampicin, simultaneous co-administration of LESTAVOR with rifampicin is not recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations (see CONTRA-INDICATIONS).
Co-administration of atorvastatin with cimetidine does not alter plasma concentration and LDL reduction.
Co-administration of atorvastatin with diltiazem was associated with a 51% increase in the AUC of atorvastatin. Therefore the combination should be avoided (see CONTRA-INDICATIONS).
Severe muscle problems such as rhabdomyolysis have been reported with the concomitant use of fucidic acid and atorvastatin. Patients on fucidic acid and LESTAVOR should be closely monitored and temporary suspension of LESTAVOR may be appropriate.
Inhibitors of the OATP1 B1 (organic anion-transporting polypeptide-1 B1) transport system, such as ciclosporin, can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and ciclosporin 5,2 mg/kg per day resulted in a 7,7 fold increase in exposure to atorvastatin.
A possible increase in the anticoagulant effect of warfarin may occur. Patients taking warfarin should have their INR determined before starting LESTAVOR therapy. The INR should be monitored frequently enough in the early stages of therapy until stabilised. Once a stable INR has been documented, INR can be monitored at the intervals usually recommended for patients on warfarin. When there is a dose adjustment of LESTAVOR, this procedure should be repeated.
Concurrent use may cause an elevation in serum digoxin concentrations by approximately 20%.
LESTAVOR should be taken 1 hour before or 4 hours after cholestyramine. Concurrent use may decrease the bioavailability of LESTAVOR.
Azole antifungals, ciclosporin, gemfibrozil, other fibrates, immunosuppressants, macrolide antibiotics or niacin Concurrent use with LESTAVOR may be associated with an increased risk of myopathy, myositis, rhabdomyolysis and acute renal failure (see WARNINGS).
Concurrent use may decrease plasma concentrations of atorvastatin by approximately 35%. LDL-C reduction is however not altered.
Concurrent use with atorvastatin may increase the AUC value for norethindrone and ethinyl oestradiol by approximately 30% and 20% respectively.
Safety and efficacy in pregnancy and lactation have not been established. The use of LESTAVOR during pregnancy and lactation, or in women who plan to become pregnant, is contra-indicated.
Women of child-bearing potential should use appropriate contraceptive measures. In the event of planning a pregnancy, an interval of one month should be allowed from stopping LESTAVOR treatment.
LESTAVOR may cause blurred vision, dizziness and confusion. Patients should therefore not operate hazardous machinery, including motor vehicles, until they are reasonably certain that LESTAVOR does not adversely affect them.
Less frequent: Thrombocytopenia, anaemia, neutropenia.
Frequent: Hypersensitivity reactions, including anaphylaxis and angioedema.
Less frequent: Hypoglycaemia, hyperglycaemia, weight gain, anorexia.
Frequent: Insomnia.
Frequent: Dizziness, headache, paraesthesia, hypoaesthesia.
Less frequent: Peripheral neuropathy, cognitive impairment such as memory loss, forgetfulness, amnesia, memory impairment and confusion.
Less frequent: Blurred vision, visual disturbance.
Less frequent: Tinnitus, hearing loss.
Less frequent: Peripheral oedema.
Frequency unknown: Sinusitis, pharyngitis.
Frequent: Constipation, diarrhoea, flatulence, heartburn, abdominal pain and cramps, nausea, dyspepsia.
Less frequent: Dysgeusia (taste disturbances), vomiting, pancreatitis, anorexia.
Less frequent: Hepatitis, cholestatic jaundice, hepatic failure.
Frequent: Skin rash, pruritus.
Less frequent: Alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes, urticaria.
Frequent: Myalgia, arthralgia, back pain.
Less frequent: Myopathy, characterised by myalgia and muscle weakness, and associated with increased creatine phosphokinase concentrations, rhabdomyolysis with acute renal failure, myositis, muscle cramps, tendon rupture.
Less frequent: Impotence (decreased sexual ability), gynaecomastia.
Frequent: Fatigue, asthenia, chest pain, infection.
Less frequent: Malaise.
Marked and persistent increases of serum transaminases and elevated alkaline phosphatase and gammaglutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatinine kinase (CK) levels, derived from skeletal muscle, have been reported (see “Special Precautions”).
LESTAVOR should be used with caution in:
Mild transient increases are common and may not be medication related. Medication related marked increases, with myositis and possible renal failure occur in about 0,5 to 1% of patients, although the incidence may be higher in organ transplant patients treated concurrently with immunosuppressants or gemfibrozil.
Determination of serum creatine kinase is recommended if the patient develops muscle tenderness during therapy or during concurrent therapy with niacin or immunosuppressive medications. A level of 10 times higher than the upper limit of normal in a patient with unexplained muscle symptoms indicates myopathy.
Increased risk of rhabdomyolysis and renal failure.
LESTAVOR contains lactose. Patients who are lactose intolerant or have rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take LESTAVOR.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
