Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Kowa Pharmaceutical Europe Co. Ltd., Winnersh Triangle, Wokingham RG41 5RB, UK
Livazo is contraindicated:
In common with other HMG-CoA reductase inhibitors (statins), there is the potential for myalgia, myopathy and, rarely, rhabdomyolysis to develop. Patients should be asked to report any muscle symptoms. Creatine kinase (CK) levels should be measured in any patient reporting muscle pain, muscle tenderness or weakness especially if accompanied by malaise or fever.
Creatine kinase should not be measured following strenuous exercise or in the presence of any other plausible cause of CK increase which may confound interpretation of the result. When elevated CK concentrations (>5x ULN) are noted, a confirmatory test should be performed within 5 to 7 days.
There have been very 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 creatine kinase, which persist despite discontinuation of statin treatment.
Livazo 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 Livazo and fusidic acid should only be considered on a case by case basis and under close medical supervision.
In common with other statins, Livazo should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatinine kinase level should be measured, to establish a reference baseline, in the following situations:
In such situations, clinical monitoring is recommended and the risk of treatment should be considered in relation to the possible benefit. Treatment with Livazo should not be started if CK values are >5x ULN.
Patients must be encouraged to report muscle pain, weakness or cramps immediately. Creatine kinase levels should be measured and treatment stopped if CK levels are elevated (>5x ULN). Stopping treatment should be considered if muscular symptoms are severe even if CK levels are ≤5x ULN. If symptoms resolve and CK levels return to normal, then re-introduction of Livazo may be considered at a dose of 1mg and with close monitoring.
In common with other statins, Livazo should be used with caution in patients with a history of liver disease or who regularly consume excessive quantities of alcohol. Liver function tests should be performed prior to initiating treatment with Livazo and then periodically during treatment. Livazo treatment should be discontinued in patients who have a persistent increase in serum transaminases (ALT and AST) exceeding 3x ULN.
Livazo should be used with caution in patients with moderate or severe renal impairment. Dose increments should be instituted only with close monitoring. In those with severe renal impairment, 4mg dose is not recommended (see section 4.2).
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 of hyperglycaemia (fasting glucose 5.6 to 6.9 mmol/L, BMI>30 kg/m², raised triglycerides, hypertension), should be monitored both clinically and biochemically according to national guidelines. However, there has been no confirmed signal of a diabetes risk for pitavastatin either in post-marketing safety surveillance studies or in prospective studies (see section 5.1).
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive 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.
There is limited data on the long term effect on growth and sexual maturation in paediatric patients 6 years of age or older taking Livazo. Adolescent females should be counselled on appropriate contraceptive precautions during treatment with Livazo (see section 4.3, section 4.6).
A temporary suspension of Livazo is recommended for the duration of treatment with erythromycin, other macrolide antibiotics or fusidic acid (see section 4.5). Livazo should be used with caution in patients taking drugs known to cause myopathy (e.g. fibrates or niacin see section 4.5).
The tablets contain lactose. Patients with the rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pitavastatin is actively transported into human hepatocytes by multiple hepatic transporters (including organic anion transporting polypeptide, OATP), which may be involved in some of the following interactions.
Ciclosporin: Co-administration of a single dose of ciclosporin with Livazo at steady state resulted in a 4.6-fold increase in pitavastatin AUC. The effect of steady state ciclosporin on steady state Livazo is not known. Livazo is contraindicated in patients being treated with ciclosporin (see section 4.3).
Erythromycin: Co-administration with Livazo resulted in a 2.8-fold increase in pitavastatin AUC. A temporary suspension of Livazo is recommended for the duration of treatment with erythromycin or other macrolide antibiotics.
Gemfibrozil and other fibrates: The use of fibrates alone is occasionally associated with myopathy. Co-administration of fibrates with statins has been associated with increased myopathy and rhabdomyolysis. Livazo should be administered with caution when used concomitantly with fibrates (see section 4.4). In Pharmacokinetic studies co-administration of Livazo with Gemfibrozil resulted in a 1.4-fold increase in pitavastatin AUC; with Fenofibrate AUC, increased 1.2-fold.
Niacin: Interaction studies with Livazo and niacin have not been conducted. The use of niacin alone has been associated with myopathy and rhabdomyolysis when used as a monotherapy. Thus Livazo should be administered with caution when used concomitantly with niacin.
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, Livazo treatment should be discontinued throughout the duration of the fusidic acid treatment (see section 4.4).
Rifampicin: Co-administration with Livazo at the same time resulted in a 1.3-fold increase in pitavastatin AUC due to reduced hepatic uptake.
Protease inhibitors: Co-administration with Livazo at the same time may result in minor changes in pitavastatin AUC.
Ezetimibe and its glucuronide metabolite inhibit the absorption of dietary and biliary cholesterol. Coadministration of Livazo had no effect on plasma ezetimibe or the glucuronide metabolite concentrations and ezetimibe had no impact on pitavastatin plasma concentrations.
Inhibitors of CYP3A4: Interaction studies with itraconazole and grapefruit juice, known inhibitors of CYP3A4, had no clinically significant effect on the plasma concentrations of pitavastatin.
Digoxin, a known P-gp substrate, did not interact with Livazo. During co-administration there was no significant change in either pitavastatin or digoxin concentrations.
Warfarin: The steady-state pharmacokinetics and pharmacodynamics (INR and PT) of warfarin in healthy volunteers was unaffected by the co-administration of Livazo 4mg daily. However, as for other statins, patients receiving warfarin should have their prothrombin time or INR monitored when Livazo is added to their therapy.
Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.
Livazo is contraindicated during pregnancy (see section 4.3). Women of childbearing potential must take appropriate contraceptive precautions during treatment with Livazo. Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the fetus, the potential risk for inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies show evidence of reproductive toxicity, but no teratogenic potential (see section 5.3). If the patient is planning to become pregnant, treatment should be stopped at least one month prior to conception. If a patient becomes pregnant during use of Livazo, treatment must be discontinued immediately.
Livazo is contraindicated during breastfeeding (see section 4.3). Pitavastatin is excreted in rat milk. It is not known whether it is excreted in human milk.
No current data.
There is no pattern of adverse events that suggests that patients taking Livazo will have any impairment of ability to drive and use hazardous machinery, but it should be taken into account that there have been reports of dizziness and somnolence during treatment with Livazo.
In controlled clinical trials, at the recommended doses, less than 4% of Livazo treated patients were withdrawn due to adverse events. The most commonly reported pitavastatin related adverse reaction in controlled clinical trials was myalgia.
Adverse reactions and frequencies observed in worldwide controlled clinical trials and extension studies, at the recommended doses, are listed below by system organ class. Frequencies are defined as: very common (≥1/10), common (≥1/100, to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000) and not known.
Uncommon: Anaemia
Uncommon: Anorexia
Uncommon: Insomnia
Common: Headache
Uncommon: Dizziness, Dysgeusia, Somnolence
Rare: Visual acuity reduced
Uncommon: Tinnitus
Common: Constipation, Diarrhoea, Dyspepsia, Nausea
Uncommon: Abdominal Pain, Dry Mouth, Vomiting
Rare: Glossodynia, pancreatitis acute
Uncommon: Transaminases (aspartate aminotransferase, alanine aminotransferase) increased
Rare: Jaundice cholestatic
Uncommon: Pruritus, Rash
Rare: Urticaria, Erythema
Common: Myalgia, Arthralgia
Uncommon: Muscle spasms
Frequency unknown: Immune-mediated necrotising myopathy (see section 4.4)
Uncommon: Pollakiuria
Uncommon: Asthenia, Malaise, Fatigue, Peripheral Oedema
Elevated blood creatinine kinase of >3 times the upper limit of normal (ULN) occurred in 49 out of 2800 (1.8%) patients receiving Livazo in the controlled clinical trials. Levels of ≥10 times ULN with concurrent muscle symptoms were rare and only observed in one patient out of 2406 treated with 4mg Livazo (0.04%) in the clinical trial programme.
The clinical safety database includes safety data for 142 paediatric patients who received pitavastatin among which 87 patients were in the age range of 6 to 11, and 55 patients were in the age range of 12 to 17. In total, 91 patients received pitavastatin for 1 year with 12 patients receiving pitavastatin for 2.5 years and 2 patients for 3 years. Less than 3% of pitavastatin treated patients were withdrawn due to adverse events. The most commonly reported pitavastatin related adverse reactions in the clinical programme were headache (4.9%), myalgia (2.1%) and abdominal pain (4.9%). Based on the data available, the frequency, type and severity of adverse reactions are expected to be similar in children and adolescents to adults.
A two year prospective post-marketing surveillance study was conducted in nearly 20,000 patients in Japan. The overwhelming majority of the 20,000 patients in the study were treated with 1mg or 2mg pitavastatin and not 4mg. 10.4% of patients reported adverse events for which a causal relationship to pitavastatin could not be ruled out and 7.4% of patients withdrew from therapy due to adverse events. The myalgia rate was 1.08%. The majority of adverse events were mild. Adverse event rates were higher over 2 years in patients with a history of drug allergy (20.4%), or hepatic or renal disease (13.5%).
Adverse reactions and frequencies observed in the prospective post-marketing surveillance study but not in worldwide controlled clinical trials, at the recommended doses are listed below.
Rare: Hepatic function abnormal, Liver disorder
Rare: Myopathy, Rhabdomyolysis
In the post-marketing surveillance study there were two reports of rhabdomyolysis requiring hospitalisation (0.01% of patients).
In addition there are unsolicited post-marketing reports of skeletal muscle effects including myalgia and myopathy in Livazo treated patients at all recommended doses. Reports of rhabdomyolysis, with and without acute renal failure, including fatal rhabdomyolysis have also been received. Unsolicited reports of the following events have also been received (the frequency is based on that observed in post-marketing studies):
Uncommon: Hypoaesthesia
Rare: Abdominal discomfort
The following adverse events have been reported with some statins:
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 the national reporting system listed in Appendix V.
Not applicable.
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