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Statins Safety - pitavastatin [LIVALO] Product Insert
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Download the PDF here
Download the PDF here
Product Insert:
Dosage in Patients with Renal Impairment
Patients with moderate and severe renal impairment (glomerular filtration rate 30 - 59 mL/min/1.73 m2and 15 - 29 mL/min/1.73 m2
not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of
LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily.
CONTRAINDICATIONS
The use of LIVALO is contraindicated in the following conditions:
⋅Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus,
and urticaria have been reported with LIVALO[see Adverse Reactions (6.1)].
⋅Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels[see
Warnings and Precautions (5.2), Use in Specific Populations (8.7)].
⋅Co-administration with cyclosporine[see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
⋅Pregnancy.[see Use in Specific Populations (8.1, 8.3)].
⋅Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk.
Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, women who
require pitavastatin treatment should not breastfeed their infants[see Use in Specific Populations (8.2)].
The duration of therapy before the onset ofmyopathy varied from a few weeks to over 2 years. Someof the late-appearing cases are probably related tochanges in concomitant therapy.
Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMGCoA
reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.
LIVALO should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age
(≥65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent
administration of fibrates or lipid-modifying doses of niacin. LIVALO should be administered with caution in patients with impaired
renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin[see Drug Interactions
(7.6), Use in Specific Populations (8.5, 8.6) and Clinical Pharmacology (12.3)].
Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with
colchicine, and caution should be exercised when prescribing LIVALO with colchicine [seeDrug Interactions(7.7)].
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin
use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation
of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with
immunosuppressive agents.
LIVALO therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or
suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of
myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration,
major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised
to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle
signs and symptoms persist after discontinuing LIVALO.
HEPATIC EFFECTS lovastain 40 mg
Small increases in transaminases, particularly serumglutamic pyruvic transaminase (alanine transaminase),sometimes occur, often within 6 weeks of starting therapy. 8-10, 16Such increases are often transient and have notrequired withdrawal of therapy. The same phenomenonhas been reported with most other lipid-lowering drugs.29
In a large clinical trial comparing lovastatin and cholestyramine 10the 2 drugs raised transaminase levels equally.Because cholestyramine is not absorbed from the gastrointestinaltract, small increasesin transaminasesm ay be aresponse to changes in lipid metabolism, rather than adirect effect of lipid-lowering drugs on the liver. A moreimportant finding is that 1.9% of the patients treated withlovastatin in clinical trials have had asymptomatic butmarked and persistent transaminase increases, againparticularly serum glutamic pyruvic transaminase.15,17 When the drug was discontinued, transaminases returnedto pretreatment levels, usually within a few weeks. Incontrast to the small increases in transaminases that appearearly in therapy, the larger increases have usuallyoccurred between 3 and 12 months after starting therapy.Alkaline phosphatase remained essentially normal, indicatingthat the effect is most probably hepatocellularrather than cholestatic. A liver biopsy specimen was obtained in 1 of these patients, which showed areas of focalhepatitis.17 Eleven patients have been rechallenged; 6 hada positive rechallenge, 2 had a positive rechallenge followed by a negative rechallenge, and 3 had a negativerechallenge. The increase in transaminase levels in thepatients with positive rechallenges was delayed for atleast 4 weeks.It is believed that a reduction of alcoholconsumption may have been instrumental in producingsome of the negative rechallenges. All the patients whohave had increased transaminase levels have been asymptomaticthroughout. The lack of symptoms, together withthe delayed response on rechallenge, indicates that theeffect is not a hypersensitivity phenomenon. As with myopathy, the mechanism is presently unknown. Althoughnot seen in clinical trials, the possibility that symptomaticliver injury could occur if therapy were continued in theface of increasing serum transaminase levels requires theregular monitoring of these enzymes. They should bemeasured before therapy, at intervals of 4 to 6 weeksduring the first 15 months of therapy, and periodicallythereafter.1
Lovastatin has not been reported to have an effect onreported adrenal 7,6,8,9,30,31 or testicular 7,8,9,37 stroidogenesis, or on human spermatogenesis. 32
MYOPATHY
Myopathy, defined as muscle pain or weakness, orboth, plus a creatine kinase (CK) value of at least 10times the upper limit of normal, has been reported in 17(<0.5%) of approximately 4,000 patients who had participatedin clinical trials up to March 1988.10, 16, 18-20usually increased to between 8,000 and 30,000 U/liter,with the highest reported value at 223,000 U/liter. Thereis very little correlation between the magnitude of the CKelevation and the intensity of the symptoms. In 2 of the 17patients, both of whom had a cardiac transplant and werereceiving immunosuppressant therapy including cyclosporine,a frank rhabdomyolysis that precipitated renalfailure occurred. 18-20 These 2 patients and the other 15recovered promptly when therapy with lovastatin wasdiscontinued. The duration of therapy before the onset of
myopathy varied from a few weeks to over 2 years. Someof the late-appearing cases are probably related tochanges in concomitant therapy.
The clinical features of these 17 patients with myopathy,and their concomitant therapy with cyclosporine,gemfibrozil and niacin are listed in Table III. It is evidentthat most of these patients have a variety of complicatingfactors, particularly cardiac transplantation with immunosuppressanttherapy. However, the phenomenon hasbeen observed in 4 patients with no particular complicatingfactors other than ischemic heart disease, 3 of whomwere taking none of the 3 concomitant therapies in question.
Most of the patients were women, whereas the patientpopulation as a whole is about two-thirds men.
Three patients had various biliary disorders that couldhave reduced biliary clearance, an important route ofelimination for lovastatin. l 7 Concomitant therapy with
immunosuppressant drugs including cyclosporine withgemfibrozil or niacin, or a combination, appears to great-
The risk of myopathy can be minimized by certainprecautions.......
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