^ Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of one drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
^ Description
LIVALO (pitavastatin) tablets for oral use is an HMG-CoA reductase inhibitor.
The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. The structural formula is:
The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light.
Each film-coated tablet of LIVALO contains 1 mg, 2 mg, or 4 mg of pitavastatin, which is equivalent to 1.045 mg, 2.09 mg, or 4.18 mg, respectively, of pitavastatin calcium and the following inactive ingredients: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium aluminometasilicate, and magnesium stearate. The film coating contains the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide, and triethyl citrate.
^ Hepatic Impairment
LIVALO is contraindicated in patients with active liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].
^Principal Display Panel - 1 Mg Tablet Bottle Label
NDC 66869-104-90
Livalo® (pitavastatin) tablets
1 mg*
Rx Only
Kowa
^ Overdosage
No specific treatment for LIVALO overdose is known. Contact Poison Control (1-800-222-1222) for latest recommendations. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of LIVALO.
^ Immune-mediated Necrotizing Myopathy
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use , including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue LIVALO if IMNM is suspected.
^ Renal Impairment
Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Due to the risk of myopathy, a dosage modification of LIVALO is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2, respectively), as well as end-stage renal disease receiving hemodialysis. [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
^3 Dosage Forms And Strengths
Tablets:
^ Recommended Dosage In Patients With Renal Impairment
^ Pediatric Use
The safety and effectiveness of LIVALO as an adjunctive therapy to diet to reduce elevated LDL-C in pediatric patients aged 8 years and older with HeFH have been established. Use of LIVALO for this indication is supported by a 12-week, double-blind, placebo-controlled trial in 82 pediatric patients 8 to 16 years of age with HeFH [see Clinical Studies (14.2)] and a 52-week open-label trial in 85 pediatric patients with HeFH.
The safety and effectiveness of LIVALO have not been established in pediatric patients younger than 8 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).
^4 Contraindications
LIVALO is contraindicated in the following conditions:
^ Postmarketing Experience
The following adverse reactions have been identified during postapproval use of LIVALO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
^ How Supplied/storage And Handling
LIVALO tablets are supplied as follows:
^ Geriatric Use
In controlled clinical studies, 1,209 (43%) patients were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Advanced age (≥65 years) is a risk factor for LIVALO-associated myopathy and rhabdomyolysis. Dose selection for a geriatric patient should be cautious, reognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LIVALO for the increased risk of myopathy [see Warnings and Precautions (5.1)].
^ Increases In Hba1c And Fasting Serum Glucose Levels
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LIVALO. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg daily, there was an absence of drug-related tumors.
In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg daily maximum human dose.
In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested, which also elicited high levels of cytotoxicity.
Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg daily based on AUC.
Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg daily based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.
^ Myopathy And Rhabdomyolysis
LIVALO may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including LIVALO.
^ Dosage Modifications Due To Drug Interactions
^ Hepatic Dysfunction
Increases in serum transaminases have been reported with LIVALO [see Adverse Reactions (6)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LIVALO.
Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
Consider liver enzyme testing before the initiation of LIVALO and when clinically indicated thereafter. LIVALO is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIVALO.
^ Important Dosage And Administration Information
^6 Adverse Reactions
The following serious adverse reactions are discussed in other sections of the labeling:
^7 Drug Interactions
Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with LIVALO and instructions for preventing or managing drug interactions [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
^1 Indications And Usage
LIVALO is indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in:
^ Recommended Dosage For Adults And Pediatric Patients Aged 8 Years And Older
^ Mechanism Of Action
Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins.