Livalo Drug Information

LIVALO is indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

Important Dosage and Administration Information Take

LIVALO orally once daily with or without food at the same time each day. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving LIVALO 4 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LIVALO, and adjust the dosage if necessary.

Recommended Dosage for Adults and Pediatric Patients Aged 8 Years and Older The recommended dosage range of LIVALO is 2 mg to 4 mg daily. The maximum recommended dose for these patients is LIVALO 2 mg once daily. There are no dosage adjustment recommendations for patients with mild renal impairment.

Dosage Modifications Due to Drug Interactions

In patients taking erythromycin, do not exceed LIVALO 1 mg once daily. In patients taking rifampin, do not exceed LIVALO 2 mg once daily.

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. In controlled clinical studies and their open-label extensions, mg, and 3.7% (4 mg) of LIVALO-treated patients were discontinued due to adverse reactions. Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1.

These studies had treatment duration of up to 12 weeks. Table 1. Adverse Reactions ( ≥ 2% and ≥ placebo) in Adults with Primary Hyperlipidemia in Studies up to 12 Weeks Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.

Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO. The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose. Adverse Reactions in Adult HIV-Infected Patients with Dyslipidemia In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either LIVALO 4 mg once daily (n=126) or another statin (n=126).

All patients were taking antiretroviral therapy (excluding darunavir) and had HIV-1 RNA less than 200 copies/mL and CD4 count greater than 200 cell/µL for at least 3 months prior to randomization. The safety profile of LIVALO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with LIVALO had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously.

Four patients (3%) treated with LIVALO had at least one ALT value exceeding 3 times but less than 5 times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with LIVALO, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline. Adverse Reactions in Pediatric Patients Aged 8 Years and Older with HeFH In a 12-week, double-blind, placebo-controlled trial of LIVALO 1 mg, 2 mg, and 4 mg once daily in 82 pediatric patients 8 years to 16 years of age with HeFH and a 52-week open-label trial in 85 pediatric patients with HeFH, the safety profile was similar to that observed in the adult population.

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. Gastrointestinal disorders: abdominal discomfort, abdominal pain, dyspepsia, nausea General disorders: asthenia, fatigue, malaise, dizziness Hepatobiliary disorders: hepatitis, jaundice, fatal and non-fatal hepatic failure Immune system disorders: angioedema, immune-mediated necrotizing myopathy associated with statin use Metabolism and nutrition disorders: increases in HbA1c, fasting serum glucose levels Musculoskeletal and connective tissue disorders: muscle spasms, myopathy, rhabdomyolysis Nervous system disorders: hypoesthesia, peripheral neuropathy.

There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Psychiatric disorders: insomnia, depression Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: interstitial lung disease Skin and subcutaneous tissue disorders: lichen planus

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. Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LIVALO Cyclosporine Clinical Impact: Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: Concomitant use of cyclosporine with LIVALO is contraindicated.

In patients taking erythromycin, do not exceed LIVALO 1 mg once daily. Rifampin Clinical Impact: Rifampin significantly increases peak pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: In patients taking rifampin, do not exceed LIVALO 2 mg once daily.

See full prescribing information for details regarding concomitant use of LIVALO with other drugs that increase the risk of myopathy and rhabdomyolysis.

Pregnancy Risk Summary Discontinue LIVALO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. LIVALO decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LIVALO may cause fetal harm when administered to pregnant patients based on the mechanism of action.

In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations.

Published data from prospective and retrospective observational cohort studies with statin use in pregnant women are insufficient to determine if there is a drug associated risk of miscarriage (see Data ). In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats and rabbits orally administered pitavastatin during the period of organogenesis at doses which were 22 and 4 times, respectively, the human exposure at the maximum recommended human dosage (MRHD) of 4 mg, based on AUC. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods.

The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC).

In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at mg/kg/day from organogenesis through weaning (gestation day 17 to lactation day 21), maternal toxicity consisting of mortality at ≥0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately 1 time human systemic exposure at 4 mg/day dose based on AUC). Reproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at ≤36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation (at the end of organogenesis).

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 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).

LIVALO is contraindicated in the following conditions: Concomitant use of cyclosporine. Acute liver failure or decompensated cirrhosis. Hypersensitivity to pitavastatin or any excipents in LIVALO.

Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with LIVALO. Cyclosporine Active liver failure or decompensated cirrhosis Hypersensitivity to pitavastatin or any excipients in LIVALO

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.