Pitavastatin Calcium Drug Information

• Pitavastatin tablets are 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). Pitavastatin tablets are a HMG-CoA reductase inhibitor (statin) indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: ( 1 )
• Adults with primary hyperlipidemia.
• Adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

• Take orally once daily with or without food at the same time each day. ( 2.1 )
• For patients requiring a high-intensity statin or are unable to achieve their LDL-C goal receiving pitavastatin tablets 4 mg daily, prescribe alternative LDL-C-lowering treatment. ( 2.1 )
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiation of pitavastatin tablets, and adjust the dosage if necessary. ( 2.1 )
• Recommended dosage is 2 mg to 4 mg once daily. Maximum recommended dosage is 4 mg once daily. ( 2.2 )
• Recommended starting dosage for patients with moderate and severe renal impairment and end-stage renal disease on hemodialysis is 1 mg once daily. Maximum recommended dosage is 2 mg once daily. ( 2.3 )
• See full prescribing information for pitavastatin tablets dosage modifications due to drug interactions. ( 2.4 ) 2.1 Important Dosage and Administration Information
• Take pitavastatin tablets 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 pitavastatin tablets 4 mg daily, prescribe alternative LDL-C-lowering treatment.
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pitavastatin tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage for Adults and Pediatric Patients Aged 8 Years and Older
• The recommended dosage range of pitavastatin tablets is 2 mg to 4 mg daily.
• The maximum recommended dosage is pitavastatin tablets 4 mg once daily. 2.3 Recommended Dosage in Patients with Renal Impairment
• The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30–59 mL/minute/1.73 m 2 and 15–29 mL/minute/1.73 m 2 , respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin tablets 1 mg once daily. The maximum recommended dose for these patients is pitavastatin tablets 2 mg once daily [see Use in Specific Populations (8.5) ] .
• There are no dosage adjustment recommendations for patients with mild renal impairment. 2.4 Dosage Modifications Due to Drug Interactions
• In patients taking erythromycin, do not exceed pitavastatin tablets 1 mg once daily [see Drug Interactions (7) ] .
• In patients taking rifampin, do not exceed pitavastatin tablets 2 mg once daily [see Drug Interactions (7) ] .

• The following serious adverse reactions are discussed in other sections of the labeling:
• Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ]
• Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ]
• Hepatic Dysfunction [see Warnings and Precautions (5.3) ]
• Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] The most frequent adverse reactions (rate ≥ 2%) were myalgia, constipation, diarrhea, back pain, and pain in extremity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adverse Reactions in Adults with Primary Hyperlipidemia In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered pitavastatin tablets 1 mg to 4 mg daily. The mean continuous exposure of pitavastatin (1 mg to 4 mg) was 36.7 weeks (median 51.1 weeks). The mean age of the patients was 60.9 years (range; 18 years–89 years) and 52% were females. Approximately 93% of the patients were White, 7% were Asian/Indian, 0.2% were African American and 0.3% were Hispanic and other. In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin tablets-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg). 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 Adverse Reactions Placebo (n = 208) % Pitavastatin Tablets 1 mg (n = 309) % Pitavastatin Tablets 2 mg (n = 951) % Pitavastatin Tablets 4 mg (n = 1540) % Myalgia 1.4 1.9 2.8 3.1 Constipation 1.9 3.6 1.5 2.2 Diarrhea 1.9 2.6 1.5 1.9 Back pain 2.9 3.9 1.8 1.4 Pain in extremity 1.9 2.3 0.6 0.9 Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin tablets. 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 pitavastatin tablets 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 pitavastatin tablets was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin tablets had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin tablets 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 pitavastatin tablets, 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 pitavastatin tablets 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pitavastatin tablets. 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 pitavastatin tablets and instructions for preventing or managing drug interactions . Table 2. Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pitavastatin Tablets Cyclosporine Clinical Impact: Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: Concomitant use of cyclosporine with pitavastatin tablets is contraindicated . Gemfibrozil Clinical Impact: Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including pitavastatin tablets.

Intervention: Avoid concomitant use of gemfibrozil with pitavastatin tablets. Erythromycin Clinical Impact: Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: In patients taking erythromycin, do not exceed pitavastatin tablets 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 pitavastatin tablets 2 mg once daily . Fibrates Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins, including pitavastatin tablets. Intervention: Consider if the benefit of using fibrates concomitantly with pitavastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis.

Niacin Clinical Impact: The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid-modifying doses (≥ 1 g/day) of niacin with pitavastatin tablets. Intervention: Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with pitavastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including pitavastatin tablets.

Intervention: Consider the risk/benefit of concomitant use of colchicine with pitavastatin tablets. See full prescribing information for details regarding concomitant use of pitavastatin tablets with other drugs that increase the risk of myopathy and rhabdomyolysis.

Pregnancy Risk Summary Discontinue pitavastatin tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pitavastatin tablets decrease synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pitavastatin tablets 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. Animal Data Embryo-fetal developmental studies were conducted in pregnant rats administered 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis (gestation days 7-17). No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits administered 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis (gestation days 6-18). 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 0.1, 0.3, 1, 3, 10, 30 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 pitavastatin tablets 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 pitavastatin tablets 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 pitavastatin tablets 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).

• Pitavastatin tablets are contraindicated in the following conditions:
• Concomitant use of cyclosporine [see Drug Interactions (7) ] .
• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] .
• Hypersensitivity to pitavastatin or any excipients in pitavastatin tablets. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with pitavastatin tablets [see Adverse Reactions (6) ] .
• Cyclosporine ( 4 , 7 )
• Active liver failure or decompensated cirrhosis ( 4 , 5.3 )
• Hypersensitivity to pitavastatin or any excipients in pitavastatin tablets ( 4 )

No specific treatment for pitavastatin tablets 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 pitavastatin tablets.