Pitavastatin Calcium

Pitavastatin 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).

• Take orally once daily with or without food at the same time each day. (
  2.1 Important Dosage and Administration Information

  • Take pitavastatin 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 4 mg daily, prescribe alternative LDL-C-lowering treatment.
  • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pitavastatin, and adjust the dosage if necessary.
  )
• For patients requiring a high-intensity statin or are unable to achieve their LDL-C goal receiving pitavastatin 4 mg daily, prescribe alternative LDL-C-lowering treatment. (
  2.1 Important Dosage and Administration Information

  • Take pitavastatin 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 4 mg daily, prescribe alternative LDL-C-lowering treatment.
  • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pitavastatin, and adjust the dosage if necessary.
  )
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiation of pitavastatin, and adjust the dosage if necessary. (
  2.1 Important Dosage and Administration Information

  • Take pitavastatin 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 4 mg daily, prescribe alternative LDL-C-lowering treatment.
  • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pitavastatin, and adjust the dosage if necessary.
  )
• Recommended dosage is 2 mg to 4 mg once daily. Maximum recommended dosage is 4 mg once daily. (
  2.2 Recommended Dosage for Adults and Pediatric Patients Aged 8 Years and Older

  • The recommended dosage range of pitavastatin is 2 mg to 4 mg daily.
  • The maximum recommended dosage is pitavastatin 4 mg once daily.
  )
• 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 Recommended Dosage in Patients with Renal Impairment

  • The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 mL/minute/1.73 m²to 59 mL/minute/1.73 m²and 15 mL/minute/1.73 m²to 29 mL/minute/1.73 m², respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin 1 mg once daily. The maximum recommended dose for these patients is pitavastatin 2 mg once daily
    [see Use in Specific Populations ]
    .
  • There are no dosage adjustment recommendations for patients with mild renal impairment.
  )
• See full prescribing information for pitavastatin dosage modifications due to drug interactions. (
  2.4 Pitavastatin Dosage Adjustments Due to Drug Interactions

  • In patients taking erythromycin, do not exceed pitavastatin 1 mg once daily
    [see Drug Interactions ]
    .
  • In patients taking rifampin, do not exceed pitavastatin 2 mg once daily
    [see Drug Interactions ]
    .
  )

• 1 mg: White to off-white, beveled-edge, round-shaped, film-coated tablets debossed with "481" on one side and plain on the other side.
• 2 mg: White to off-white, beveled-edge, round-shaped, film-coated tablets debossed with "482" on one side and plain on the other side.
• 4 mg: White to off-white, beveled-edge, round-shaped, film-coated tablets debossed with "483" on one side and plain on the other side.

• Pregnancy:
  May cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Discontinue pitavastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.

  Pitavastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pitavastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action

  [see Clinical Pharmacology ].

  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

  [see Data].

  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% to 4% and 15% to 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 mg/kg/day, 10 mg/kg/day, 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 mg/kg/day, 0.3 mg/kg/day, 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 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, 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).
  )
• Lactation:
  Breastfeeding not recommended during treatment with pitavastatin. (
  8.2 Lactation

  Risk Summary

  There is no available information about the prescence of pitavastatin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including pitavastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

  Because of the potential for serious adverse reactions in a breastfed infant, based upon the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pitavastatin.

  [see Use in Specific Populations , Clinical Pharmacology ]
  )

• Myopathy and Rhabdomyolysis:
  Risk factors include age 65 or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher pitavastatin dosage. Discontinue pitavastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pitavastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pitavastatin dosage. Instruct patients to promptly report unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever. (
  5.1 Myopathy and Rhabdomyolysis

  Pitavastatin 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 pitavastatin.

  Risk Factors for Myopathy

  Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs (including other lipid-lowering therapies), and higher pitavastatin dosage

  [see Dosage and Administration , Drug Interactions , and Use in Specific Populations ].

  Dosages of pitavastatin greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of pitavastatin is 4 mg once daily.

  Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

  Pitavastatin is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil

  [see Contraindications (4) and Drug Interactions ]

  . There are pitavastatin dosage restrictions for patients taking erythromycin or rifampin

  [see Dosage and Administration ]

  . The following drugs when used concomitantly with pitavastatin may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (> 1 grams/day), fibrates, and colchicine

  [see Drug Interactions ]

  .

  Discontinue pitavastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if pitavastatin is discontinued. Temporarily discontinue pitavastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

  Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pitavastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.
  ,
  7 DRUG INTERACTIONS

  Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with pitavastatin and instructions for preventing or managing drug interactions

  [see Warnings and Precautions , Clinical Pharmacology ]

  .

  Table 2 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pitavastatin

  Cyclosporine
  Clinical Impact:	Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis .
  Intervention:	Concomitant use of cyclosporine with pitavastatin is contraindicated [see Contraindications ].
  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.
  Intervention:	Avoid concomitant use of gemfibrozil with pitavastatin.
  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 1 mg once daily [see Dosage and Administration ].
  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 2 mg once daily [see Dosage and Administration ].
  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.
  Intervention:	Consider if the benefit of using fibrates concomitantly with pitavastatin 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.
  Intervention:	Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with pitavastatin 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.
  Intervention:	Consider the risk/benefit of concomitant use of colchicine with pitavastatin.

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

  ,
  8.5 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 pitavastatin-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 pitavastatin for the increased risk of myopathy

  [see Warnings and Precautions ]

  .
  ,
  8.6 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 pitavastatin is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 mL/min/1.73 m²to 59 mL/min/1.73 m²and 15 mL/min/1.73 m²to 29 mL/min/1.73 m², respectively), as well as end-stage renal disease receiving hemodialysis

  [see Dosage and Administration , Warnings and Precautions , Clinical Pharmacology ]

  .
  )
• Immune-Mediated Necrotizing Myopathy (IMNM):
  Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue pitavastatin if IMNM is suspected. (
  5.2 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 pitavastatin if IMNM is suspected.
  )
• Hepatic Dysfunction:
  Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pitavastatin. (
  5.3 Hepatic Dysfunction

  Increases in serum transaminases have been reported with pitavastatin

  [see Adverse Reactions ]

  . 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 pitavastatin.

  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 pitavastatin and when clinically indicated thereafter. Pitavastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis

  [see Contraindications ]

  . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pitavastatin.
  )