Drug Safety-related Labeling Changes (SrLC)

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LIVALO (NDA-022363)

(PITAVASTATIN CALCIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/14/2024 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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

11/09/2022 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

LIVALO is 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 inactive excipents in LIVALO. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with LIVALO [see Adverse Reactions (6)].

5 Warnings and Precautions

5.1 Myopathy and Rhabdomyolysis

(Additions and/or revisions underlined)

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.

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 LIVALO dosage [see Dosage and Administration (2.2), Drug Interactions (7), and Use in Specific Populations (8.5, 8.6)]. Dosages of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of LIVALO is 4 mg once daily…

Discontinue LIVALO if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if LIVALO is discontinued. Temporarily discontinue LIVALO 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).

5.2 Immune-Mediated Necrotizing Myopathy

(Additions and/or revisions underlined)

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.

5.3 Hepatic Dysfunction

(Additions and/or revisions underlined)

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.

6 Adverse Reactions

6.2  Postmarketing Experience

(Additions and/or revisions underlined)

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

Psychiatric disorders: insomnia, depression. 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).

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: interstitial lung disease

Skin and subcutaneous tissue disorders: lichen planus

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

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 [see Clinical Pharmacology (12.1)]. 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 2-4% 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 greater than or equal to 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 less than or equal to 36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation (at the end of organogenesis).

8.2 Lactation

(Additions and/or revisions underlined)

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 LIVALO, 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 LIVALO. [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

8.5 Geriatric Use

(Additions and/or revisions underlined)

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 (greater than or equal to 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)].

8.6 Renal Impairment

(Additions and/or revisions underlined)

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)].

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

LIVALO is contraindicated in patients with active liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Myopathy and Rhabdomyolysis

Advise patients that LIVALO may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1)].

Hepatic Dysfunction

Inform patients that LIVALO may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with LIVALO. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LIVALO should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with LIVALO [see Use in Specific Populations (8.2)].

09/25/2020 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

(Additions underlined)

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; 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. Consider the risk of IMNM carefully prior to the initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

10/18/2019 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

LIVALO is contraindicated in the following conditions:

Known hypersensitivity to pitavastatin or any inactive ingredient in LIVALO. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with LIVALO.

6 Adverse Reactions

Postmarketing Experience

Additions and/or revisions underlined:

Immune system disorders: angioedema

05/16/2019 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

• Concomitant use of cyclosporine

5 Warnings and Precautions

Below four subsections have extensive changes; please refer to label for complete information

5.1 Myopathy and Rhabdomyolysis

5.2 Immune-Mediated Necrotizing Myopathy

5.3 Hepatic Dysfunction

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

6 Adverse Reactions

Additions and/or revisions underlined:

• Myopathy and Rhabdomyolysis

• Immune-Mediated Necrotizing Myopathy

• Hepatic Dysfunction

• Increases in HbA1c and Fasting Serum Glucose Levels

  Below two subsections have extensive changes; please refer to label for complete information.

  6.1 Clinical Studies Experience

  6.2 Postmarketing Experience

7 Drug Interactions

Newly added information:

Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LIVALO

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.

Prior subsections have been converted into Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LIVALO; please refer to table for complete information.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.4 Pediatric Use

The safety and effectiveness of LIVALO as an adjunctive therapy to diet to reduce elevated TC, LDL-C, and Apo B 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).

8.5 Geriatric Use

In controlled clinical studies, 1,209 (43%) patients were 65 years and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients.

Advanced age (greater than or equal to 65 years) is a risk factor for myopathy and rhabdomyolysis. In general, dose selection for a geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. 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.

 

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Extensively changed; please refer to label for complete information.

11/18/2016 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

(Addition underlined)

The use of LIVALO is contraindicated in the following conditions:

• Pregnancy

• 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.

6 Adverse Reactions

6.1 Clinical Studies Experience (Addition underlined)

In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either LIVALO 4mg 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 (10x ULN), which resolved spontaneously. Four patients (3%) treated with LIVALO had at least one ALT value exceeding 3x but less than 5x 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.

6.2 Postmarketing Experience (Addition underlined)

Adverse reactions associated with LIVALO therapy reported since market introduction, regardless of causality assessment, include the following: abdominal discomfort, abdominal pain, dyspepsia, nausea, asthenia, fatigue, malaise, hepatitis, jaundice, fatal and non-fatal hepatic failure, dizziness, hypoesthesia, insomnia, depression, interstitial lung disease, erectile dysfunction, muscle spasms and peripheral neuropathy.

8 Use in Specific Populations

8.1 Pregnancy (Addition underlined – PLLR conversion)

Risk Summary

LIVALO is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with LIVALO during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, LIVALO may cause fetal harm when administered to pregnant women. LIVALO should be discontinued as soon as pregnancy is recognized. Limited published data on the use of LIVALO are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed when pregnant rats and rabbits were orally administered pitavastatin during organogenesis at exposures which were 22 and 4 times, respectively, the maximum recommended human dose (MRHD).

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

Limited published data on LIVALO have not reported a drug-associated risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate to exclude a greater than or equal to a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

8.2 Lactation (Addition underlined - PLLR conversion)

Risk Summary

LIVALO is contraindicated during It breastfeeding. There is no available information on 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. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with LIVALO.

8.3 Females and Males of Reproductive Potential (New subsection added - PLLR conversion)

Contraception

Females

LIVALO may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LIVALO.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION (Addition underlined)

Embryo-fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment and to inform their healthcare professional of a known or suspected pregnancy.

 

Lactation

Advise women not to breastfeed during treatment with LIVALO