Drug Safety-related Labeling Changes (SrLC)

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NIKITA (NDA-209875)

(PITAVASTATIN SODIUM)

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

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10/30/2023 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:
NIKITA 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 excipients in NIKITA.

…

5 Warnings and Precautions

5.1 Myopathy and Rhabdomyolysis

Additions and/or revisions underlined:

NIKITA 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 NIKITA.

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 NIKITA dosage [see Dosage and Administration (2.2), Drug Interactions (7), and Use in Specific Populations (8.5, 8.6)]. 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 NIKITA is 4 mg once daily.

…

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 NIKITA if IMNM is suspected.

5.3 Hepatic Dysfunction

Additions and/or revisions underlined:

Increases in serum transaminases have been reported with NIKITA [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 NIKITA.

…

Consider liver enzyme testing before the initiation of NIKITA and when clinically indicated thereafter. NIKITA 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 NIKITA.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes to table 1; please refer to label for complete information

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

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.

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

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information

8.2 Lactation

PLLR Conversion

Additions and/or revisions underlined:

Risk Summary

There is no available information about the presence 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 NIKITA, 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 NIKITA. [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 (?65 years) is a risk factor for NIKITA-associated myopathy and rhabdomyolysis. Dose selection for a geriatric patient should be cautious, recognizing 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 NIKITA 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.

…

8.7 Hepatic Impairment

Additions and/or revisions underlined:

NIKITA 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)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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 NIKITA should be discontinued [see Use in Specific Populations (8.1)].

Lactation

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

09/25/2020 (SUPPL-2)

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

05/05/2020 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

NIKITA is contraindicated in the following conditions:

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

• Concomitant use of cyclosporine.

• Active liver disease including unexplained persistent elevations of hepatic transaminase levels.

• 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, females who require pitavastatin treatment should not breastfeed their infants

5 Warnings and Precautions

5.1             Myopathy and Rhabdomyolysis

(Additions and/or revisions underlined)

NIKITA may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including NIKITA.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs, and higher NIKITA dosage. 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 NIKITA is 4 mg once daily.

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

NIKITA is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil. There are NIKITA dosage restrictions for patients taking erythromycin or rifampin. The following drugs when used concomitantly with NIKITA may also increase therisk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine.

Discontinue NIKITA if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if NIKITA is discontinued. Temporarily discontinue NIKITA 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 NIKITA dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

 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. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.

 5.3             Hepatic Dysfunction

(Additions and/or revisions underlined)

Increases in serum transaminases have been reported with NIKITA. In most cases, the elevations were transient and either 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 NIKITA.

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 NIKITA and thereafter, when clinically indicated. NIKITA is contraindicated in patients with active liver disease including unexplained persistent elevations in hepatic transaminase levels. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue NIKITA.

 5.4             Increases in HbA1c and Fasting Serum Glucose Levels

(Additions and/or revisions underlined)

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including NIKITA. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in other sections of the labeling:

• Myopathy and Rhabdomyolysis

• Immune-Mediated Necrotizing Myopathy

• Hepatic Dysfunction

• Increases in HbA1c and Fasting Serum Glucose Levels

 6.1             Clinical Studies Experience

(Additions and/or revisions underlined)

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 and Mixed Dyslipidemia

In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia or mixed dyslipidemia were administered pitavastatin 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 to 89 years) and the gender distribution was 48% males and 52% females. Approximately 93% of the patients were Caucasian, 7% were Asian/Indian, 0.2% were African American and 0.3% were Hispanic and other.

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 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 was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin 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, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline. Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

6.2             Postmarketing Experience:

(Additions and/or revisions underlined

The following adverse reactions have been identified during postapproval use of pitavastatin. 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

7 Drug Interactions

(Additions and/or revisions underlined; please refer to label for newly added Table 2)

Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with NIKITA Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with NIKITA and instructions for preventing or managing drug interactions.

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

8 Use in Specific Populations

8.4         Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of NIKITA in pediatric patients have not been established.

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5             Geriatric Use

(Additions and/or revisions underlined)

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

(Additions and/or revisions underlined)

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Due to the risk of myopathy, a dosage modification of NIKITA is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/min/1.73 m2 and 15 to 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)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

The patient should be informed of the following:

Myopathy and Rhabdomyolysis

Advise patients that NIKITA 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 patientsto promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

Hepatic Dysfunction

Inform patients that NIKITA may cause liver enzyme elevations and possibly liver failure.

Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with NIKITA. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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.