Drug Safety-related Labeling Changes (SrLC)

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ZYPITAMAG (NDA-208379)

(PITAVASTATIN MAGNESIUM)

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

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02/07/2020 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

ZYPITAMAG is contraindicated in the following conditions:

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

  • 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

(Subsection title revised; Additions and/or revisions underlined)

ZYPITAMAG 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 pitavastatin.

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 ZYPITAMAG 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 ZYPITAMAG is 4 mg once daily.

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

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

Discontinue ZYPITAMAG if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if ZYPITAMAG is discontinued. Temporarily discontinue ZYPITAMAG 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 ZYPITAMAG 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

(Subsection title revised; 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

(Subsection title revised; Additions and/or revisions underlined)

Increases in serum transaminases have been reported with ZYPITAMAG. 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 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 ZYPITAMAG and thereafter, when clinically indicated. ZYPITAMAG 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 ZYPITAMAG.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

(Subsection title revised; Additions and/or revisions underlined)

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin. 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 – 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.

In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-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 (greater than or equal to 2% and greater than or equal to placebo) in Adult Patients with Primary Hyperlipidemia and Mixed Dyslipidemia 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 pitavastatin. 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 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 post-approval 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

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

ZYPITAMAG is contraindicated during 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 ZYPITAMAG.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of ZYPITAMAG have not been established in pediatric patients younger than 8 years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia (other than HeFH).

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 ZYPITAMAG 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.

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

ZYPITAMAG is contraindicated in patients with active liver disease including unexplained persistent elevations of hepatic transaminase levels.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

The patient should be informed of the following:

Myopathy and Rhabdomyolysis

Advise patients that ZYPITAMAG 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.

Hepatic Dysfunction

Inform patients that ZYPITAMAG 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 ZYPITAMAG. 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.

Lactation

Advise women not to breastfeed during treatment with ZYPITAMAG.

Liver Enzymes

It is recommended that liver enzyme tests be checked before the initiation of ZYPITAMAG and if signs or symptoms of liver injury occur. All patients treated with ZYPITAMAG should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Please address medical inquiries to (medical.information@medicure.com) Tel.: 1-800-509-0544.

This product’s label may have been updated. For current full prescribing information, please visit www.medicure.com

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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