Zypitamag® vs. Livalo®

Zypitamag® vs. Livalo®

Zypitamag and Livalo

Zypitamag (pitavastatin magnesium) is a pharmaceutical alternative to Livalo (pitavastatin calcium) that was approved through the 505(b)(2) regulatory pathway. According to U.S. FDA definitions, drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but a different salt.2 Therefore, these therapeutics are not classified as pharmaceutical equivalents; rather, they are classified as a pharmaceutical alternative.

Bioequivalence Studies


The approval of Zypitamag was based on unpublished studies demonstrating the bioequivalence of Zypitamag and Livalo (described below), as well as the clinical and safety data currently available for Livalo.3 For this reason, the prescribing information for Zypitamag and Livalo contain the same recommendations.1,4

The FDA requested that two studies be performed to evaluate the bioequivalence of Zypitamag and Livalo:

  1. A single-dose, fasting bioequivalence study, comparing Zypitamag 4 mg tablets against Livalo 4 mg tablets.
  2. A single-dose, food-effect study, comparing Zypitamag 4 mg tablets under fasting and fed conditions.

1. Single-Dose, Fasting Bioequivalence Study

A single-dose, fasting bioequivalence study was performed to assess serum concentrations of pitavastatin after administration of Zypitamag 4 mg tablets in comparison to Livalo 4 mg tablets. This study was unpublished, but was provided to the FDA as part of the 505(b)(2) application.5 The study design is illustrated below. Blood samples were collected pre-dose and at intervals over 48 hours post-product administration. Safety parameters were assessed throughout the duration of the study (vitals, laboratory safety tests etc.).

Zypitamag vs Livalo

Bioequivalence was determined by a statistical comparison of total area under the curve (AUCt; from time 0 - 48 hrs), infinite area under the curve (AUCi; from time 0 - ∞) and maximum concentration (Cmax) for both treatments. The 90% confidence interval conformed to the limits for AUCt, AUCi and Cmax set by the FDA in Guidance for Industry. Based on these results, the Zypitamag 4 mg tablet and Livalo 4 mg tablet were considered to be bioequivalent under fasting conditions.

Livalo vs. Zypitamag

Figure 1: Mean Plasma Concentration of Zypitamag (pitavastatin magnesium) 4 mg tablet and Livalo (pitavastatin calcium) 4 mg tablet vs. Time (hr) Under Fasting Conditions.5

2. Single-Dose, Food Effect Bioavailability Study

A single-dose, food-effect study was performed to compare serum concentrations of pitavastatin after administration of Zypitamag 4 mg tablets under fasting and fed conditions. This study was unpublished, but was provided to the FDA as part of the 505(b)(2) application.5 The study design is illustrated below. Blood samples were collected pre-dose and at intervals over 48 hours post-product administration. Safety parameters were assessed throughout study (vitals, laboratory safety tests etc).

Pitavastatin study

Food effect bioavailability was determined by a statistical comparison of AUCt, AUCi and Cmax for the test product in fasting and fed conditions. The 90% confidence intervals were within the limits for AUCt and AUCi but not for Cmax as set by the FDA, Guidance for Industry, meaning that Zypitamag exhibits a food effect observed in Cmax but not in AUCt and AUCi. This was found to be consistent with the following statement made in the Livalo PI. "Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC." From the above studies it is evident that Zypitamag 4 mg tablets are bioequivalent to and exhibit the same behavior as that of Livalo 4 mg tablets.

Pitavastatin with or without food

Figure 2: Mean Plasma Concentration of Zypitamag (pitavastatin magnesium) 4 mg tablets vs. Time (hr) Under Fasting and Fed Conditions.5

Based on the results obtained in the bioequivalence study under fasting conditions and the single dose food effect study, Zypitamag 4 mg tablets and Livalo 4 mg tablets are considered bioequivalent by the FDA.5

The FDA also required data on the dissolution profile of Zypitamag in comparison to Livalo.6 Dissolution studies were performed for the following strengths of Zypitamag (2 mg and 4 mg) in comparison to the corresponding strengths of Livalo (2 mg and 4 mg, respectively). Studies were performed at 37 °C ± 0.5 °C in a variety of acidic, basic and neutral buffers. Comparative dissolution profiles were found between Livalo and Zypitamag in all experimental settings tested. One representative dissolution curve is included for reference.

Zypitamag and Livalo comparison

Figure 3: Representative In Vitro Dissolution Curve for Zypitamag (pitavastatin magnesium) and Livalo (pitavastatin calcium) in 900 mL of 0.05 M phosphate buffer; pH 6.8. (n = 12 for each treatment).6

Overall, based on the review of the clinical and laboratory safety data, both the study products were found to have an acceptable risk-benefit profile by the FDA.5

For further details on indications and dosing, please refer to the Zypitamag Prescribing Information and the Important Safety Information below.

References


1 Zypitamag Prescribing Information. Cadila Healthcare Ltd. 2020(September).
2 Approved Drug Products with Therapeutic Equivalence Evaluations - 38th Edition. U.S. Department of Health and Human Services. Food and Drug Administration, Office of Medical Products and Tobacco, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Generic Drug Policy;2018.
3 Zypitamag FDA Approval Documents - Clinical Review. Center for Drug Evaluation And Research;2017.
4 Livalo Prescribing Information. Kowa Pharmaceuticals America, Inc. 2020(September).
5 Zypitamag FDA Approval Documents - Clinical Pharmacology and Biopharmaceutics Review. Center for Drug Evaluation and Research;2017.
6 Zydus Pharmaceuticals (USA) Inc. Pitavastatin Tablets, 1 mg, 2 mg and 4 mg (Magnesium Salt) Module 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods - Original 505(b)(2) Application.

IMPORTANT SAFETY INFORMATION FOR ZYPITAMAG™ (pitavastatin) tablets

INDICATIONS & USAGE

ZYPITAMAG is indicated as an adjunctive therapy to diet in adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C). Limitations of Use: The effect of ZYPITAMAG on cardiovascular morbidity and mortality has not been determined.

CONTRAINDICATIONS: ZYPITAMAG is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

WARNINGS & PRECAUTIONS

  • Myopathy and Rhabdomyolysis: Risk factors include age 65 and greater, renal impairment, inadequately treated hypothyroidism, concomitant use of certain drugs, and higher doses of ZYPITAMAG. ZYPITAMAG is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil. The following drugs when used concomitantly with ZYPITAMAG may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1 g/day), fibrates, and colchicine. Discontinue ZYPITAMAG if markedly elevated CK levels occur or myopathy is diagnosed or suspected. 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.
  • Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of 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.
  • Hepatic Dysfunction: Increases in serum transaminases can occur. Rare postmarketing reports of fatal and non-fatal hepatic failure have occurred. Consider liver enzyme testing before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZYPITAMAG.
  • Increases in HbA1c and Fasting Serum Glucose Levels: Increases of each have been reported with statins, including ZYPITAMAG. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

ADVERSE REACTIONS: The most frequent adverse reactions (rate ≥ 2%) are myalgia, back pain, diarrhea, constipation and pain in extremity. This is not a complete list of all reported adverse events.

For additional information, refer to full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

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