Zypitamag Drug Information

ZYPITAMAG is indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Pediatric use information is approved for Kowa Co Ltd LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd marketing exclusivity rights, this drug product is not labeled with that information.

Important Dosage and Administration Information Take

ZYPITAMAG 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 ZYPITAMAG 4 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZYPITAMAG, and adjust the dosage if necessary.

Recommended Dosage for Adults

The recommended dosage range of ZYPITAMAG is 2 mg to 4 mg daily. ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin for the 1 mg dose. The maximum recommended dose for these patients is ZYPITAMAG 2 mg once daily.

There are no dosage adjustment recommendations for patients with mild renal impairment.

Dosage Adjustments Due to Drug Interactions

In patients taking erythromycin, do not exceed pitavastatin 1 mg once daily. In patients taking rifampin, do not exceed ZYPITAMAG 2 mg once daily. 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.

Clinical Studies Experience

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. In controlled clinical studies and their open-label extensions, mg, and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. 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 (≥ 2% and ≥ 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.

Postmarketing Experience

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, 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). 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

See full prescribing information for details regarding concomitant use of ZYPITAMAG with other drugs that increase the risk of myopathy and rhabdomyolysis. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with ZYPITAMAG and instructions for preventing or managing drug interactions. Table 2.

Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with ZYPITAMAG Cyclosporine Clinical Impact: Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: Concomitant use of cyclosporine with ZYPITAMAG is contraindicated. In patients taking erythromycin, do not exceed ZYPITAMAG 1 mg once daily.

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 ZYPITAMAG 2 mg once daily.

Pregnancy Risk Summary Discontinue ZYPITAMAG when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. ZYPITAMAG decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ZYPITAMAG may cause fetal harm when administered to pregnant patients based on the mechanism of action.

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 or rabbits orally administered pitavastatin during the period of organogenesis at doses that resulted in 22 and 4 times, respectively, the human exposure at the maximum recommended human dose (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.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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 use of a statin, and a lack of information on non-live births.

No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. 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). 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).

Pediatric Use The safety and effectiveness of ZYPITAMAG in pediatric patients have not been established. Pediatric use information is approved for Kowa Co Ltd LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd marketing exclusivity rights, this drug product is not labeled with that information.

ZYPITAMAG is contraindicated in the following conditions: Concomitant use of cyclosporine. Acute liver failure or decompensated cirrhosis Hypersensitivity to pitavastatin or any excipients in ZYPITAMAG. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with pitavastatin.

No specific treatment for pitavastatin overdose is known. Contact Poison Control (1-800-222-1222) for latest recommendations. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of pitavastatin.