Zypitamag Tablet, Film Coated
FDA Label NDC 25208-202

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.

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.

• Take ZYPITAMAG orally once daily with or without food at the same time each day.
• Individualize the dose of ZYPITAMAG according to patient characteristics, goal of therapy, and response.
• After initiation or upon titration of ZYPITAMAG, analyze lipid levels after 4 weeks and adjust the dosage accordingly.

• The recommended starting ZYPITAMAG dosage is 2 mg once daily.
• The maximum recommended dosage is ZYPITAMAG 4 mg once daily [see Warnings and Precautions (5.1)].

• The recommended starting dose for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 – 59 mL/minute/1.73 m² and 15 – 29 mL/minute/1.73 m², respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin 1 mg once 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 [see Use in Specific Populations (8.6)].

• In patients taking erythromycin, do not exceed pitavastatin 1 mg once daily [see Drug Interactions (7)].  ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin for the 1 mg dose.
• In patients taking rifampin, do not exceed ZYPITAMAG 2 mg once daily [see Drug Interactions (7)].

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

• 2 mg: White to off-white, beveled-edge, round-shaped tablets debossed with “877” on one side and plain on the other side.
• 4 mg: White to off-white, beveled-edge, round-shaped tablets debossed with “878” on one side and plain on the other side.

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

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 [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

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 [see Contraindications (4)].
Gemfibrozil
Clinical Impact:	Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including pitavastatin.
Intervention:	Avoid concomitant use of gemfibrozil with ZYPITAMAG.
Erythromycin
Clinical Impact:	Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.
Intervention:	In patients taking erythromycin, do not exceed ZYPITAMAG 1 mg once daily [see Dosage and Administration (2.4)].
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 [see Dosage and Administration (2.4)].
Fibrates
Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins, including pitavastatin.
Intervention:	Consider if the benefit of using fibrates concomitantly with ZYPITAMAG outweighs the increased risk of myopathy and rhabdomyolysis.
Niacin
Clinical Impact:	The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid-modifying doses (1 g/day) of niacin with pitavastatin.
Intervention:	Consider if the benefit of using lipid-modifying doses (>1 g/day) of niacin concomitantly with ZYPITAMAG outweighs the increased risk of myopathy and rhabdomyolysis.
Colchicine
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including pitavastatin.
Intervention:	Consider the risk/benefit of concomitant use of colchicine with ZYPITAMAG.

Rev.: 09/2020

PIM-ZYP-06

Manufactured by: Cadila Healthcare Ltd. Ahmedabad, India Distributed by: Medicure Princeton, NJ 08540 USA

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 [see Adverse Reactions (6.1)].
• Concomitant use of cyclosporine [see Drug Interactions (7)].
• Active liver disease including unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.3)].
• Pregnancy [see Use in Specific Populations (8.1, 8.3)].
• 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 [see Use in Specific Populations (8.2)].

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 [see Dosage and Administration (2.2)].

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 [see Contraindications (4) and Drug Interactions (7)]. There are ZYPITAMAG dosage restrictions for patients taking erythromycin or rifampin [see Dosage and Administration (2.4)]. The following drugs when used concomitantly with ZYPITAMAG may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1 grams/day), fibrates, and colchicine [see Drug Interactions (7)].

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.

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.

Increases in serum transaminases have been reported with ZYPITAMAG [see Adverse Reactions (6)]. 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 [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZYPITAMAG.

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.

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

• Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)].
• Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]
• Hepatic Dysfunction [see Warnings and Precautions (5.3)]
• Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)].

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.

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.

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

Risk Summary

ZYPITAMAG 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 pitavastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZYPITAMAG may cause fetal harm when administered to pregnant women. ZYPITAMAG should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of pitavastatin 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 times and 4 times, respectively, the maximum recommended human dose (MRHD) (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% to 4% and 15% to 20%, respectively.

Data

Human Data

Limited published data on pitavastatin 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.

Animal Data

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.

Embryo-fetal developmental studies were conducted in pregnant rats treated with 3 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. 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 treated with 0.1 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. 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 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at ≥ 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).

Risk Summary

ZYPITAMAG is contraindicated during breastfeeding [see Contraindications (4)]. 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.

Contraception
Females
ZYPITAMAG may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ZYPITAMAG.

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.

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 (≥ 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 [see Warnings and Precautions (5.1)].

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 [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

ZYPITAMAG is contraindicated in patients with active liver disease including unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4), Warnings and Precautions (5.3)].

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.

ZYPITAMAG (pitavastatin) tablets for oral use is an HMG-CoA reductase inhibitor.

The chemical name for pitavastatin is (3R,5S)-7-[2-Cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl]3,5-dihydroxy-6(E)-heptanoic acid hemi magnesium. The structural formula is:

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 01)

The molecular formula for pitavastatin is C₅₀H₄₆MgF₂N₂O₈ and the molecular weight is 865.21. Pitavastatin is a white to off-white powder. It is freely soluble in acetone, ethyl acetate; soluble in dimethylsulfoxide and insoluble in dichloromethane and isopropyl alcohol. Pitavastatin is hygroscopic and slightly unstable in light.

Each film-coated tablet of ZYPITAMAG contains 2.053 mg or 4.106 mg of pitavastatin magnesium, which is equivalent to 2 mg or 4 mg, respectively of free base and the following inactive ingredients: calcium carbonate, crospovidone, hypromellose, lactose monohydrate, magnesium stearate and sodium carbonate anhydrous and film-coating containing the following inactive ingredients: hypromellose, polyethylene glycol, talc and titanium dioxide.

Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins.

Cardiac Electrophysiology
In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum dose of 4 mg daily).

Absorption

Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both C_max and AUC_0-inf increased in an approximately dose-proportional manner for single pitavastatin doses from 1 mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. The C_max and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.

Effect of Food
Administration of pitavastatin with a high fat meal (50% fat content) decreases pitavastatin C_max by 43% but does not significantly reduce pitavastatin AUC.

Distribution
Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.

Elimination
Metabolism
The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by UGTs (UGT1A3 and UGT2B7).

Excretion
A mean of 15% of radioactivity of orally administered, single 32 mg ¹⁴C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.

Specific Populations
Racial or Ethnic Groups
In pharmacokinetic studies pitavastatin C_max and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in C_max and AUC.

Male and Female Patients
In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin C_max and AUC were 60 and 54% higher, respectively in females.

Geriatric Patients
In a pharmacokinetic study which compared healthy young and geriatric (≥ 65 years) volunteers, pitavastatin C_max and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations (8.5)]

Pediatric Patients
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.

Patients with Renal Impairment

In patients with moderate renal impairment (estimated glomerular filtration rate of 30 mL/min/1.73 m² to 59 mL/min/1.73 m²) and end stage renal disease receiving hemodialysis, pitavastatin AUC_0-inf is 102% and 86% higher than those of healthy volunteers, respectively, while pitavastatin C_max is 60% and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33% and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively [see Use in Specific Populations (8.6)].

In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 mL/min/1.73 m² to 29 mL/min/1.73 m²) not receiving hemodialysis were administered a single dose of pitavastatin 4 mg. The AUC_0-inf and the C_max were 36% and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6% [see Use in Specific Populations (8.6)].

The effect of mild renal impairment on pitavastatin exposure has not been studied.

Patients with Hepatic Impairment
The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin C_max and AUC_inf in patients with moderate hepatic impairment (Child-Pugh B disease) was 2.7-fold and 3.8-fold higher, respectively as compared to health volunteers. In patients with mild hepatic impairment (Child-Pugh A disease), pitavastatin C_max and AUC_inf were 30% and 60% higher as compared to healthy volunteers. Mean pitavastatin half-life for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)].

Drug Interaction Studies

Warfarin
The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin 4 mg daily.

Table 3 presents the effect of coadministered drugs on pitavastatin systemic exposure:

Table 4 presents the effect of pitavastatin coadministration on systemic exposure of other drugs:

In a 92 week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg daily, there was an absence of drug-related tumors.

In a 92 week carcinogenicity study in rats given pitavastatin at 1 mg/kg/day, 5 mg/kg/day, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg daily maximum human dose.

In a 26 week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30 mg/kg/day, 75 mg/kg/day, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.

Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.

Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 mg/kg/day and 30 mg/kg/day, respectively, at systemic exposures 56 and 354 times clinical exposure at 4 mg daily based on AUC.

Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30 times clinical systemic exposure at 4 mg daily based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15 times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.

Central Nervous System Toxicity
Central Nervous System (CNS) vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons).

Active-Controlled Study with Atorvastatin (Study 301)

Pitavastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 817 adult patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either pitavastatin or atorvastatin (Table 5). Non-inferiority of pitavastatin to a given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, pitavastatin was non-inferior to atorvastatin for the two pairwise comparisons: pitavastatin 2 mg vs. atorvastatin 10 mg and pitavastatin 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% ( 2%, 4%), respectively.

Active-Controlled Study with Simvastatin (Study 302)

Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 843 adult patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6 to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either pitavastatin or simvastatin (Table 6). Non-inferiority of pitavastatin to a given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, pitavastatin was non-inferior to simvastatin for the two pairwise comparisons: pitavastatin 2 mg vs. simvastatin 20 mg and pitavastatin 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Active-Controlled Study with Pravastatin in Geriatric Patients (Study 306)

Pitavastatin was compared with Pravastatin Sodium Tablets (referred to as pravastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study of 942 geriatric patients (≥ 65 years) with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period, and then were randomized to a once daily dose of pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of pitavastatin to a given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 7. Pitavastatin significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: pitavastatin 1 mg vs. pravastatin 10 mg, pitavastatin 2 mg vs. pravastatin 20 mg and pitavastatin 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13%), respectively.

Active-Controlled Study with Simvastatin in Patients with ≥ 2 Risk Factors for Coronary Heart Disease (Study 304)

Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 351 adult patients with primary hyperlipidemia or mixed dyslipidemia with ≥ 2 risk factors for coronary heart disease. After a 6- to 8-week wash-out/dietary lead-in period, patients were randomized to a 12-week treatment with either pitavastatin or simvastatin (Table 8). Non-inferiority of pitavastatin to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 8. Pitavastatin 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).

Active- Controlled Study with Atorvastatin in Patients with Type 2 Diabetes Mellitus (Study 305)

Pitavastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study of 410 adult patients with type 2 diabetes mellitus and mixed dyslipidemia. Patients entered a 6 to 8 week wash-out/dietary lead-in period and were randomized to a once daily dose of pitavastatin or atorvastatin for 12 weeks. Non-inferiority of pitavastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.

Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit The study failed to demonstrate that pitavastatin was not significantly different than atorvastatin in lowering LDL-C in patients with type 2 diabetes mellitus and mixed dyslipidemia.

The treatment differences in efficacy in LDL-C change from baseline between pitavastatin and active controls (i.e., atorvastatin, simvastatin, or pravastatin) in the in the active-controlled studies described above are summarized in Figure 1.

Figure 1 Treatment Difference in Adjusted Mean Percent Change in LDL-C between Pitavastatin and the Comparator (Atorvastatin, Simvastatin, or Pravastatin)

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 02)

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.

ZYPITAMAG (pitavastatin) Tablets, 2 mg are white to off-white, beveled-edge, round-shaped tablets debossed with “877” on one side and plain on the other side and are supplied as follows:

NDC 25208-201-13 in bottle of 30 tablets with child-resistant closure
NDC 25208-201-09 in bottle of 90 tablets with child-resistant closure
NDC 25208-201-14 in bottle of 100 tablets
NDC 25208-201-15 in bottle of 500 tablets
NDC 25208-201-11 in bottle of 1000 tablets
NDC 25208-201-12 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets

ZYPITAMAG (pitavastatin) Tablets, 4 mg are white to off-white, beveled-edge, round-shaped tablets
debossed with “878” on one side and plain on the other side and are supplied as follows:

NDC 25208-202-13 in bottle of 30 tablets with child-resistant closure
NDC 25208-202-09 in bottle of 90 tablets with child-resistant closure
NDC 25208-202-14 in bottle of 100 tablets
NDC 25208-202-15 in bottle of 500 tablets
NDC 25208-202-11 in bottle of 1000 tablets
NDC 25208-202-12 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets

Storage
Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].
Protect from moisture and light.

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 [see Warnings and Precautions (5.1)].

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 [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 ZYPITAMAG. 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)].

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 [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].

Lactation
Advise women not to breastfeed during treatment with ZYPITAMAG [see Contraindications (4), Use in Specific Populations (8.2)].

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 ([email protected]) Tel.: 1-800-509-0544.
This product’s label may have been updated. For current full prescribing information, please visit www. medicure.com

NDC 25208-201-09

Zypitamag (Pitavastatin) Tablets, 2 mg

90 Tablets

Rx only

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 05)

NDC 25208-201-10

Zypitamag (Pitavastatin) Tablets, 2 mg

7 Tablets Blister Carton

Rx only

Professional Sample-Not For Sale

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 06)

NDC 25208-202-09

Zypitamag (Pitavastatin) Tablets, 4 mg

90 Tablets

Rx only

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 07)

NDC 25208-202-10

Zypitamag (Pitavastatin) Tablets, 4 mg

7 Tablets Blister Carton

Rx only

Professional Sample-Not For Sale

Image (2bd9cad5 C46f 4e69 810e F8f7b8a79f4b 08)