Livalo (pitavastatin calcium 2.09 mg) Dailymed

10 Overdosage

No specific treatment for LIVALO 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 LIVALO.

11 Description

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

The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. The structural formula is:

The empirical formula for pitavastatin is C₅₀H₄₆CaF₂N₂O₈ and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light.

Each film-coated tablet of LIVALO contains 1 mg, 2 mg, or 4 mg of pitavastatin, which is equivalent to 1.045 mg, 2.09 mg, or 4.18 mg, respectively, of pitavastatin calcium and the following inactive ingredients: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium aluminometasilicate, and magnesium stearate. The film coating contains the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide, and triethyl citrate.

12 Clinical Pharmacology

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, LIVALO 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).

12.3 Pharmacokinetics

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 LIVALO 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 LIVALO 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.

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

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 (8.4)]

Pediatric Patients

A 12-week study in pediatric patients 8 to 16 years of age treated with pitavastatin 1 mg, 2 mg and 4 mg administered once daily, showed a dose-dependent increase in pitavastatin plasma concentrations at trough (for 2 mg and 4 mg doses) and 1 hour post dose. A dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and 1 hour post dose.

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.

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 White healthy volunteers. In pharmacokinetic comparison between White volunteers and Japanese volunteers, there were no significant differences in C_max and AUC.

Patients with Renal Impairment

In patients with moderate renal impairment (estimated glomerular filtration rate of 30 – 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 (8.5)].

In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 – 29 mL/min/1.73 m²) not receiving hemodialysis were administered a single dose of LIVALO 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 (8.5)].

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 healthy 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 volunteers 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 LIVALO 4 mg daily.

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

Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic Exposure

Coadministered drug	Dosage regimen	Change in AUCData presented as x-fold change represent the ratio between coadministration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change).	Change in Cmax
BID = twice daily; QD = once daily; LA = Long Acting
Cyclosporine	Pitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6	↑ 4.6 fold Considered clinically significant [see Dosage and Administration (2.4),Drug Interactions (7)]	↑ 6.6 fold
Erythromycin	Pitavastatin 4 mg single dose on Day 4 + erythromycin 500 mg 4 times daily for 6 days	↑ 2.8 fold	↑ 3.6 fold
Rifampin	Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days	↑ 29%	↑ 2.0 fold
Atazanavir	Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days	↑ 31%	↑ 60%
Darunavir/Ritonavir	Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16	↓ 26%	↓ 4%
Lopinavir/Ritonavir	Pitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24	↓ 20%	↓4 %
Gemfibrozil	Pitavastatin 4 mg QD + gemfibrozil 600 mg BID for 7 days	↑ 45%	↑ 31%
Fenofibrate	Pitavastatin 4 mg QD + fenofibrate 160 mg QD for 7 days	↑18%	↑ 11%
Ezetimibe	Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days	↓ 2%	↓0.2%
Enalapril	Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days	↑ 6%	↓ 7%
Digoxin	Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days	↑ 4%	↓ 9%
Diltiazem LA	Pitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15	↑10%	↑15%
Grapefruit Juice	Pitavastatin 2 mg single dose on Day 3 + grapefruit juice for 4 days	↑ 15%	↓ 12%
Itraconazole	Pitavastatin 4 mg single dose on Day 4 + itraconazole 200 mg daily for 5 days	↓ 23%	↓ 22%

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

Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other Drugs

Coadministered drug	Dosage regimen		Change inAUCData presented as % change represent % difference relative to the investigated drug alone (i.e., 0% = no change).	Change in Cmax
BID = twice daily; QD = once daily; LA = Long Acting
Atazanavir	Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days		↑ 6%	↑ 13%
Darunavir	Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16		↑ 3%	↑ 6%
Lopinavir	Pitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24		↓ 9%	↓ 7%
Ritonavir	Pitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24		↓ 11%	↓ 11%
Ritonavir	Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16		↑ 8%	↑ 2%
Enalapril	Pitavastatin 4 mg QD + enalapril 20 mgdaily for 5 days	Enalapril	↑ 12%	↑ 12%
		Enalaprilat	↓ 1%	↓ 1%
Warfarin	Individualized maintenance dose of warfarin (2 - 7 mg) for 8 days + pitavastatin 4 mg QD for 9 days	R-warfarin	↑ 7%	↑ 3%
		S-warfarin	↑ 6%	↑ 3%
Ezetimibe	Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days		↑ 9%	↑ 2%
Digoxin	Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days		↓ 3%	↓ 4%
Diltiazem LA	Pitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15		↓ 2%	↓ 7%
Rifampin	Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days		↓ 15%	↓ 18%

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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, 5, 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, 75, 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 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.

14 Clinical Studies

Primary Hyperlipidemia in Adults

Study with Atorvastatin (Study 301)

LIVALO 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 LIVALO 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, LIVALO was non-inferior to atorvastatin for the two pairwise comparisons: LIVALO 2 mg vs. atorvastatin 10 mg and LIVALO 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.

Table 5. Lipid Response by Dose of LIVALO and Atorvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 301 (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TG	HDL-C	non-HDL-C
LIVALO2 mg daily	315	-38	-30	-28	-14	4	-35
LIVALO 4 mg daily	298	-45	-35	-32	-19	5	-41
Atorvastatin 10 mg daily	102	-38	-29	-28	-18	3	-35
Atorvastatin 20 mg daily	102	-44	-36	-33	-22	2	-41

Study with Simvastatin (Study 302)

LIVALO 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 LIVALO 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, LIVALO was non-inferior to simvastatin for the two pairwise comparisons: LIVALO 2 mg vs. simvastatin 20 mg and LIVALO 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Table 6. Lipid Response by Dose of LIVALO and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 302 (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TG	HDL-C	non-HDL-C
LIVALO2 mg daily	307	-39	-30	-28	-16	6	-36
LIVALO4 mg daily	319	-44	-35	-32	-17	6	-41
Simvastatin20 mg daily	107	-35	-27	-25	-16	6	-32
Simvastatin40 mg daily	110	-43	-34	-31	-16	7	-39

Study with Pravastatin in Geriatric Patients (Study 306)

LIVALO 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 LIVALO or pravastatin for 12 weeks (Table 7). Non-inferiority of LIVALO 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. LIVALO significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: LIVALO 1 mg vs. pravastatin 10 mg, LIVALO 2 mg vs. pravastatin 20 mg and LIVALO 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.

Table 7. Lipid Response by Dose of LIVALO and Pravastatin in Geriatric Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 306 (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TG	HDL-C	non-HDL-C
LIVALO1 mg daily	207	-31	-25	-22	-13	1	-29
LIVALO2 mg daily	224	-39	-31	-27	-15	2	-36
LIVALO 4 mg daily	210	-44	-37	-31	-22	4	-41
Pravastatin 10 mg daily	103	-22	-17	-15	-5	0	-20
Pravastatin 20 mg daily	96	-29	-22	-21	-11	-1	-27
Pravastatin 40 mg daily	102	-34	-28	-24	-15	1	-32

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

LIVALO 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 LIVALO or simvastatin (Table 8). Non-inferiority of LIVALO 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. LIVALO 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%).

Table 8. Lipid Response by Dose of LIVALO and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥2 Risk Factors for Coronary Heart Disease in Study 304 (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TG	HDL-C	non-HDL-C
LIVALO4 mg daily	233	-44	-34	-31	-20	7	-40
Simvastatin 40 mg daily	118	-44	-34	-31	-15	5	-39

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

LIVALO 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 washout/dietary lead-in period and were randomized to a once daily dose of LIVALO or atorvastatin for 12 weeks. Non-inferiority of LIVALO 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 LIVALO was not significantly different than atorvastatin in lowering LDL-C in patients with type 2 diabetes mellitus and mixed dyslipidemia.

Table 9. Lipid Response by Dose of LIVALO and Atorvastatin in Adult Patients with Type 2 Diabetes Mellitus and Mixed Dyslipidemia in Study 305 (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TG	HDL-C	non-HDL-C
LIVALO4 mg daily	274	-41	-32	-28	-20	7	-36
Atorvastatin20 mg daily	136	-43	-34	-32	-27	8	-40

The treatment differences in efficacy in LDL-C change from baseline between LIVALO 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 LIVALO and the Comparator (Atorvastatin, Simvastatin, or Pravastatin)



NL=non-inferiority limit.

HeFH in Pediatric Patients

In a double-blind, placebo-controlled, 12-week trial, 82 pediatric patients (36 boys and 46 girls), 8 to 16 years of age with genetically confirmed HeFH, fasting low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL or LDL-C ≥160 mg/dL with an additional cardiovascular risk factor (male gender, a family history of premature CV disease, presence of low HDL (<45 mg/dL) or high TG (>150 mg/dL), presence of high lipoprotein (a) (>75 nmol/L), presence of type 2 diabetes mellitus or presence of hypertension) were randomized to LIVALO 1 mg, 2 mg, and 4 mg. Mean LDL-C at baseline was 235 mg/dL (range 160.5 mg/dL to 441mg/dL). Approximately 39% of patients were Tanner Stage 1 at baseline.

LIVALO significantly reduced plasma LDL-C, non-HDL-C, TC, and Apo-B compared to placebo. The reductions in LDL-C, Apo-B, TC, and non-HDL-C were dose dependent. There was no statistically significant improvement in HDL-C or TG at any LIVALO dose. See the lipid results in Table 10.

Table 10. Lipid Response in Pediatric Patients with HeFH (Mean % Change from Baseline at Week 12)

Treatment	N	LDL-C	Apo-B	TC	TGDifference from placebo not statistically significant Median Percent Change from Baseline at Week 12	HDL-C	non-HDL-C
Placebo	19	-1	-3	-1	-3	-1	-1
LIVALO1 mg daily	20	-21	-20	-16	-14	7	-21
LIVALO2 mg daily	24	-30	-25	-25	-15	-3	-29
LIVALO4 mg daily	19	-38	-28	-30	5	-2	-36

16 How Supplied/storage And Handling

LIVALO tablets are supplied as follows:

Tablet Strength	Package Size	Tablet Description	NDC
1 mg	Bottle of 90	Round white film-coated tablet debossed "KC" on one face and "1" on the reverse	66869-104-90
2 mg	Bottle of 90	Round white film-coated tablet debossed "KC" on one face and "2" on the reverse	66869-204-90
4 mg	Bottle of 90	Round white film-coated tablet debossed "KC" on one face and "4" on the reverse	66869-404-90

STORAGE AND HANDLING SECTION

Store at room temperature between 15°C and 30°C (59° to 86° F) [see USP]. Protect from light.

17 Patient Counseling Information

Myopathy and Rhabdomyolysis

Advise patients that LIVALO 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 LIVALO 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 LIVALO. 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)].

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

Lactation

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

Manufactured for:Kowa Company, Limited Tokyo 103-8433 JapanManufactured by:Patheon, Inc. Cincinnati, OH 45237 USA or by Kowa Company, LTD Nagoya, 462-0024 JapanMarketed and Distributed by:Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 USA

LIV-RA-0148 01/2024LIVALO is a trademark of the Kowa group of companies. © Kowa Pharmaceuticals America, Inc. (2009)

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*Each tablet contains:Active ingredient: pitavastatin calcium 4.18 mg equivalent to pitavastatin 4 mg.