1.1 Primary Hyperlipidemia and Mixed Dyslipidemia

LIVALO® is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.

1.2 Limitations of Use

Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4 mg once daily dosing of LIVALO.

The effect of LIVALO on cardiovascular morbidity and mortality has not been determined.

LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias.

2.1 General Dosing Information

The dose range for LIVALO is 1 to 4mg orally once daily at any time of the day with or without food. The recommended starting dose is 2mg and the maximum dose is 4mg. The starting dose and maintenance doses of LIVALO should be individualized according to patient characteristics, such as goal of therapy and response.

After initiation or upon titration of LIVALO, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.

2.2 Dosage in Patients with Renal Impairment

Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily.

2.3 Use with Erythromycin

In patients taking erythromycin, a dose of LIVALO 1 mg once daily should not be exceeded [see Drug Interactions (7.2)].

2.4 Use with Rifampin

In patients taking rifampin, a dose of LIVALO 2 mg once daily should not be exceeded [see Drug Interactions (7.3)].

5.1 Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.

LIVALO should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (>65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent administration of fibrates or lipid-modifying doses of niacin. LIVALO should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin [see Drug Interactions (7.6), Use in Specific Populations (8.5, 8.6) and Clinical Pharmacology (12.3)].

LIVALO therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

5.2 Liver Enzyme Abnormalities and Monitoring

Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including LIVALO. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.

In placebo-controlled Phase 2 studies, ALT >3 times the upper limit of normal was not observed in the placebo, LIVALO 1 mg, or LIVALO 2 mg groups. One out of 202 patients (0.5%)administered LIVALO 4 mg had ALT >3 timesthe upper limit of normal.

It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose and periodically (e.g., semiannually) thereafter.

Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of >3 times upper limit of normal persist, reduction of dose or withdrawal of LIVALO is recommended.

As with other HMG-CoA reductase inhibitors, LIVALO should be used with caution in patients who consume substantial quantities of alcohol. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of LIVALO [see Contraindications (4)].

6.1 Clinical Studies Experience

Because clinical studies on LIVALO are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of LIVALO cannot be directly compared with that in the clinical studies of other HMG-CoA reductase inhibitors and may not reflect the frequency of adverse reactions observed in clinical practice.

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.

The following laboratory abnormalities have also been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.

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).

Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO.

7.1 Cyclosporine

Cyclosporine significantly increased pitavastatin exposure. Co-administration of cyclosporine with LIVALO is contraindicated [see Contraindications (4), and Clinical Pharmacology (12.3)].

7.2 Erythromycin

Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of LIVALO 1mg once daily should not be exceeded [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

7.3 Rifampin

Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of LIVALO 2 mg once daily should not be exceeded [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

7.4 Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors may be increased with concurrent administration of fibrates, LIVALO should be administered with caution when used concomitantly with gemfibrozil or other fibrates [see Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

7.5 Niacin

The risk of skeletal muscle effects may be enhanced when LIVALO is used in combination with niacin; a reduction in LIVALO dosage should be considered in this setting [see Warnings and Precautions (5.1)].

7.6 Warfarin

LIVALO had no significant pharmacokinetic interaction with R- and S- warfarin. LIVALO had no significant effect on prothrombin time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment [see Clinical Pharmacology (12.3)]. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk. Because another drug in this class passes into human milk and HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require LIVALO treatment should be advised not to nurse their infants or to discontinue LIVALO [see Contraindications (4)].

8.4 Pediatric Use

Safety and effectiveness of LIVALO in pediatric patients have not been established.

8.5 Geriatric Use

Of the 2,800patients randomized to LIVALO 1 mg to 4 mg in controlled clinical studies, 1,209(43%) were 65years and older. No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Patients with moderate and severe renal impairment (glomerular filtration rate 30– 59 mL/min/1.73 m2 and 15 – 29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

LIVALO is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.

12.1 Mechanism of Action

Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. 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. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.

12.2 Pharmacodynamics

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 daily dose).

12.3 Pharmacokinetics

Warfarin: The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of LIVALO 4mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.

Table 2. Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure

*Data presented as x-fold change represent the ratio between co-administration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change).
† Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]
BID = twice daily; QD = once daily
Co-administered drug	Dose regimen	Change in AUC*	Change in Cmax*
Cyclosporine	Pitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6	↑ 4.6 fold†	↑ 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%
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%
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 3. Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs

Data presented as % change represent % difference relative to the investigated drug alone (i.e., 0% = no change).
BID = twice daily; QD = once daily
Co-administered drug	Dose regimen		Change in AUC*	Change in Cmax*
Atazanavir
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