1. DESCRIPTION
Ezetimibe/atorvastatin contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. Its structural formula is:
Empirical formula: C24H21F2NO3 - Molecular weight: 409.4
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water.
Atorvastatin is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1). Its structural formula is:
Empirical formula: (C33H34FN2O5)2Ca - Molecular weight: 1155.37
Atorvastatin calcium is a white to off-white amorphous powder that is very slightly soluble in water, insoluble in acetonitrile, and soluble in methanol.
Ezetimibe/atorvastatin is available for oral use as tablets containing 10 mg of ezetimibe and: 10.34 mg of atorvastatin calcium, equivalent to 10 mg of atorvastatin (ezetimibe/atorvastatin 10 mg/10 mg); 20.68 mg of atorvastatin calcium, equivalent to 20 mg of atorvastatin (ezetimibe/atorvastatin 10 mg/20 mg); 41.37 mg of atorvastatin calcium, equivalent to 40 mg of atorvastatin (ezetimibe/atorvastatin 10 mg/40 mg); or 82.73 mg of atorvastatin calcium, equivalent to 80 mg of atorvastatin (ezetimibe/atorvastatin 10 mg/80 mg).
Each film-coated tablet of ezetimibe/atorvastatin contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, lactose anhydrous, hydroxypropyl cellulose, and sodium bicarbonate. In addition, the film coating contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, titanium dioxide, and carnauba wax.
2. INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
2.1 Primary Hyperlipidemia
Ezetimibe/atorvastatin is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
2.2 Homozygous Familial Hypercholesterolemia (HoFH)
Ezetimibe/atorvastatin is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
2.3 Limitations of Use
No incremental benefit of ezetimibe/atorvastatin on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. Ezetimibe/atorvastatin has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
3. DOSAGE AND ADMINISTRATION
3.1 Recommended Dosing
The dosage range of ezetimibe/atorvastatin is 10/10 mg/day to 10/80 mg/day. The recommended starting dose of ezetimibe/atorvastatin is 10/10 mg/day or 10/20 mg/day. Ezetimibe/atorvastatin can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10/40 mg/day. After initiation and/or upon titration of ezetimibe/atorvastatin, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.
Patients should swallow ezetimibe/atorvastatin tablets whole. Tablets should not be crushed, dissolved, or chewed.
3.2 Patients with Homozygous Familial Hypercholesterolemia
The dosage of ezetimibe/atorvastatin in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day. Ezetimibe/atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
3.3 Coadministration with Other Drugs
Bile Acid Sequestrants
Dosing of ezetimibe/atorvastatin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.11)].
Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with ezetimibe/atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing ezetimibe/atorvastatin and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with ezetimibe/atorvastatin should be limited to 10/20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of ezetimibe/atorvastatin is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with ezetimibe/atorvastatin should be limited to 10/40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of ezetimibe/atorvastatin is employed. [See Warnings and Precautions (5.1) and Drug Interactions (7).]
Other Concomitant Lipid-Lowering Therapy
The combination of ezetimibe/atorvastatin and gemfibrozil is not recommended [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].
4. CONTRAINDICATIONS
Active liver disease or unexplained persistent elevations of hepatic transaminase levels.
Hypersensitivity to any component of ezetimibe/atorvastatin [see Adverse Reactions (6.2)].
Women who are pregnant or may become pregnant. Ezetimibe/atorvastatin may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe/atorvastatin use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. Ezetimibe/atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, ezetimibe/atorvastatin should be discontinued immediately, and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Nursing mothers. It is not known whether atorvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe/atorvastatin treatment should not breast-feed their infants [see Use in Specific Populations (8.2)].
5. WARNINGS AND PRECAUTIONS
5.1 Myopathy/Rhabdomyolysis
Atorvastatin
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times upper limit of normal (ULN). The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
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 creatinine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ezetimibe/atorvastatin. Ezetimibe/atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with ezetimibe/atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of ezetimibe/atorvastatin should be considered when taken concomitantly with the aforementioned drugs. [See Drug Interactions (7).] Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (3.3), Drug Interactions (7)].
Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin
* Use with caution and with the lowest dose necessary
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe/atorvastatin with colchicine [see Drug Interactions (7.10)].
Ezetimibe/atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Ezetimibe
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 times ULN was 0.2% for ezetimibe vs. 0.1% for placebo, and 0.1% for ezetimibe coadministered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. Ezetimibe/atorvastatin and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the ULN indicates myopathy.
5.2 Liver Enzymes
Atorvastatin
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times ULN occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg atorvastatin, respectively.
One patient in clinical trials of atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.
Ezetimibe
In controlled clinical studies, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ezetimibe coadministered with atorvastatin, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was 0.6% for patients treated with ezetimibe administered with atorvastatin. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.
Ezetimibe/atorvastatin
It is recommended that liver enzyme tests be obtained prior to initiating therapy with ezetimibe/atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ezetimibe/atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart ezetimibe/atorvastatin.
Ezetimibe/atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of ezetimibe/atorvastatin [see Contraindications (4)].
5.3 Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve and that ezetimibe did not impair adrenocortical steroid hormone production. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if ezetimibe/atorvastatin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
5.4 Use in Patients with Recent Stroke or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin (38, 1.6%) group as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
5.5 CNS Toxicity
Atorvastatin
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC(0-24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
6. ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
• Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Ezetimibe/atorvastatin
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In a ezetimibe/atorvastatin placebo-controlled clinical trial, 628 patients (age range 18-86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on ezetimibe/atorvastatin and 5% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with ezetimibe/atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were:
• Myalgia (0.8%)
• Abdominal pain (0.8%)
• Increased hepatic enzymes (0.8%)
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in this trial were: increased ALT (5%), increased AST (4%), and musculoskeletal pain (4%).
Ezetimibe/atorvastatin has been eva luated for safety in 2403 patients in 7 clinical trials (one placebo-controlled trial and six active-controlled trials).
Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with ezetimibe/atorvastatin (n=255) and at an incidence greater than placebo, regardless of causality assessment, from the placebo-controlled trial.
Table 2*: Clinical and Selected Laboratory Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe/atorvastatin and at an Incidence Greater than Placebo, Regardless of Causality
* Placebo-controlled combination study in which the active ingredients equivalent to ezetimibe/atorvastatin were coadministered.
† All doses.
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After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to ezetimibe/atorvastatin (10/10-10/80) or atorvastatin (10-80 mg/day) for an additional 48 weeks. The long-term coadministration of ezetimibe plus atorvastatin had an overall safety profile similar to that of atorvastatin alone.
Ezetimibe
In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9-86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo regardless of causality assessment are shown in Table 3.
Table 3: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality
Atorvastatin
In an atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality.
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 4 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials.
Table 4: Clinical Adverse Reactions Occurring in > 2% in Patents Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients).
* Adverse Reaction >2% in any dose greater than placebo
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6.2 Postmarketing Experience
Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The additional events described below have been identified during post-approval use of ezetimibe and/or atorvastatin.
Blood and lymphatic system disorders: thrombocytopenia
Nervous system disorders: headache; paresthesia; peripheral neuropathy
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Gastrointestinal disorders: pancreatitis
Skin and subcutaneous tissue disorders: angioedema; bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis); rash; urticaria
Musculoskeletal and connective tissue disorders: myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
Injury, poisoning and procedural complications: tendon rupture
Immune system disorders: anaphylaxis; hypersensitivity reactions
Hepatobiliary disorders: hepatitis; cholelithiasis; cholecystitis; fatal and nonfatal hepatic failure
Psychiatric disorders: depression
Laboratory abnormalities: elevated creatine phosphokinase
7. DRUG INTERACTIONS
Ezetimibe/atorvastatin
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1)].
7.1 Strong Inhibitors of Cytochrome P450 3A4
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP3A4. Because ezetimibe/atorvastatin contains atorvastatin, the risk of myopathy during treatment with ezetimibe/atorvastatin is increased with concurrent administration of:
Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of 80 mg atorvastatin with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the ezetimibe/atorvastatin dose exceeds 10/20 mg [see Warnings and Precautions (5.1) and Dosage and Administration (3.3)].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of ezetimibe/atorvastatin should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing ezetimibe/atorvastatin and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of ezetimibe/atorvastatin should not exceed 10/20 mg and should be used with caution [see Warnings and Precautions (5.1) and Dosage and Administration (3.3)]. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of ezetimibe/atorvastatin should not exceed 10/40 mg daily and close clinical monitoring is recommended.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, do not use a ezetimibe/atorvastatin dose that exceeds 10/20 mg [see Warnings and Precautions (5.1) and Dosage and Administration (3.3)].
7.2 Cyclosporine
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone.
In addition, ezetimibe and cyclosporine used concomitantly can increase exposure to both ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal impairment. The coadministration of ezetimibe/atorvastatin with cyclosporine should be avoided [see Warnings and Precautions (5.1)].
7.3 Grapefruit Juice
Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
7.4 Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of ezetimibe/atorvastatin with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].
7.5 Fenofibrates (e.g., fenofibrate and fenofibric acid)
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fenofibrates, ezetimibe/atorvastatin should be administered with caution when used concomitantly with a fenofibrate [see Warnings and Precautions (5.1)].
Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected in a patient receiving ezetimibe/atorvastatin and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid].
7.6 Niacin
The risk of skeletal muscle effects may be enhanced when ezetimibe/atorvastatin is used in combination with niacin; a reduction in ezetimibe/atorvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1)].
7.7 Digoxin
When multiple doses of atorvastatin and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
7.8 Oral Contraceptives
Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradio. These increases should be considered when selecting an oral contraceptive for a woman taking ezetimibe/atorvastatin.
7.9 Rifampin or Other Inducers of Cytochrome P450 3A4
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous coadministration of ezetimibe/atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
7.10 Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe/atorvastatin with colchicine.
7.11 Cholestyramine
Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.
7.12 Coumarin Anticoagulants
If ezetimibe/atorvastatin is added to warfarin, a coumarin anticoagulant, the International Normlized Ratio (INR) should be appropriately monitored.
8. USE IN SPECIFIC POPULATIONS
8.1 Usage in Pregnancy
Pregnancy Category X
[See Contraindications (4).]
Ezetimibe/atorvastatin
Ezetimibe/atorvastatin is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of ezetimibe/atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Statins may cause fetal harm when administered to a pregnant woman. Because ezetimibe/atorvastatin contains atorvastatin, ezetimibe/atorvastatin should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking ezetimibe/atorvastatin, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Ezetimibe
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.
Atorvastatin
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2).
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation Day 7 through to lactation Day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on Days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at Days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Rare reports of congenital anomalies have been received following intrauterine exposure to statin reductase inhibitors.
8.2 Nursing Mothers
In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma.
It is not known whether ezetimibe is excreted into human breast milk. It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver atorvastatin levels of 50% and 40%, respectively, of that in their mother’s milk. Because of the potential for adverse reactions in nursing infants, women taking ezetimibe/atorvastatin should not breast-feed [see Contraindications (4)].
8.3 Pediatric Use
Ezetimibe/atorvastatin
Safety and effectiveness have not been established in pediatric patients.
Ezetimibe
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.
Atorvastatin
Pharmacokinetic data in the pediatric population are not available.
8.4 Geriatric Use
Of the patients who received ezetimibe coadministered with atorvastatin in clinical studies, 1166 were 65 and older (this included 291 who were 75 and older). The effectiveness and safety of ezetimibe/atorvastatin were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, ezetimibe/atorvastatin should be prescribed with caution in the elderly.
In geriatric patients, no dosage adjustment of ezetimibe/atorvastatin is necessary.
8.5 Hepatic Impairment
Ezetimibe/atorvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4), Warnings and Precautions (5.2)].
8.6 Renal Impairment
A history of renal impairment may be a risk factor for statin-associated myopathy. These patients merit closer monitoring for skeletal muscle effects [see Warnings and Precautions (5.1)].
In patients with renal impairment, no dosage adjustment of ezetimibe/atorvastatin is necessary.
9. OVERDOSAGE
Ezetimibe/atorvastatin
No specific treatment of overdosage with ezetimibe/atorvastatin can be recommended. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks, was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.
Atorvastatin
Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.
10. MECHANISM OF ACTION
Ezetimibe/atorvastatin
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe/atorvastatin contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action.
Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins.
Atorvastatin
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
11. PHARMACODYNAMICS
Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (3)].
12. PHARMACOKINETICS
Ezetimibe/atorvastatin
Ezetimibe/atorvastatin 10/10 and 10/80 tablets have been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets. Ezetimibe/atorvastatin 10/20 and 10/40 tablets have been shown to be clinically equivalent in LDL-C response to the corresponding coadministered doses of ezetimibe and atorvastatin tablets.
Absorption
Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Atorvastatin
Maximum plasma atorvastatin concentrations after oral administration occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.
Effect of Food on Oral Absorption
Ezetimibe/atorvastatin
A high-fat meal decreased atorvastatin AUC and Cmax 11% and 35%, respectively, of the ezetimibe/atorvastatin 10/80 tablet. A high-fat meal decreased unconjugated ezetimibe AUC 2% and increased unconjugated ezetimibe Cmax 10% of the ezetimibe/atorvastatin 10/80 tablet.
Ezetimibe/atorvastatin can be taken with or without food [see Dosage and Administration (3.1)].
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Atorvastatin
Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications (4); Use in Specific Populations (8.2)].
Metabolism and Excretion
Ezetimibe
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species eva luated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Atorvastatin
Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Specific Populations
Geriatric Patients
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
Atorvastatin
Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.
Pediatric Patients: [See Use in Specific Populations (8.3).]
Gender
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Atorvastatin
Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Race
Ezetimibe
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
Hepatic Impairment
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold on both Day 1 and Day 14 when compared to healthy subjects.
Atorvastatin
In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Child-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease [see Contraindications (4)].
Renal Impairment
[See Warnings and Precautions (5.1), Use in Specific Populations (8.6)]
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
Atorvastatin
Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin.
Hemodialysis
Atorvastatin
While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
13. HOW SUPPLIED/STORAGE AND HANDLING
1) How Available:
a) Brand name: LIPTRUZET, by Merck Sharp Dohme.
b) Generic drugs: None.
2) How Supplied:
Tablets LIPTRUZET 10 mg/10 mg are white to off-white capsule-shaped, biconvex film-coated tablets with code “320” on one side. They are supplied as follows:
NDC 66582-320-30 unit of use packages of 30 (three foil pouches each containing one 10-count blister card)
NDC 66582-320-54 unit of use packages of 90 (nine foil pouches each containing one 10-count blister card)
Tablets LIPTRUZET 10 mg/20 mg are white to off-white round, biconvex film-coated tablets with code “321” on one side. They are supplied as follows:
NDC 66582-321-30 unit of use packages of 30 (three foil pouches each containing one 10-count blister card)
NDC 66582-321-54 unit of use packages of 90 (nine foil pouches each containing one 10-count blister card)
Tablets LIPTRUZET 10 mg/40 mg are white to off-white oval, biconvex film-coated tablets with code “322” on one side. They are supplied as follows:
NDC 66582-322-30 unit of use packages of 30 (three foil pouches each containing one 10-count blister card)
NDC 66582-322-54 unit of use packages of 90 (nine foil pouches each containing one 10-count blister card)
Tablets LIPTRUZET 10 mg/80 mg are white to off-white capsule-shaped, biconvex film-coated tablets with code “323” on one side. They are supplied as follows:
NDC 66582-323-30 unit of use packages of 30 (three foil pouches each containing one 10-count blister card)
NDC 66582-323-54 unit of use packages of 90 (nine foil pouches each containing one 10-count blister card)
3) Storage and Handling:
Store at 20° to 25°C (68° to 77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Store in the foil pouch until use. After the foil pouch is opened, protect LIPTRUZET from moisture and light. Once a tablet is removed, slide blister card back into case. Store the case in a dry place, and discard any unused tablets 30 days after the pouch is opened.
