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The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Rhabdomyolysis and myopathy [see WARNINGS AND PRECAUTIONS]
- Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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 LIPTRUZET (ezetimibe and 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 LIPTRUZET and 5% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with LIPTRUZET that led to treatment discontinuation and occurred at a rate greater than placebo were:
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%).
LIPTRUZET has been evaluated 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 LIPTRUZET (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 LIPTRUZET and
at an Incidence Greater than Placebo, Regardless of Causality
|Body System/ Organ Class
|Ezetimibe 10 mg (%)
|Nervous system disorders|
|Respiratory, thoracic, and mediastinal disorders|
|Musculoskeletal and connective tissue disorders|
|Metabolism and nutrition disorders|
|Infections and infestations|
|Hot flushes||0||0||< 1||2|
|AST increased||0||0||< 1||4|
|* Placebo-controlled combination study in which the
active ingredients equivalent to LIPTRUZET were coadministered.
† All doses.
After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to LIPTRUZET (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.
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
|Body System/ Organ Class
|Ezetimibe 10 mg (%)
|General disorders and administration site conditions|
|Infections and infestations|
|Upper respiratory tract infection||4.3||2.5|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||2.7||2.5|
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*||Any dose
|Atorvastatin 10 mg
|Atorvastatin 20 mg
|Atorvastatin 40 mg
|Atorvastatin 80 mg
|Pain in extremity||6||8.5||3.7||9.3||3.1||5.9|
|Urinary tract infection||5.7||6.9||6.4||8||4.1||5.6|
|*Adverse Reaction > 2% in any dose greater than placebo|
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
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
Musculoskeletal and connective tissue disorders: myopathy/rhabdomyolysis [see WARNINGS AND PRECAUTIONS]
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS AND PRECAUTIONS].
Immune system disorders: anaphylaxis; hypersensitivity reactions
Psychiatric disorders: depression
Laboratory abnormalities: elevated creatine phosphokinase
Read the Liptruzet (ezetimibe and atorvastatin tablets) Side Effects Center for a complete guide to possible side effects
[See CLINICAL PHARMACOLOGY.]
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 and CLINICAL PHARMACOLOGY].
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 LIPTRUZET contains atorvastatin, the risk of myopathy during treatment with LIPTRUZET 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 [see CLINICAL PHARMACOLOGY]. Therefore, in patients taking clarithromycin, caution should be used when the LIPTRUZET dose exceeds 10/20 mg [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
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 [see CLINICAL PHARMACOLOGY]. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LIPTRUZET should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LIPTRUZET 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 LIPTRUZET should not exceed 10/20 mg and should be used with caution [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of LIPTRUZET 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 [see CLINICAL PHARMACOLOGY]. Therefore, in patients taking itraconazole, do not use a LIPTRUZET dose that exceeds 10/20 mg [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
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 [see CLINICAL PHARMACOLOGY].
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 LIPTRUZET with cyclosporine should be avoided [see WARNINGS AND PRECAUTIONS].
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).
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of LIPTRUZET with gemfibrozil should be avoided [see WARNINGS AND PRECAUTIONS].
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, LIPTRUZET should be administered with caution when used concomitantly with a fenofibrate [see WARNINGS AND PRECAUTIONS].
Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected in a patient receiving LIPTRUZET and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid].
The risk of skeletal muscle effects may be enhanced when LIPTRUZET is used in combination with niacin; a reduction in LIPTRUZET dosage should be considered in this setting [see WARNINGS AND PRECAUTIONS].
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.
Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see CLINICAL PHARMACOLOGY]. These increases should be considered when selecting an oral contraceptive for a woman taking LIPTRUZET.
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 LIPTRUZET with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing LIPTRUZET with colchicine.
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.
Last reviewed on RxList: 5/17/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Liptruzet Information
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