LIPTRUZET SIDE EFFECTS
- Generic Name: ezetimibe and atorvastatin tablets
- Brand Name: Liptruzet
SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Rhabdomyolysis and myopathy
- Liver enzyme abnormalities
Clinical Trials Experience
LIPTRUZET
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:
- 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%).
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 1: 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 Adverse Reaction |
Placebo (%) n=60 |
Ezetimibe 10 mg (%) n=65 |
Atorvastatin† (%) n=248 |
LIPTRUZET† (%) n=255 |
| Nervous system disorders | ||||
| Dizziness | 0 | 6 | <1 | 2 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Coughing | 0 | 3 | <1 | 2 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 2 | 2 | 4 | 3 |
| Nausea | 0 | 2 | 5 | 3 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 0 | 5 | 6 | 3 |
| Muscle weakness | 0 | 2 | 0 | 2 |
| Musculoskeletal pain | 3 | 8 | 5 | 4 |
| Metabolism and nutrition disorders | ||||
| Hyperkalemia | 0 | 0 | <1 | 2 |
| Infections and infestations | ||||
| Bronchitis | 0 | 2 | 2 | 2 |
| Sinusitis | 0 | 3 | 2 | 2 |
| Vascular disorders | ||||
| Hot flushes | 0 | 0 | <1 | 2 |
| Investigations | ||||
| ALT increased | 0 | 0 | 2 | 5 |
| AST increased | 0 | 0 | <1 | 4 |
| * Placebo-controlled combination study in which the active ingredients equivalent to LIPTRUZET 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 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.
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 2: 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 Adverse Reaction |
Ezetimibe 10 mg (%) n=2396 |
Placebo (%) n=1159 |
| Gastrointestinal disorders | ||
| Diarrhea | 4.1 | 3.7 |
| General disorders and administration site conditions | ||
| Fatigue | 2.4 | 1.5 |
| Infections and infestations | ||
| Influenza | 2.0 | 1.5 |
| Sinusitis | 2.8 | 2.2 |
| Upper respiratory tract infection | 4.3 | 2.5 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 3.0 | 2.2 |
| Pain in extremity | 2.7 | 2.5 |
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 3 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 3: Clinical Adverse Reactions Occurring in >2% in Patients Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients)
| Adverse Reaction* | Any dose n=8755 |
Atorvastatin 10 mg n=3908 |
Atorvastatin 20 mg n=188 |
Atorvastatin 40 mg n=604 |
Atorvastatin 80 mg n=4055 |
Placebo n=7311 |
| Nasopharyngitis | 8.3 | 12.9 | 5.3 | 7.0 | 4.2 | 8.2 |
| Arthralgia | 6.9 | 8.9 | 11.7 | 10.6 | 4.3 | 6.5 |
| Diarrhea | 6.8 | 7.3 | 6.4 | 14.1 | 5.2 | 6.3 |
| Pain in extremity | 6.0 | 8.5 | 3.7 | 9.3 | 3.1 | 5.9 |
| Urinary tract infection | 5.7 | 6.9 | 6.4 | 8.0 | 4.1 | 5.6 |
| Dyspepsia | 4.7 | 5.9 | 3.2 | 6.0 | 3.3 | 4.3 |
| Nausea | 4.0 | 3.7 | 3.7 | 7.1 | 3.8 | 3.5 |
| Musculoskeletal pain | 3.8 | 5.2 | 3.2 | 5.1 | 2.3 | 3.6 |
| Muscle spasms | 3.6 | 4.6 | 4.8 | 5.1 | 2.4 | 3.0 |
| Myalgia | 3.5 | 3.6 | 5.9 | 8.4 | 2.7 | 3.1 |
| Insomnia | 3.0 | 2.8 | 1.1 | 5.3 | 2.8 | 2.9 |
| Pharyngolaryngeal pain | 2.3 | 3.9 | 1.6 | 2.8 | 0.7 | 2.1 |
| *Adverse Reaction >2% in any dose greater than placebo | ||||||
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; dizziness; 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: myositis; myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
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
Respiratory: interstitial lung disease
Laboratory abnormalities: elevated creatine phosphokinase
General disorders and administration site conditions: fatigue
SRC: NLM .