SELZENTRY SIDE EFFECTS
- Generic Name: maraviroc
- Brand Name: Selzentry
- Drug Class: HIV, CRAs
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Hepatotoxicity
- Severe Skin and Hypersensitivity Reactions
- Cardiovascular Events
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience In Adult Subjects
Treatment-Experienced Subjects
The safety profile of SELZENTRY is primarily based on 840 HIV-1–infected subjects who received at least 1 dose of SELZENTRY during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.
Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with SELZENTRY for subjects in these trials was 48 weeks, with the total exposure on SELZENTRY twice daily at 309 patient-years versus 111 patient-years on placebo each administered with optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with twice-daily therapy with SELZENTRY with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of SELZENTRY.
The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with 2 subjects (0.5%) on SELZENTRY permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 5. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on placebo are not displayed.
Table 1. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on SELZENTRY (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
| Body System/ Adverse Event | SELZENTRY Twice Dailya |
Placebo | ||
| (n = 426) % |
Exposure-Adjusted Rate (per 100 pt-yrs) PYE = 309b |
(n = 209) % |
Exposure-Adjusted Rate (per 100 pt-yrs) PYE = 111b |
|
| Eye Disorders | ||||
| Conjunctivitis | 2 | 3 | 1 | 3 |
| Ocular infections, inflammations, and associated manifestations | 2 | 3 | 1 | 2 |
| Gastrointestinal Disorders | ||||
| Constipation | 6 | 9 | 3 | 6 |
| General Disorders and Administration Site Conditions | ||||
| Pyrexia | 13 | 20 | 9 | 17 |
| Pain and discomfort | 4 | 5 | 3 | 5 |
| Infections and Infestations | ||||
| Upper respiratory tract infection | 23 | 37 | 13 | 27 |
| Herpes infection | 8 | 11 | 4 | 8 |
| Sinusitis | 7 | 10 | 3 | 6 |
| Bronchitis | 7 | 9 | 5 | 9 |
| Folliculitis | 4 | 5 | 2 | 4 |
| Anogenital warts | 2 | 3 | 1 | 3 |
| Influenza | 2 | 3 | 0.5 | 1 |
| Otitis media | 2 | 3 | 0.5 | 1 |
| Metabolism and Nutrition Disorders | ||||
| Appetite disorders | 8 | 11 | 7 | 13 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Joint-related signs and symptoms | 7 | 10 | 3 | 5 |
| Muscle pains | 3 | 4 | 0.5 | 1 |
| Neoplasms Benign, Malignant, and Unspecified | ||||
| Skin neoplasms benign | 3 | 4 | 1 | 3 |
| Nervous System Disorders | ||||
| Dizziness/postural dizziness | 9 | 13 | 8 | 17 |
| Paresthesias and dysesthesias | 5 | 7 | 3 | 6 |
| Sensory abnormalities | 4 | 6 | 1 | 3 |
| Disturbances in consciousness | 4 | 5 | 3 | 6 |
| Peripheral neuropathies | 4 | 5 | 3 | 6 |
| Psychiatric Disorders | ||||
| Disturbances in initiating and maintaining sleep | 8 | 11 | 5 | 10 |
| Depressive disorders | 4 | 6 | 3 | 5 |
| Anxiety symptoms | 4 | 5 | 3 | 7 |
| Renal and Urinary Disorders | ||||
| Bladder and urethral symptoms | 5 | 7 | 1 | 3 |
| Urinary tract signs and symptoms | 3 | 4 | 1 | 3 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||||
| Coughing and associated symptoms | 14 | 21 | 5 | 10 |
| Upper respiratory tract signs and symptoms | 6 | 9 | 3 | 6 |
| Nasal congestion and inflammations | 4 | 6 | 3 | 5 |
| Breathing abnormalities | 4 | 5 | 2 | 5 |
| Paranasal sinus disorders | 3 | 4 | 0.5 | 1 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash | 11 | 16 | 5 | 11 |
| Apocrine and eccrine gland disorders | 5 | 7 | 4 | 7.5 |
| Pruritus | 4 | 5 | 2 | 4 |
| Lipodystrophies | 3 | 5 | 0.5 | 1 |
| Erythema | 2 | 3 | 1 | 2 |
| Vascular Disorders | ||||
| Vascular hypertensive disorders | 3 | 4 | 2 | 4 |
| a 300-mg dose equivalent. b PYE = Patient-years of exposure. |
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Laboratory Abnormalities
Table 2 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving SELZENTRY.
Table 2. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
| Laboratory Parameter Preferred Term | Limit | SELZENTRY Twice Daily + OBT (n = 421)a % |
Placebo + OBT (n = 207)a % |
| Aspartate aminotransferase | >5.0 x ULN | 4.8 | 2.9 |
| Alanine aminotransferase | >5.0 x ULN | 2.6 | 3.4 |
| Total bilirubin | >2.5 x ULN | 5.5 | 5.3 |
| Amylase | >2.0 x ULN | 5.7 | 5.8 |
| Lipase | >2.0 x ULN | 4.9 | 6.3 |
| Absolute neutrophil count | <750/mm3 | 4.3 | 2.4 |
| ULN = Upper limit of normal. a Percentages based on total subjects evaluated for each laboratory parameter. |
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Treatment-Naive Subjects
Treatment-Emergent Adverse Events
Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received SELZENTRY 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 3. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on efavirenz are not displayed.
Table 3. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on SELZENTRY (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)
| Body System/ Adverse Event | SELZENTRY 300 mg Twice Daily + Lamivudine/ Zidovudine (n = 360) % |
Efavirenz 600 mg Once Daily + Lamivudine/ Zidovudine (n = 361) % |
| Blood and Lymphatic System Disorders | ||
| Anemias NEC | 8 | 5 |
| Neutropenias | 4 | 3 |
| Ear and Labyrinth Disorders | ||
| Ear disorders NEC | 3 | 2 |
| Gastrointestinal Disorders | ||
| Flatulence, bloating, and distention | 10 | 7 |
| Gastrointestinal atonic and hypomotility disorders NEC | 9 | 5 |
| Gastrointestinal signs and symptoms NEC | 3 | 2 |
| General Disorders and Administration Site Conditions | ||
| Body temperature perception | 3 | 1 |
| Infections and Infestations | ||
| Upper respiratory tract infection | 32 | 30 |
| Bronchitis | 13 | 9 |
| Herpes infection | 7 | 6 |
| Bacterial infections NEC | 6 | 3 |
| Herpes zoster/varicella | 5 | 4 |
| Tinea infections | 4 | 3 |
| Lower respiratory tract and lung infections | 3 | 2 |
| Neisseria infections | 3 | 0 |
| Viral infections NEC | 3 | 2 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Joint-related signs and symptoms | 6 | 5 |
| Nervous System Disorders | ||
| Paresthesias and dysesthesias | 4 | 3 |
| Memory loss (excluding dementia) | 3 | 1 |
| Renal and Urinary Disorders | ||
| Bladder and urethral symptoms | 4 | 3 |
| Reproductive System and Breast Disorders | ||
| Erection and ejaculation conditions and disorders | 3 | 2 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||
| Upper respiratory tract signs and symptoms | 9 | 5 |
| Skin and Subcutaneous Disorders | ||
| Nail and nail bed conditions (excluding infections and infestations) | 6 | 2 |
| Lipodystrophies | 4 | 3 |
| Acnes | 3 | 2 |
| Alopecias | 2 | 1 |
Laboratory Abnormalities
Table 4. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks)
| Laboratory Parameter Preferred Term |
Limit | SELZENTRY 300 mg Twice Daily + Lamivudine/ Zidovudine (n = 353)a % |
Efavirenz 600 mg Once Daily+ Lamivudine/ Zidovudine (n = 350)a % |
| Aspartate aminotransferase | >5.0 x ULN | 4.0 | 4.0 |
| Alanine aminotransferase | >5.0 x ULN | 3.9 | 4.0 |
| Creatine kinase | >10.0 x ULN | 3.9 | 4.8 |
| Amylase | >2.0 x ULN | 4.3 | 6.0 |
| Absolute neutrophil count | <750/mm3 | 5.7 | 4.9 |
| Hemoglobin | <7.0 g/dL | 2.9 | 2.3 |
| ULN = Upper limit of normal. a n = Total number of subjects evaluable for laboratory abnormalities. |
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Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.
Less Common Adverse Events in Clinical Trials
The following adverse events occurred in less than 2% of subjects treated with SELZENTRY or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on SELZENTRY or are potential risks due to the mechanism of action. Events attributed to the subjects’ underlying HIV-1 infection are not listed.
Blood and Lymphatic System: Marrow depression and hypoplastic anemia.
Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.
Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice.
Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.
Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.
Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T-and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.
Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.
Clinical Trials Experience In Pediatric Subjects
HIV-1–Infected Pediatric Subjects
Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1–infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg received SELZENTRY twice daily in combination with OBT. The dose of SELZENTRY was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The median duration of therapy with SELZENTRY was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks.
In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade 3 and 4) adverse reactions occurred in 2% of subjects. The most common adverse reactions (all grades) reported with twice-daily therapy with SELZENTRY were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). Three subjects (3%) discontinued due to adverse events.
Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the SELZENTRY oral solution (21%) compared with those who received SELZENTRY tablets (16%). Subjects were permitted to change formulations after Week 48.
HIV-1–Exposed Neonates
The IMPAACT P2007 trial was an open-label trial in which 47 full-term HIV-1–exposed neonates (born to HIV-1–infected mothers) received at least one dose of SELZENTRY in combination with other antiretrovirals, mostly zidovudine and/or nevirapine. Cohort 1 received 2 single doses of SELZENTRY: the first within 3 days of birth and the second at 7 to 14 days of age. Cohort 2 received SELZENTRY twice daily for 6 weeks beginning within 3 days of birth and continued through Week 6. Both cohorts received SELZENTRY with or without exposure to maternal efavirenz (in utero only in Cohort 1, and both in utero and after birth while breastfeeding in Cohort 2). The population was 51% male and 81% black. All infants were followed for safety through 16 weeks, with a total of 37 infants evaluable for safety.
There were no additional adverse reactions observed in neonates compared with those seen in adults. All adverse reactions reported were mild to moderate. The most common adverse reaction (all grades) reported with SELZENTRY was hemoglobin decreased (14%). One subject (3%) discontinued due to an adverse event (Grade 3 staphylococcal sepsis).
Postmarketing Experience
The following adverse events have been identified during post-approval use of SELZENTRY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).
SRC: NLM .