ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
- Hepatotoxicity [see Boxed Warning, Warnings and Precautions]
- Cardiovascular events [see Warnings and Precautions]
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety profile of SELZENTRY is primarily based on 840 HIV-infected subjects who received at least one 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 two studies in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of maraviroc therapy for subjects in these studies was 48 weeks, with the total exposure on SELZENTRY twice daily at 309 patient-years versus 111 patient-years on placebo + OBT. The population was 89% male and 84% white, with mean age of 46 years (range 17–75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with SELZENTRY twice daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. Additional adverse events that occurred with once daily dosing at a higher rate than both placebo and twice daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these two studies, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + optimized background therapy (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 SELZENTRY twice daily dosing.
The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the SELZENTRY twice daily and placebo groups, respectively. Correcting for the longer duration of exposure on SELZENTRY compared to 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 and 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 A4001027 and A4001028 are summarized in Table 2. Selected events occurring at ≥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 2
Percentage of Subjects with Selected Treatment-Emergent Adverse Events (All Causality)
(≥2% on SELZENTRY and at a higher rate compared to placebo)
Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks) |
|---|
| SELZENTRY
Twice Daily300 mg dose equivalent | Exposure-adjusted rate
(per 100 pt-yrs)
PYE=309
| Placebo | Exposure-adjusted rate
(per 100 pt-yrs)
PYE=111 |
|---|
| N=426
(%) | | N=209
(%) | |
|---|
| | | | | |
| 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 |
| | | | | |
| I NFECTIONS 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 |
| Pneumonia | 2 | 3 | 5 | 10 |
| 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 |
| Erythemas | 2 | 3 | 1 | 2 |
| | | | | |
| VASCULAR DISORDERS | | | | |
| Vascular hypertensive disorders | 3 | 4 | 2 | 4 |
Less Common Adverse Events
The following adverse events occurred in <2% of SELZENTRY-treated patients. 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 patient's underlying HIV 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
Infections and Infestations: endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock
Musculoskeletal and Connective Tissue Disorders: myositis, osteonecrosis, rhabdomyolysis, blood CK increased
Neoplasms benign, malignant and Unspecified (incl Cysts and Polyps): anal cancer, anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified, basal cell carcinoma, lymphoma, metastases to liver, esophageal carcinoma, squamous cell carcinoma, tongue neoplasm (malignant stage unspecified)
Nervous System Disorders: cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital)
Laboratory Abnormalities
Table 3 shows the treatment-emergent Grade 3–4 laboratory abnormalities that occurred in >2% of patients receiving SELZENTRY.
Table 3
Maximum Shift in Laboratory Test Values (Without Regard to Baseline)
Incidence ≥2% of Grade 3–4 Abnormalities (ACTG Criteria)
Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks) |
|---|
| Laboratory Parameter Preferred Term, % | Limit | SELZENTRY
Twice daily
+ OBT | Placebo + OBT |
|---|
| | | | |
|---|
| | N =421
% | N =207
% |
|---|
| Aspartate aminotransferase | >5.0× ULN | 4.8 | 2.9 |
Alanine
aminotransferase | >5.0× ULN | 2.6 | 3.4 |
| Total bilirubin | >5.0× ULN | 5.5 | 5.3 |
| Amylase | >2.0× ULN | 5.7 | 5.8 |
| Lipase | >2.0× ULN | 4.9 | 6.3 |
| Absolute neutrophil count | <750/mm3 | 4.3 | 2.4 |
|
