Maraviroc (Page 3 of 10)

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.5 Potential Risk of Infection

Maraviroc antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, were comparable in the treatment groups during the Phase 3 adult treatment-experienced trials of maraviroc. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving maraviroc compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving maraviroc. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving maraviroc when adjusted for exposure compared with placebo (8 per 100 patient-years).

In the Phase 2b/3 trial in treatment-naive adult subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for maraviroc compared with 2.4 for efavirenz per 100 patient-years of exposure.
Patients should be monitored closely for evidence of infections while receiving maraviroc.

5.6 Potential Risk of Malignancy

While no increase in malignancy has been observed with maraviroc, due to this drug’s mechanism of action, it could affect immune surveillance and lead to an increased risk of malignancy.

The exposure-adjusted rate for malignancies per 100 patient-years of exposure in adult treatment-experienced trials was 4.6 for maraviroc compared with 9.3 on placebo. In treatment-naive adult subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for maraviroc and efavirenz, respectively.
Long-term follow-up is needed to more fully assess this risk.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

• Hepatotoxicity [ see Boxed Warning, Warnings and Precautions ( 5.1) ]

• Severe Skin and Hypersensitivity Reactions [ see Warnings and Precautions ( 5.2) ]

• Cardiovascular Events [ see Warnings and Precautions ( 5.3) ]

6.1 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 maraviroc is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of maraviroc 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 maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc 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 maraviroc 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 maraviroc 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 maraviroc.
The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either maraviroc or placebo, with 2 subjects (0.5%) on maraviroc 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 maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed.

Table 5. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on Maraviroc (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Body System/ Adverse Event Maraviroc Twice Daily a Placebo
(n = 426) % Exposure-Adjusted Rate (per 100 pt-yrs) PYE=309 b (n = 209) % Exposure-Adjusted Rate (per 100 pt-yrs) PYE=111 b
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.

Laboratory Abnormalities:

Table 6 shows the treatment-emergent Grade 3 to 4 laboratory abnormalities that occurred in greater than 2% of subjects receiving maraviroc.

Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3 to 4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Laboratory Parameter Preferred Term Limit Maraviroc 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/mm 3 4.3 2.4

ULN = Upper limit of normal. a Percentages based on total subjects evaluated for each laboratory parameter.

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 maraviroc 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 7. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed.

Table 7. Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on maraviroc (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)

Body System/ Adverse Event Maraviroc tablets 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
Parasthesias and dyesthesias 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 8. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3 to 4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks)

Laboratory Parameter Preferred Term Limit Maraviroc 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/mm 3 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.
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 maraviroc or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action. Events attributed to the subject’s 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 maraviroc twice daily in combination with OBT. The dose of maraviroc 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 maraviroc 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 maraviroc 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 maraviroc oral solution (21%) compared with those who received maraviroc tablets (16%). Subjects were permitted to change formulations after Week 48.

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