ADVERSE REACTIONS
The overall safety profile of FUZEON is based on 1188 subjects who received at least 1 dose of FUZEON during various clinical trials. This includes 1153 adults, 608 of whom received the recommended dose for greater than 24 weeks, and 35 pediatric subjects.
Assessment of treatment-emergent adverse events is based on the pooled data from the two Phase 3 studies T20-301 and T20-302.
LOCAL INJECTION SITE REACTIONS
Local injection site reactions were the most frequent adverse events associated with the use of FUZEON. In Phase 3 clinical studies (T20-301 and T20-302), 98% of subjects had at least 1 local injection site reaction (ISR). Three percent of subjects discontinued treatment with FUZEON because of ISRs. Eighty-six percent of subjects experienced their first ISR during the initial week of treatment. The majority of ISRs were associated with mild to moderate pain at the injection site, erythema, induration, and the presence of nodules or cysts. For most subjects the severity of signs and symptoms associated with ISRs did not change during the 24 weeks of treatment. In 17% of subjects an individual ISR lasted for longer than 7 days. Because of the frequency and duration of individual ISRs, 23% of subjects had six or more ongoing ISRs at any given time. Individual signs and symptoms characterizing local ISRs are summarized in Table 4. Infection at the injection site (including abscess and cellulitis) was reported in
1% of subjects.
Table 4 Summary of Individual Signs/Symptoms Characterizing Local Injection Site Reactions to Enfuvirtide in Studies T20-301 and T20-302 Combined (% of Subjects)
|
|
N=663 |
| Event Category |
Any Severity Grade |
% of Events
Comprising
Grade 3 Reactions |
% of Events
Comprising
Grade 4 Reactions |
|
Pain/Discomfort a |
95%
|
9%
|
0%
|
|
Induration b |
89%
|
41%
|
16%
|
|
Erythema c |
89%
|
22%
|
10%
|
|
Nodules and Cysts d |
76%
|
26%
|
0%
|
|
Pruritus e |
62%
|
4%
|
NA
|
|
Ecchymosis f |
48%
|
8%
|
5%
|
| a Grade 3 = severe pain requiring analgesics (or narcotic analgesics for
Grade 4 = severe pain requiring hospitalization or prolongation of hospitalization, resulting in death, or persistent or significant disability/incapacity, or life-threatening, or medically significant.
|
| b Grade 3 = >/=25 mm but <50 mm; Grade 4 = >/=50 mm average diameter.
|
| c Grade 3 = >/=50 mm but <85 mm average diameter; Grade 4 = >/=85 mm average diameter.
|
| d Grade 3 = >/=3 cm; Grade 4 = if draining. |
| e Grade 3 = refractory to topical treatment or requiring oral or parenteral treatment; Grade 4 = not applicable. |
| f Grade 3 = >3 cm but 5 cm.
|
|
OTHER ADVERSE EVENTS
Hypersensitivity reactions have been attributed to FUZEON (
The events most frequently reported in subjects receiving FUZEON + background regimen, excluding injection site reactions, were diarrhea (26.8%), nausea (20.1%), and fatigue (16.1%). These events were also commonly observed in subjects that received background regimen alone: diarrhea (33.5%), nausea (23.7%), and fatigue (17.4%).
Treatment-emergent adverse events (% of subjects), excluding ISRs, from Phase 3 studies are summarized for adult subjects, regardless of severity and causality, in Table 5. Only events occurring in >/=2% of subjects and at a higher rate in subjects treated with FUZEON are summarized in Table 5; events that occurred at a higher rate in the control arms are not displayed.
Table 5 Percentage of Patients With Selected Treatment-Emergent Adverse Events * Reported in >/=2% of Adult Patients and Occurring More Frequently in Patients Treated With FUZEON (Pooled Studies T20-301/T20-302 at 24 Weeks)
| Adverse Event (by System Organ Class) |
FUZEON +
Background Regimen |
Background Regimen |
|
|
N=663 |
N=334 |
|
Nervous System Disorders
|
|
|
|
Peripheral Neuropathy
|
8.9%
|
6.3%
|
|
Taste Disturbance
|
2.4%
|
1.5%
|
|
Psychiatric Disorders
|
|
|
|
Insomnia
|
11.3%
|
8.7%
|
|
Depression
|
8.6%
|
7.2%
|
|
Anxiety
|
5.7%
|
3.0%
|
|
Respiratory, Thoracic, and Mediastinal Disorders
|
|
|
|
Cough
|
7.4%
|
5.4%
|
|
Infections
|
|
|
|
Sinusitis
|
6.2%
|
2.1%
|
|
Herpes Simplex
|
5.0%
|
3.9%
|
|
Skin Papilloma
|
4.2%
|
1.5%
|
|
Influenza
|
3.9%
|
1.8%
|
|
General
|
|
|
|
Weight Decreased
|
6.5%
|
5.1%
|
|
Appetite Decreased
|
6.3%
|
2.4%
|
|
Asthenia
|
5.7%
|
4.2%
|
|
Anorexia
|
2.6%
|
1.8%
|
|
Influenza-like Illness
|
2.3%
|
0.9%
|
|
Skin and Subcutaneous Tissue Disorders
|
|
|
|
Pruritus Nos
|
5.1%
|
4.2%
|
|
Musculoskeletal, Connective, Tissue, and Bone Disorders
|
|
|
|
Myalgia
|
5.0%
|
2.4%
|
|
Gastrointestinal Disorders
|
|
|
|
Constipation
|
3.9%
|
2.7%
|
|
Abdominal Pain Upper
|
3.0%
|
2.7%
|
|
Pancreatitis
|
2.4%
|
0.9%
|
|
Eye Disorders
|
|
|
|
Conjunctivitis
|
2.4%
|
0.9%
|
|
Blood and Lymphatic System Disorders
|
|
|
|
Lymphadenopathy
|
2.3%
|
0.3%
|
|
*Excludes Injection Site Reactions
|
|
An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm (4.68 pneumonia events per 100 patient-years versus 0.61 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. One subject death in the FUZEON arm was attributed to pneumonia. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease. It is unclear if the increased incidence of pneumonia was related to FUZEON use. However, because of this finding patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia (see WARNINGS).
LESS COMMON EVENTS
The following adverse events have been reported in 1 or more subjects; however, a causal relationship to FUZEON has not been established. Immune System Disorders: worsening abacavir hypersensitivity reaction
Renal and Urinary Disorders: renal insufficiency (glomerulonephritis); renal failure
Blood and Lymphatic Disorders: thrombocytopenia; neutropenia, and fever
Endocrine and Metabolic: hyperglycemia
Infections and Infestations: pneumonia
Nervous System Disorders: Guillain-Barre syndrome (fatal); sixth nerve palsy
LABORATORY ABNORMALITIES
Table 6 shows the treatment-emergent laboratory abnormalities that occurred in at least 2% of subjects and more frequently in those receiving FUZEON + background regimen than background regimen alone from studies T20-301 and T20-302.
Table 6 Percentage of Treatment-Emergent Laboratory Abnormalities That Occurred in >/=2% of Adult Patients and More Frequently in Patients Receiving FUZEON (Pooled Studies T20-301 and T20-302 at 24 Weeks)
| Laboratory Parameters |
Grading |
FUZEON +
Background Regimen |
Background Regimen |
|
|
|
N=663 |
N=334 |
|
Eosinophilia
|
|
|
|
|
1-2 X ULN (0.7 × 109/L)
|
0.7-1.4 × 109/L)
|
8.3%
|
1.5%
|
|
>2 X ULN (0.7 × 109/L)
|
>1.4 × 109/L)
|
1.8%
|
0.9%
|
|
Amylase (U/L)
|
|
|
|
|
Gr. 3
|
>2-5 × ULN
|
6.2%
|
3.6%
|
|
Gr. 4
|
>5 × ULN
or clinical pancreatitis
|
0.9%
|
0.6%
|
|
Lipase (U/L)
|
|
|
|
|
Gr. 3
|
>2-5 × ULN
|
5.9%
|
3.6%
|
|
Gr. 4
|
>5 × ULN
|
2.3%
|
1.8%
|
|
Triglycerides (mmol/L)
|
|
|
|
|
Gr. 3
|
>1000 mg/dL
|
8.9%
|
7.2%
|
|
ALT
|
|
|
|
|
Gr. 3
|
>5-10 × ULN
|
3.5%
|
2.1%
|
|
Gr. 4
|
>10 × ULN
|
0.9%
|
0.6%
|
|
AST
|
|
|
|
|
Gr. 3
|
>5-10 × ULN
|
3.6%
|
3.0%
|
|
Gr. 4
|
>10 × ULN
|
1.2%
|
0.6%
|
|
Creatine Phosphokinase (U/L)
|
|
|
|
|
Gr. 3
|
>5-10 × ULN
|
5.9%
|
3.6%
|
|
Gr. 4
|
>10 × ULN
|
2.3%
|
3.6%
|
|
GGT (U/L)
|
|
|
|
|
Gr. 3
|
>5-10 × ULN
|
3.5%
|
3.3%
|
|
Gr. 4
|
>10 × ULN
|
2.4%
|
1.8%
|
|
Hemoglobin (g/dL)
|
|
|
|
|
Gr. 3
|
6.5-7.9 g/dL
|
1.5%
|
0.9%
|
|
Gr. 4
|
<6.5 g/dL
|
0.6%
|
0.6%
|
|
ADVERSE EVENTS IN PEDIATRIC PATIENTS
FUZEON has been studied in 35 pediatric subjects 6 through 16 years of age with duration of FUZEON exposure ranging from 1 dose to 48 weeks. Adverse experiences seen during clinical trials were similar to those observed in adult subjects.
|
