Side Effects of Fuzeon (enfuvirtide)

Fuzeon (enfuvirtide) is an antiretroviral drug used in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

This indication is based on results from two controlled studies of 48 weeks duration. Subjects enrolled were treatment-experienced adults; many had advanced disease. There are no studies of Fuzeon in antiretroviral naive subjects.

Common side effects of Fuzeon include

• injection site reactions (itching, swelling, redness, pain or tenderness, hardened skin, bumps, bruising, and nerve pain if injected near a nerve),
• pain and numbness in feet or legs,
• loss of sleep,
• depression,
• decreased appetite,
• sinus problems,
• enlarged lymph nodes,
• weight loss,
• weakness or loss of strength,
• muscle pain,
• constipation, and
• pancreas problems.

Serious side effects of Fuzeon include

• increased risk of bacterial pneumonia and serious allergic reactions (trouble breathing, fever with vomiting and a skin rash, blood in your urine, or swelling of your feet).

There are no noted drug interactions of Fuzeon with other drugs.

There are no adequate and well-controlled studies of Fuzeon in pregnant women. Fuzeon should be used during pregnancy only if clearly needed.

To monitor maternal-fetal outcomes of pregnant women exposed to Fuzeon and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

It is not known if Fuzeon is excreted in breast milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Fuzeon. The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid the risk of postnatal transmission of HIV.

Injection site reactions Fuzeon causes injection site reactions. Almost all people get injection site reactions with Fuzeon. Reactions are usually mild to moderate but occasionally may be severe.

Reactions on the skin where Fuzeon is injected include:

• itching
• swelling
• redness
• pain or tenderness
• hardened skin
• bumps

These reactions generally happen within the first week of Fuzeon treatment and usually happen again as you keep using Fuzeon. A reaction at one skin injection site usually lasts for less than 7 days. Injection site reactions may be worse when injections are given again in the same place on the body or when the injection is given deeper than it should be (for example, into the muscle).

If you are worried about the reaction you are having, call your healthcare provider to help you decide if you need medical care. If the injection site reaction you are having is severe, call your healthcare provider right away. If you have an injection site reaction, you can discuss with your healthcare provider ways to help the symptoms.

An injection site can get infected. It is important to follow the Fuzeon Injection Instructions that come with your medicine to lower your chances of getting an injection site infection. Call your healthcare provider right away if there are signs of infection at the injection site such as oozing, increasing heat, swelling, redness or pain.

Injection using Biojector 2000

Shooting nerve pain and tingling lasting up to 6 months from injecting close to large nerves or near joints, and bruising and/or collections of blood under the skin have been reported with use of the Biojector 2000 needlefree device to inject Fuzeon.

If you are taking any blood thinners, or have hemophilia or any other bleeding disorder, you may be at higher risk of bruising or bleeding after using the Biojector.

Pneumonia Patients with HIV get bacterial pneumonia more often than patients without HIV. Patients taking Fuzeon with other HIV medicines may get bacterial pneumonia more often than patients not receiving Fuzeon. It is unclear if this is related to the use of Fuzeon.

You should contact your healthcare provider right away if you have a cough, fever or trouble breathing.

Patients are more likely to get bacterial pneumonia if they had 4 a low number of CD4 cells, increased amount of HIV in the blood, intravenous (injected into the vein) drug use, smoking or had experienced lung disease in the past. It is unclear if pneumonia is related to Fuzeon.

Allergic reactions Fuzeon can cause serious allergic reactions. Symptoms of a serious allergic reaction with Fuzeon can include:

• trouble breathing
• fever with vomiting and a skin rash
• blood in your urine
• swelling of your feet

Call your healthcare provider right away if you get any of these symptoms. Other side effects The following side effects were seen more often in patients using Fuzeon with their other anti-HIV medicines than in patients not using Fuzeon with their other anti-HIV medicines:

• pain and numbness in feet or legs
• loss of sleep
• depression
• decreased appetite
• sinus problems
• enlarged lymph nodes
• weight decrease
• weakness or loss of strength
• muscle pain
• constipation
• pancreas problems

These are not all the side effects of Fuzeon. For more information, ask your healthcare provider or pharmacist. If you have questions about side effects, ask your healthcare provider.

Report any new or continuing symptoms to your healthcare provider. Your healthcare provider will tell you what to do and may be able to help you with these side effects.

The following adverse reactions are discussed in greater detail in other sections:

• Administration with Biojector 2000
• Hypersensitivity Reactions
• Pneumonia

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 overall safety profile of Fuzeon is based on 2131 subjects who received at least 1 dose of Fuzeon during various clinical trials. This includes 2051 adults, 658 of whom received the recommended dose for greater than 48 weeks, and 63 pediatric subjects.

Assessment of treatment-emergent adverse events is based on the pooled data from the two randomized, controlled, open-label, multicenter trials in treatment-experienced subjects, T20-301 (TORO 1) and T20-302 (TORO 2).

Local Injection Site Reactions

• Local injection site reactions were the most frequent adverse events associated with the use of Fuzeon.
• In T20-301 and T20-302, 98% of subjects had at least one local injection site reaction (ISR).
• A total of 7% of subjects discontinued treatment with Fuzeon because of ISRs (4%) or difficulties with injecting Fuzeon (3%) such as injection fatigue and inconvenience.
• Eighty-five percent of subjects experienced their first ISR during the initial week of treatment; ISRs continued to occur throughout treatment with Fuzeon.
• For most subjects the severity of signs and symptoms associated with ISRs did not change during the 48 weeks of treatment.
• The majority of ISRs were associated with erythema, induration, the presence of nodules or cysts, and mild to moderate pain at the injection site (Table 2).
• In addition, the average duration of individual ISRs was between three and seven days in 41% of subjects and more than seven days in 24% of subjects.
• Also, the numbers of ISRs per subject at any one time was between six to 14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects.
• Infection at the injection site (including abscess and cellulitis) was reported in 1.7% of adult subjects.

Table 2 : Summary of Individual Signs/Symptoms Characterizing Local Injection Site Reactions to Enfuvirtide in Studies T20-301 and T20-302 Combined (% of Subjects) Through 48 Weeks

Other Adverse Events

• In T20-301 and T20-302, after study week 8, subjects on background alone who met protocol defined criteria for virological failure were permitted to revise their background regimens and add Fuzeon.
• Exposure on Fuzeon+background was 557 patient-years, and to background alone 162 patient-years.
• Due to this difference in exposure, safety results are expressed as the number of patients with an adverse event per 100 patient-years of exposure.
• For Fuzeon+background, adverse events are also displayed by percent of subjects.
• The events most frequently reported in subjects receiving Fuzeon+background regimen, excluding ISRs, were
  • diarrhea (38 per 100 patient-years or 31.7%),
  • nausea (27 per 100 patient-years or 22.8%), and
  • fatigue (24 per 100 patient-years or 20.2%).
• These events were also commonly observed in subjects that received background regimen alone:
  • diarrhea (73 per 100 patient-years),
  • nausea (50 per 100 patient-years), and
  • fatigue (38 per 100 patient-years).
• Treatment-emergent adverse events, regardless of causality and excluding ISRs, from Phase 3 studies are summarized for adult subjects, in Table 3.
• Any Grade 2 or above events occurring at ≥2 percent of subjects and at a higher rate in subjects treated with Fuzeon are summarized in Table 3; events that occurred at a higher rate in the control arms are not displayed.
• Rates of adverse events for subjects who switched to Fuzeon after virological failure were similar.

Table 3 : Rates of Treatment-Emergent Adverse Events* (≥Grade 2) Reported in ≥2% of Subjects Treated with Fuzeon** (Pooled Studies T20-301/T20-302 at 48 Weeks)

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: glomerulonephritis; tubular necrosis; renal insufficiency; renal failure (including fatal cases)
• Blood and Lymphatic Disorders: thrombocytopenia; neutropenia; fever; lymphadenopathy
• Endocrine and Metabolic: hyperglycemia
• Infections: sepsis; herpes simplex
• Nervous System Disorders: taste disturbance; Guillain-Barre syndrome (fatal); sixth nerve palsy; peripheral neuropathy
• Cardiac Disorders: unstable angina pectoris
• Gastrointestinal Disorders: constipation; abdominal pain upper
• General: asthenia
• Hepatobiliary Disorders: toxic hepatitis; hepatic steatosis
• Investigations: increased amylase; increased lipase; increased AST; increased GGT; increased triglycerides
• Psychiatric Disorders: insomnia; depression; anxiety; suicide attempt
• Respiratory, Thoracic, and Mediastinal Disorders: pneumopathy; respiratory distress; cough
• Skin and Subcutaneous Tissue Disorders: pruritus

Laboratory Abnormalities

Table 4 shows the treatment-emergent laboratory abnormalities that occurred in at least 2 subjects per 100 patient-years and more frequently in those receiving Fuzeon+background regimen than background regimen alone from T20-301 and T20 302.

Table 4 : Treatment-Emergent Laboratory Abnormalities in ≥2% of Subjects Receiving Fuzeon* (Pooled Studies T20-301 and T20-302 at 48 Weeks)

Adverse Events In Pediatric Patients

• Fuzeon has been studied in 63 pediatric subjects 5 through 16 years of age with duration of Fuzeon exposure ranging from 1 dose to 134 weeks.
• Adverse experiences seen during clinical trials were similar to those observed in adult subjects, although infections at site of injection (cellulitis or abscess) were more frequent in adolescents than in adults, with 4 events occurring in 3 of 28 (11%) subjects.

Postmarketing Experience

The following adverse reaction has been identified during post approval use of Fuzeon. 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

• Cutaneous amyloidosis at the injection site.

• No Information provided