Fuzeon

Included as part of the "PRECAUTIONS" Section

Mechanism Of Action

Enfuvirtide is an antiviral drug [see Microbiology].

Pharmacokinetics

The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.

Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ±1.5 µg/mL, AUC was 55.8 ±12.1 µg•h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ±15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ±1.7 µg/mL, Ctrough was 3.3 ±1.6 µg/mL, AUC0-12h was 48.7 ±19.1 µg•h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).

Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.

The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ±1.1 L.

Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 µg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.

The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIVinfected subjects were below the limit of quantification (0.025 μg/mL).

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.

Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.

Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ±0.6 h and the mean ±SD apparent clearance was 24.8 ±4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ±10.6 mL/h/kg.

Special Populations

Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 – 35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.

No dose adjustment is recommended for patients with impaired renal function.

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.

Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.

No dose adjustment is recommended for weight or gender.

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.

The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.

In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 µg•h/mL, Cmax was 6.3 ±2.4 µg/mL, Ctrough was 3.1 ±1.5 µg/mL, and apparent clearance was 40 ±17 mL/h/kg [see Use In Specific Populations].

The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.

Drug Interactions

See also DRUG INTERACTIONS

Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.

Table 5 Effect of Ritonavir, Saquinavir/Ritonavir, and Rifampin on the Steady-State Pharmacokinetics of Enfuvirtide (90 mg bid)*

Microbiology

Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

The antiviral activity of enfuvirtide was assessed by infecting different CD4 cell types with laboratory and clinical isolates of HIV-1. The median EC50 value for baseline clinical isolates was 4.10 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 55.9 nM (1.56 to 1675 nM; 7 to 7526 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, F, and G (median EC50 value was 7.01 nM; range 3.78 to 27.9 nM; 17-126 ng/mL), and R5, X4, and dual tropic viruses. Enfuvirtide has no activity against HIV-2.

Enfuvirtide exhibited additive to synergistic effects in cell culture assays when combined with individual members of various antiretroviral classes, including lamivudine, zidovudine, indinavir, nelfinavir, and efavirenz.

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in cell culture. Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36 to 38 of the HIV-1 envelope glycoprotein gp41. Phenotypic analysis of site-directed mutants in positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide.

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing a FUZEON containing regimen. Posttreatment HIV-1 virus from 277 subjects experiencing protocol defined virological failure at 48 weeks exhibited a median decrease in susceptibility to enfuvirtide of 33.4-fold (range 0.4-6318-fold) relative to their respective baseline virus. Of these, 249 had decreases in susceptibility to enfuvirtide of greater than 4-fold and all but 3 of those 249 exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45. Mutations or polymorphisms in other regions of the envelope (e.g., the HR2 region or those yet to be identified) as well as co-receptor usage and density may affect susceptibility to enfuvirtide.

HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) were susceptible to enfuvirtide in cell culture.

Clinical Studies

Description Of Clinical Studies

T20-301 and T20-302 were randomized, controlled, open-label, multicenter trials in HIV-1 infected subjects. Subjects were required to have either (1) viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) or (2) viremia and documented resistance or intolerance to at least one member in each of the NRTI, NNRTI, and PI classes.

All subjects received an individualized background regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were then randomized at a 2:1 ratio to FUZEON 90 mg twice daily with background regimen or background regimen alone.

After week 8, subjects on either treatment arm who met protocol defined criteria for virological failure were permitted to revise their background regimens; those on background regimen alone were also permitted to add FUZEON.

Demographic characteristics for studies T20-301 and T20-302 are shown in Table 6. Subjects had prior exposure to a median of 12 antiretrovirals for a median of 7 years.

Table 6 T20-301 and T20-302 Pooled Subject Demographics

The disposition and efficacy outcomes of T20-301 and T20-302 are shown in Table 7.

Table 7 Outcomes at Week 48 (Pooled Studies T20-301 and T20-302)

At 48 weeks, 154 (23%) of subjects in the FUZEON+background regimen and 27 (8%) in the background regimen alone had HIV-1 RNA levels <50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background regimen had HIV-1 RNA levels <400 copies/mL compared to 44 (13%) in the background regimen alone. Subjects achieving HIV-1 RNA levels <50 copies/mL were included in the <400 copies/mL category and both categories were incorporated in the overall virologic responder category of achieving HIV-1 RNA at least 1 log10 below baseline.

The mean log change in HIV-1 RNA from baseline was -1.4 log10 copies/mL in subjects receiving FUZEON+background and -0.5 in those receiving background alone. The mean change in CD4 cell count from baseline to week 48 was +91 cells/mm3 in the FUZEON+background arm and +45 cells/mm3 in the background alone arm.

Subjects in the FUZEON+background arm achieved a better virologic and immunologic outcome than subjects in the background alone arm across all subgroups based on baseline CD4 cell count, baseline HIV-1 RNA, number of prior ARVs or number of active ARVs in the background regimen.

Fuzeon is a prescription medication used to treat human immunodeficiency virus (HIV). It is always used in combination with other medications. Fuzeon belongs to a group of drugs called HIV fusion inhibitors. It works by stopping HIV from entering human cells. HIV must enter human cells in order to replicate.

This medication comes in an injectable form. It is injected just under the skin of the upper arm, stomach area, or thigh, twice daily.

Common side effects of Fuzeon include redness, pain, and other effects at the injection site. Other common side effects include weight loss, sinus infection and dizziness. Do not drive a car or operate machinery until you know how this medication affects you.

• Roche Pharmaceuticals

Tell your healthcare provider about all the medicines you use, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fuzeon has not been tested with all medicines. 

Fuzeon does not affect other anti-HIV medicines or the medicine rifampin (also known as rifampicin, Rifadin or Rimactane). You can take Fuzeon at the same times or at different times than your other anti-HIV medicines.

If you take too much Fuzeon, call your healthcare provider right away or seek emergency medical attention.

For all patients taking this medicine:

• Tell all of your health care providers that you take Fuzeon. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Do not run out of Fuzeon.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you smoke, talk with your doctor.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• This medicine is not a cure for HIV. Stay under the care of your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

Children:

• If giving to your child, the dose of Fuzeon may need to be changed as your child's weight changes. Have your child's weight checked often. Talk with the doctor before changing your child's dose.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Keep taking Fuzeon as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of this medicine during treatment.
• It is given as a shot into the fatty part of the skin on the top of the thigh, belly area, or upper arm.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• If solution is foamy or jelly-like, wait before using.
• Move the site where you give the shot with each shot.
• Do not give into red or irritated skin.
• Do not give into a mole, scar, or bruise.
• Wash your hands before and after use.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Lyophilized powder for injection: 108 mg enfuvirtide per vial

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

• Administration with Biojector® 2000 [see Warnings and Precautions (5.2)]
• Pneumonia [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

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.

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.

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.

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 postapproval 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.

How Supplied

Fuzeon (enfuvirtide) for Injection is a white to off-white, sterile, lyophilized powder and it is packaged in a single-use clear glass vial containing 108 mg of enfuvirtide for the delivery of approximately 90 mg/1 mL when reconstituted with 1 mL of Sterile Water for Injection.

Fuzeon is available in a Convenience Kit containing 60 single-use vials of Fuzeon (90 mg strength), 60 vials (2 cartons of 30 each) of Sterile Water for Injection (1 mL per vial), 60 reconstitution syringes (3 cc), 60 administration syringes (1 cc), Package Insert, Patient Package Insert, and Injection Instructions (NDC 0004-0381-40).

Storage Conditions

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Reconstituted solution should be stored in the original vial under refrigeration at 2° to 8°C (36° to 46°F) and used within 24 hours.

You should not use Fuzeon if you are allergic to enfuvirtide.

Before using Fuzeon, tell your doctor if you have a bleeding or blood clotting disorder (such as hemophilia), or a history of breathing problems.

Do not use Fuzeon as your only medication to treat HIV. Fuzeon must be used in combination with other HIV medications. Your disease may become resistant to Fuzeon if you do not use it in combination with other medicines your doctor has prescribed. Most people using this medication have a skin reaction (itching, redness, swelling, pain, bruising, tenderness) where the medicine is injected. Call your doctor if these symptoms get worse or last longer than 7 days.

To best treat your condition, use all of your medications as directed by your doctor. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor. Your blood will need to be tested often. Visit your doctor regularly.

Stop using Fuzeon and call your doctor at once if you have a serious side effect such as fever, cough with yellow or green mucus, stabbing chest pain, wheezing, trouble breathing, sore throat, flu symptoms, swollen glands, easy bruising or bleeding, mouth sores, severe pain in your upper stomach, ongoing nerve pain or tingly feeling, signs of infection such as swelling or oozing where an injection was given.

Having HIV makes it easier for you to get other infections, and some people using Fuzeon have developed pneumonia. It is not clear whether Fuzeon is the actual cause of pneumonia but it may increase your risk. You may also be more likely to have pneumonia if you smoke, if you have ever had lung disease, or if you have a history of intravenous (IV) drug use.

Get emergency medical help if you have any of these signs of an allergic reaction to Fuzeon: skin rash or hives; fever with vomiting; blood in your urine; difficulty breathing; fainting; swelling of your feet, face, lips, tongue, or throat.

Stop using Fuzeon and call your doctor at once if you have any of these serious side effects:

• fever, chills, chest congestion, cough with yellow or green mucus, stabbing chest pain, wheezing, feeling short of breath;

• signs of a new infection such as sore throat, flu symptoms, swollen glands, easy bruising or bleeding (bleeding from your nose or gums), loss of appetite, mouth sores;

• severe pain in your upper stomach spreading to your back, nausea and vomiting;

• rapid heart rate, increased sweating, tremors, feeling anxious or irritable;

• diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;

• swelling in your neck or throat (enlarged thyroid);

• problems with balance or eye movement, trouble speaking or swallowing;

• severe lower back pain, loss of bladder or bowel control;

• weakness or prickly feeling in your fingers or toes, tingling or nerve pain lasting for several weeks or months; or

• pain, warmth, swelling, oozing, or redness where an injection was given, especially if these symptoms get worse or last longer than 7 days.

Less serious Fuzeon side effects may include:

• constipation;

• itching, irritation, mild redness, mild swelling, or raised bumps under your skin where the medicine was injected;

• pain or numbness in your feet or legs;

• tired feeling, muscle weakness or loss of strength;

• muscle pain;

• runny or stuffy nose;

• sleep problems (insomnia); or

• depression.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.