Drug Detail:Fuzeon (Enfuvirtide [ en-fyoo-vir-tide ])
Drug Class: Miscellaneous antivirals
Highlights of Prescribing Information
FUZEON® (enfuvirtide) for Injection
Initial U.S. Approval: 2003
Indications and Usage for Fuzeon
FUZEON is an HIV-1 gp41 fusion inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with HIV-1 replication despite ongoing antiretroviral therapy. (1)
Fuzeon Dosage and Administration
- Adults: Recommended dosage of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen. (2.2)
- Pediatric Patients (weighing at least 11kg): Recommended dose of 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously. Weight should be monitored periodically and the FUZEON dose should be adjusted accordingly. (2.3)
- FUZEON must only be reconstituted with 1 mL of Sterile Water for Injection provided in the Convenience Kit. (2.4)
- Reconstituted FUZEON must be injected immediately or kept refrigerated in the original vial. It must be used within 24 hours. (2.4)
Dosage Forms and Strengths
- Lyophilized powder: 108 mg of enfuvirtide per single-dose vial. (3)
Contraindications
- Hypersensitivity to FUZEON or any of its components. (4)
Warnings and Precautions
- Injection Site Reaction: 98% of subjects experienced at least one injection site reaction during FUZEON treatment in randomized, controlled, open-label, multicenter trials. Manifestations included pain and discomfort, erythema, nodules and cysts, and ecchymosis. (5.1)
- Biojector® 2000: Administration of FUZEON with Biojector 2000 may result in neuralgia and/or paresthesia, bruising and hematomas. (5.2)
- Post-Injection Bleeding: Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding. (5.3)
- Hypersensitivity: FUZEON should be discontinued immediately upon signs and symptoms of systemic hypersensitivity reactions. (5.4)
- Pneumonia: Monitor for signs and symptoms of pneumonia in HIV-infected patients, especially those predisposed to pneumonia (e.g., low initial CD4 cell count). (5.5)
- Immune Reconstitution: Patients treated with combination antiretroviral therapy, including FUZEON, may experience immune reconstitution syndrome requiring further evaluation and treatment. (5.7)
Adverse Reactions/Side Effects
Most common adverse reactions are local injection site reactions, diarrhea, nausea, and fatigue. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Use In Specific Populations
- Lactation: Breastfeeding is not recommended due to risk of HIV-1 transmission. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 12/2019
Full Prescribing Information
1. Indications and Usage for Fuzeon
FUZEON® in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
2. Fuzeon Dosage and Administration
2.1 General Dosing Information
FUZEON is available in a single-dose lyophilized powder for injection containing 108 mg enfuvirtide per vial.
FUZEON is administered subcutaneously into the upper arm, anterior thigh or abdomen after reconstituting the lyophilized powder containing 108 mg enfuvirtide with 1 mL of Sterile Water for Injection [see Dosage and Administration (2.5)]. Patients should contact their healthcare provider for any questions regarding the administration of FUZEON by calling the toll-free number 1-877-4-FUZEON (1-877-438-9366) or visiting the FUZEON website, www.FUZEON.com.
2.2 Recommended Dosage for Adults
The recommended dosage of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen [see Dosage and Administration (2.5 and 2.6)].
2.3 Recommended Dosage for Pediatric Patients
The recommended dosage of FUZEON in pediatric patients weighing at least 11 kg is 2 mg per kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen [see Dosage and Administration (2.5 and 2.6) and Use in Specific Populations (8.4)]. Table 1 contains dosing recommendations for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.
| Weight | Recommended Daily Dosage (mg) | Injection Volume (mL) |
|---|---|---|
| Kilograms (kg) | ||
| 11.0 to 15.5 | 27 mg twice daily | 0.3 mL twice daily |
| 15.6 to 20.0 | 36 mg twice daily | 0.4 mL twice daily |
| 20.1 to 24.5 | 45 mg twice daily | 0.5 mL twice daily |
| 24.6 to 29.0 | 54 mg twice daily | 0.6 mL twice daily |
| 29.1 to 33.5 | 63 mg twice daily | 0.7 mL twice daily |
| 33.6 to 38.0 | 72 mg twice daily | 0.8 mL twice daily |
| 38.1 to 42.5 | 81 mg twice daily | 0.9 mL twice daily |
| ≥42.6 | 90 mg twice daily | 1.0 mL twice daily |
2.4 Preparation
FUZEON for injection can be administered by patients after training by medical professional using aseptic technique. Refer patients to FUZEON Injection Instructions for step by step instructions during self-administration.
A vial is suitable for single-dose only; unused portions must be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Patients should return product to pharmacy if there is evidence of particulate matter after mixing FUZEON with sterile water as described below.
- Remove the flip-off cap from the single-dose Sterile Water for Injection vile and from the FUZEON vial.
- Wipe each vial with a new sterile alcohol swab and let the tops air-dry.
- Using the 3 mL (large) syringe with the plunger pulled back to the 1 mL mark, slowly inject the air into the sterile water vial.
- Insert sterile syringe needle into the vial through the center of the stopper.
- Turn the vial upside down and draw 1 mL of the sterile water into the syringe then remove the needle and syringe from the vial.
- Insert the syringe with sterile water into the FUZEON vial at an angle.
- Inject the sterile water slowly, so that it drips down the side of the vial into the FUZEON powder.
- Never shake the vial but gently tap the FUZEON vial with fingertip for 10 seconds to start dissolving the powder.
- Then gently roll the FUZEON vial between hands to reduce the mixing time, making sure no FUZEON is stuck to the vial wall.
- Once the powder starts to dissolve, just set it aside and it will completely dissolve; it could take up to 45 minutes for the powder to completely dissolve and become a solution.
- When completely mixed, the FUZEON solution should be clear, colorless and without bubbles or particulate matter. If the FUZEON is foamy or jelled, allow more time for it to dissolve.
FUZEON contains no preservatives. Once reconstituted, FUZEON should be injected immediately or kept refrigerated in the original vial until use. Reconstituted FUZEON must be used within 24 hours. Refrigerated reconstituted solution should be brought to room temperature before injection and the vial should be inspected visually again to ensure that the contents are fully dissolved in solution and that the solution is clear, colorless, and without bubbles or particulate matter.
The subsequent dose of FUZEON can be reconstituted in advance but must be stored in the refrigerator in the original vial and used within 24 hours.
2.5 Assessment Prior to Administration
Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose.
Do not inject FUZEON:
- Near anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks.
- Directly over or near skin abnormalities such as moles, scar tissue, bruises, surgical scars, tattoos or burn sites.
- Directly over a blood vessel.
- Near the naval.
2.6 Administration
- Clean the injection site with a new sterile alcohol pad.
- Clean the FUZEON vial top again, using a new sterile alcohol pad.
- Using the 1 mL (small) syringe with plunger pulled back to 1 mL, insert the syringe with needle into the vial FUZEON solution.
- Before turning the vial upside down, slowly inject the air into the FUZEON.
- Gently turn the vial upside down and slowly pull the plunger to get 1 mL of FUZEON solution and remove the needle and syringe from the vial.
- Pinch and hold a fold of skin around the injection site and pierce the skin. The needle should be inserted most of the way in. Slowly push the plunger all the way to inject FUZEON.
- Remove the needle from the injection site.
- Instruct patients how to safely discard the syringe and needle.
- Cover the injection site with a small bandage if needed.
3. Dosage Forms and Strengths
Lyophilized powder for injection: 108 mg enfuvirtide per single-dose vial
4. Contraindications
FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components [see Warnings and Precautions (5.4)].
5. Warnings and Precautions
5.1 Local Injection Site Reactions (ISRs)
The majority of subjects (98%) receiving FUZEON in randomized, controlled, open-label, multicenter clinical trials had at least one local injection site reaction; ISRs occurred throughout treatment with FUZEON. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis [see Adverse Reactions (6)]. Reactions are often present at more than one injection site. Patients must be familiar with the FUZEON Injection Instructions in order to know how to inject FUZEON appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.
5.2 Administration with Biojector® 2000
Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON.
5.3 Post-Injection Bleeding
Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.
5.4 Hypersensitivity Reactions
Systemic hypersensitivity reactions have been associated with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions have occurred in <1% of subjects studied and have included combinations of: rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving FUZEON include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue FUZEON and should seek medical evaluation immediately. Therapy with FUZEON should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to FUZEON have not been identified.
5.5 Pneumonia
An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm. The incidence of pneumonia was 2.7% or 3.2 events/100 patient-years in subjects receiving FUZEON+background regimen. On analysis of all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) in T20-301 and T20-302, an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. Three subject deaths in the FUZEON arm were attributed to pneumonia; all three had serious concomitant AIDS-related illnesses that contributed to their deaths. 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.
Because it was unclear whether the higher incidence rate of pneumonia was related to FUZEON use, an observational study in 1850 HIV-infected patients (740 FUZEON treated patients and 1110 non-FUZEON treated patients) was conducted to evaluate the risk of pneumonia in patients treated with FUZEON. A total of 123 patients had a confirmed or probable pneumonia event in this study (62 in the FUZEON treatment arm with 1962 patient-years of observation and 61 in the non-FUZEON treatment arm with 3378 patient-years of observation). The incidence of pneumonia was 3.2 events/100 patient-years in the FUZEON treatment arm and 1.8 events/100 patient-years in the non-FUZEON treatment arm. The hazard ratio, adjusting for other baseline risk factors, was 1.34 (95% C.I. = 0.90 – 2.00). Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with FUZEON compared to non-FUZEON treated patients.
It is unclear if the increased incidence of pneumonia is related to FUZEON use. However, because of these findings, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
5.6 Non-HIV Infected Individuals
There is a theoretical risk that FUZEON use may lead to the production of anti-enfuvirtide antibodies which cross react with HIV gp41. This could result in a false positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. FUZEON has not been studied in non-HIV infected individuals.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FUZEON. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP] or tuberculosis), 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.
6. Adverse Reactions/Side Effects
The following adverse reactions are discussed in greater detail in other sections:
- Administration with Biojector® 2000 [see Warnings and Precautions (5.2)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
- Pneumonia [see Warnings and Precautions (5.5)]
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 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.
| N=663 | |||
|---|---|---|---|
| Event Category | Any Severity Grade | % of Subjects with Grade 3 Reactions | % of Subjects with Grade 4 Reactions |
|
|||
| Pain/Discomfort * | 96% | 11% | 0% |
| Induration | 90% | 39% >25 but <50 mm | 18% ≥50 mm |
| Erythema | 91% | 22% >50 but <85 mm | 10% ≥85 mm |
| Nodules and Cysts | 80% | 23% >3 cm average diameter | 0.2% Draining |
| Pruritus † | 65% | 3% | NA |
| Ecchymosis | 52% | 5% >3 but ≤5 cm | 2% >5 cm |
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.
| Adverse Event (by System Organ Class) | FUZEON+Background Regimen (N=663) | FUZEON+Background Regimen (N=663) | Background Regimen (N=334) |
|---|---|---|---|
| 663 subjects total | 557 total patient-years | 162 total patient-years | |
| % frequency | rate/100 patient-years | rate/100 patient-years | |
|
|||
| Weight Decreased | 6.6% | 7.9 | 6.2 |
| Sinusitis | 6.0% | 7.2 | 4.9 |
| Abdominal Pain | 3.9% | 4.7 | 3.7 |
| Cough | 3.9% | 4.7 | 2.5 |
| Herpes Simplex | 3.5% | 4.1 | 3.7 |
| Appetite Decreased | 3.2% | 3.8 | 2.5 |
| Pancreatitis | 3.0% | 3.6 | 2.5 |
| Pain in Limb | 2.9% | 3.4 | 3.1 |
| Pneumonia (see text below) | 2.7% | 3.2 | 0.6 |
| Myalgia | 2.7% | 3.2 | 1.2 |
| Influenza-Like Illness | 2.4% | 2.9 | 1.9 |
| Folliculitis | 2.4% | 2.9 | 2.5 |
| Anorexia | 2.3% | 2.7 | 1.9 |
| Dry Mouth | 2.1% | 2.5 | 1.9 |
| Conjunctivitis | 2.0% | 2.3 | 1.9 |
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.
| Laboratory Parameters | Grading | FUZEON+Background Regimen (N=663) | FUZEON+Background Regimen (N=663) | Background Regimen (N=334) |
|---|---|---|---|---|
| 663 subjects total | 557 total patient-years | 162 total patient-years | ||
| % frequency | rate/100 patient-years | rate/100 patient-years | ||
|
||||
| Eosinophilia | ||||
| 1-2 × ULN (0.7 × 109/L) | 0.7-1.4 × 109/L | 9.1% | 10.8 | 3.7 |
| >2 × ULN (0.7 × 109/L) | >1.4 × 109/L | 1.8% | 2.2 | 1.8 |
| ALT | ||||
| Grade 3 | >5-10 × ULN | 4.1% | 4.8 | 4.3 |
| Grade 4 | >10 × ULN | 1.2% | 1.4 | 1.2 |
| Creatine Phosphokinase (U/L) | ||||
| Grade 3 | >5-10 × ULN | 6.9% | 8.3 | 8.0 |
| Grade 4 | >10 × ULN | 2.6% | 3.1 | 8.6 |
6.2 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.
8. Use In Specific Populations
8.4 Pediatric Use
Use of FUZEON in pediatric patients weighing at least 11kg is supported by evidence from adequate and well-controlled studies of FUZEON in adult and by two pediatric studies evaluating the safety, pharmacokinetics and efficacy of FUZEON in subjects 6 years of age and older:
- T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in 11, treatment-experienced pediatric subjects 6 to 12 years (median age of 9 years) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
- T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in 52, treatment-experienced pediatric subjects 5 years and older (median age of 12 years) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
Overall, the adverse experiences, including ISRs in the 63 pediatric subjects 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 [see Adverse Reactions (6.1)].
8.5 Geriatric Use
Clinical studies of FUZEON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of FUZEON in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
10. Overdosage
There are no reports of human experience of acute overdose with FUZEON. The highest dose administered to 12 subjects in a clinical trial was 180 mg as a single-dose subcutaneously. There is no specific antidote for overdose with FUZEON. Treatment of overdose should consist of general supportive measures.
11. Fuzeon Description
FUZEON (enfuvirtide) is an inhibitor of the fusion of HIV-1 with CD4 cells. Enfuvirtide is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide. It is composed of naturally occurring L-amino acid residues.
Enfuvirtide is a white to off-white amorphous solid. It has negligible solubility in pure water and the solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL. The empirical formula of enfuvirtide is C204H301N51O64, and the molecular weight is 4492. It has the following primary amino acid sequence:
CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 and the following structural formula:
The drug product, FUZEON (enfuvirtide) for Injection, is a white to off-white, sterile, lyophilized powder. Each single-dose vial contains 108 mg of enfuvirtide for the delivery of 90 mg. Prior to subcutaneous administration, the contents of the vial are reconstituted with 1 mL of Sterile Water for Injection to provide the delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution contains approximately 90 mg of enfuvirtide with approximate amounts of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium carbonate (anhydrous), and sodium hydroxide and hydrochloric acid for pH adjustment as needed. The reconstituted solution has an approximate pH of 9.0.
12. Fuzeon - Clinical Pharmacology
12.3 Pharmacokinetics
The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.
Specific Populations
No clinically significant changes in pharmacokinetics have been observed based on renal impairment (any degree of renal impairment, including hemodialysis), gender, adult weight, or race.
Pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment or subjects over 65 years of age.
Drug Interaction Studies
Based on the results from an in vitro human microsomal study, enfuvirtide is not an inhibitor of CYP450 enzymes. In an in vivo human metabolism study (N=12), FUZEON at the recommended dose of 90 mg twice daily did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates.
Based on the available data, co-administration of FUZEON and other drugs which are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide. No dose adjustments are needed when FUZEON is co-administered with other antiretroviral and non-antiretroviral drugs.
Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.
| Coadministered Drug | Dose of Coadministered Drug | N | % Change of Enfuvirtide Pharmacokinetic Parameters†‡ (90% CI) | ||
|---|---|---|---|---|---|
| Cmax | AUC | Ctrough | |||
|
|||||
| Ritonavir | 200 mg, q12h, 4 days | 12 | ↑24 (↑9 to ↑41) | ↑22 (↑8 to ↑37) | ↑14 (↑2 to ↑28) |
| Saquinavir/Ritonavir | 1000/100 mg, q12h, 4 days | 12 | ⇔ | ↑14 (↑5 to ↑24) | ↑26 (↑17 to↑35) |
| Rifampin | 600 mg, qd, 10 days | 12 | ⇔ | ⇔ | ↓15 (↓22 to ↓7) |
14. Clinical Studies
14.1 Antiretroviral-experienced Adult Subjects
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.
| FUZEON+Background Regimen N=663 | Background Regimen N=334 |
|
|---|---|---|
| Sex | ||
| Male | 90% | 90% |
| Female | 10% | 10% |
| Race | ||
| White | 89% | 89% |
| Black | 8% | 7% |
| Mean Age (yr) (range) | 42 (16-67) | 43 (24-82) |
| Median Baseline HIV-1 RNA (log10 copies/mL) (range) | 5.2 (3.5-6.7) | 5.1 (3.7-7.1) |
| Median Baseline CD4 Cell Count (cells/mm3) (range) | 89 (1-994) | 97 (1-847) |
The disposition and efficacy outcomes of T20-301 and T20-302 are shown in Table 7.
|
|||
| Outcomes | FUZEON+Background Regimen 90 mg bid N=663 | Background Regimen N=334 |
|
| Virological Responder (at least 1 log10 below baseline) | 304 (46%) | 61 (18%) | |
| Virological Non-responder: | |||
| 0 | 220 (66%) | |
| 191 (29%) | 12 (4%) | |
| Continued Background Regimen (N=112) | Switched to FUZEON (N=220) |
||
| Discontinued due to insufficient treatment response† | 37 (5%) | 13 (12%) | 22 (10%) |
| Discontinued due to adverse reactions/intercurrent illness/labs | 46 (7%) | 9 (8%) | 13 (6%) |
| Deaths | 15 (2%) | 5 (4%) | 2 (1%) |
| Discontinued due to injection: | |||
| 27 (4%) | NA | 10 (5%) |
| 18 (3%) | NA | 2 (1%) |
| Discontinued due to other reasons§ | 25 (4%) | 14 (13%) | 6 (3%) |
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.
14.2 Treatment-experienced Pediatric Subjects
Sixty-three HIV-1 infected pediatric subjects ages 5 through 16 years have received FUZEON in two open-label, single-arm clinical trials.
T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 495 cells/µL and the median baseline HIV-1 RNA was 4.6 log10 copies/mL.
Ten of the 11 study subjects completed 48 weeks of chronic therapy. At week 48, 6/11 (55%) subjects had ≥1 log10 decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.48 log10 copies/mL and +122 cells/µL, respectively.
T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Fifty-two subjects from 5 through 16 years were enrolled (median age of 12 years). Median baseline CD4 cell count was 117 cells/µL and the median baseline HIV-1 RNA was 5.0 log10 copies/mL.
Thirty-two of the 52 study subjects completed 48 weeks of chronic therapy. At week 48, 17/52 (33%) of subjects had ≥1 log10 decline in HIV-1 RNA, 11/52 (21%) of subjects were below 400 copies/mL of HIV-1 RNA and 5/52 (10%) were below 50 copies/mL. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.17 log10 copies/mL and +106 cells/µL, respectively.
17. Patient Counseling Information
See FDA-Approved Patient Labeling (Patient Information, Instructions for Use)
To assure safe and effective use of FUZEON, the following information and instructions should be given to patients:
Patient Information
FUZEON® (few'-zee-on)
(enfuvirtide) Injection
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: 12/2019 | ||||
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What is FUZEON? FUZEON is a prescription medicine used in combination with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in people who have taken other antiretroviral medicines and whose HIV-1 levels have continued to increase while on treatment. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if FUZEON is safe and effective for use in children under 6 years of age. |
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Do not use FUZEON if you are allergic to enfuvirtide or any of the ingredients in FUZEON. See the end of this leaflet for a complete list of ingredients in FUZEON. |
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Before using FUZEON, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take medicines that affect blood clotting. Some medicines interact with FUZEON. Keep a list of your medicines to show to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with FUZEON. Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to use FUZEON with other medicines. |
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How should I use FUZEON?
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What should I avoid while using FUZEON?
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What are the possible side effects of FUZEON? FUZEON may cause serious side effects, including:
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The most common side effects of FUZEON include: |
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These are not all the possible side effects of FUZEON. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store FUZEON?
Keep FUZEON and all medicines out of the reach of children. |
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General information about the safe and effective use of FUZEON Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FUZEON for a condition for which it was not prescribed. Do not give FUZEON to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about FUZEON that is written for health professionals. What are the ingredients in FUZEON? Active ingredient: enfuvirtide Inactive ingredients: mannitol, sodium carbonate, sodium hydroxide, and hydrochloric acid Distributed by: © 2019 Genentech, Inc. and Alexion Pharmaceuticals, Inc. All rights reserved. FUZEON is a trademark of Hoffmann-La Roche Inc. FUZEON has been jointly developed by Alexion Pharmaceuticals, Inc. and Hoffmann-La Roche Inc. FUZEON is manufactured by Hoffmann-La Roche Inc. More information go to www.FUZEON.com or call 1-877-438-9366. |
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Instructions for Use
FUZEON™ (few'-zee-on)
(enfuvirtide)
Injection, for subcutaneous use
108 mg vial
1 Before You Begin
Important Information:
- Your healthcare provider should show you how to prepare and inject FUZEON before you inject it for the first time. Do not inject yourself or someone else until you have been shown how to inject FUZEON the right way.
- Call your healthcare provider if you have any questions about how to inject FUZEON the right way. You may also call 1-877-438-9366 or visit www.FUZEON.com.
- Do not reuse or share syringes or needles with other people. You may give other people a serious infection or get a serious infection from them.
- The instructions below are for mixing a single dose. If you want to mix 2 doses at the same time you will need 2 vials of FUZEON, 2 vials of sterile water, new sterile alcohol pads and syringes.
How should I store FUZEON?
- Store FUZEON vials that have not been mixed with sterile water at room temperature between 68°F to 77°F (20°C to 25°C).
- Store FUZEON that has been mixed with sterile water in the original vial and in the refrigerator between 36°F to 46°F (2°C to 8°C) for up to 24 hours. Throw away (discard) any unused FUZEON left in the vial after 24 hours.
- Keep FUZEON and all medicines out of the reach of children.
2 Getting Started
| Gather Supplies:
Supplies you will need to give your FUZEON injection:
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3 Prepare Your FUZEON Dose
- Check the expiration date printed on the FUZEON vial label.
- Check to make sure that none of the items in your kit have been opened.
- Check that the FUZEON vial is not cracked or damaged.
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Do not use the FUZEON vial, properly throw it away and get a new one if:
- the expiration date printed on the FUZEON vial label has passed
- the items in your FUZEON kit have been opened
- the FUZEON vial is cracked or damaged
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Step 2:
The safety syringes have a green colored piece of plastic that is attached to the needle. This piece of plastic is a safety feature that covers the needle after use. Your healthcare provider may recommend other types of syringes for use with FUZEON. Step 3:
|  *The measuring line of the syringe is the edge line of the plunger closest to the needle. |
Step 4:
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4 Mixing FUZEON
- Do not mix FUZEON with tap water. Use only the sterile water provided to mix FUZEON.
- Do not mix anything or any other medicine in the same syringe as FUZEON.
- Do not touch the needle when holding the syringe. If you touch the needle, you will need to start over with a new syringe. If you run out of syringes, call your pharmacy.
- To save time, you can mix both of your daily doses of FUZEON at the same time, but you will need to keep the second vial of mixed FUZEON in the refrigerator. Write the date and time on the vial when mixed if you are mixing the dose to be used later.
- Before using the dose of refrigerated FUZEON, be sure it is clear and allow it to warm to room temperature. You may want to hold it in your hand to help bring it to room temperature before you inject it. Do not microwave the vial or put it in hot water.
- Do not store mixed FUZEON in the syringe.
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5 Choose and prepare your injection site
- Inject FUZEON exactly as your healthcare provider has shown you.
- Inject FUZEON just under the skin (subcutaneous). FUZEON should never be given directly into your veins (intravenous) or directly into your muscle (intramuscular).
- You should change (rotate) your injection site with each injection. Do not use the same injection site 2 times in a row.
- Talk with your healthcare provider if you have any questions about where on your body to inject FUZEON.
Step 14:
|  Abdomen |  Upper Thighs |  Upper Arms |
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6 Inject FUZEON
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Dispose of (throw away) your used FUZEON needle and syringe:
- Put your used FUZEON needle and syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) your FUZEON needle and syringe in your household trash.
- If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
- made of a heavy-duty plastic,
- can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
- upright and stable during use,
- leak-resistant,
- properly labeled to warn of hazardous waste inside the container.
- When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: www.fda.gov/safesharpsdisposal
- Do not recycle your used sharps disposal container.
Rx only
FUZEON has been jointly developed by Alexion Pharmaceuticals, Inc. and Hoffmann-La Roche Inc.
FUZEON is manufactured by Hoffmann-La Roche Inc.
Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080
© 2019 Genentech, Inc. and Alexion Pharmaceuticals, Inc. All rights reserved.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: 12/2019
| FUZEON
enfuvirtide kit |
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| Labeler - Genentech, Inc. (080129000) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| F. Hoffmann-La Roche Ltd | 485244961 | ANALYSIS(0004-0381) , LABEL(0004-0381) , PACK(0004-0381) | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Roche Diagnostics GmbH | 315028860 | ANALYSIS(0004-0381) , MANUFACTURE(0004-0381) | |
