Fuzeon
(enfuvirtide)Dosage & Administration
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Fuzeon Prescribing Information
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.
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.
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)].
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 |
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.
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.
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.
Lyophilized powder for injection: 108 mg enfuvirtide per single-dose vial
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to antiretroviral medicines during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or fetal outcomes. Limited number of reports on the use of enfuvirtide during pregnancy has been submitted to the APR and the number of exposures to enfuvirtide is insufficient to make a risk assessment compared to a reference population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the U.S. general population is 15–20%.
In animal reproduction studies, no adverse developmental effects were observed with subcutaneous administration of enfuvirtide at exposures greater than or equal to approximately 2 times higher than human exposure at the recommended human dose (RHD) based on surface area (see Data).
Data
Animal Data
In the embryofetal development studies, enfuvirtide was administered by subcutaneous injection to pregnant rats at doses up to 500 mg/kg/day from gestation days 6 to 17, and to pregnant rabbits at doses up to 30 mg/kg/day from gestation days 6 to 18. No embryofetal toxicities were observed at doses up to the highest doses tested (27 times and 3.2 times higher than human exposure at the RHD in rats and rabbits, respectively, based on surface area).
In the pre/postnatal development study, enfuvirtide was administered by subcutaneous injection to pregnant rats at doses up to 30 mg/kg/day from gestation day 6 to postnatal day 20. No toxicities were observed at doses up to 30 mg/kg/day (1.6 times higher than human exposure at the RHD based on surface area).
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommends that HIV-1 infected mothers not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1.
There are no human data available regarding the presence of enfuvirtide or its metabolites (amino acids and peptide fragments) in human milk, the effects on the breastfed infant, or the effects on milk production. When enfuvirtide was administered to lactating rats, enfuvirtide was likely present in the milk (see Data).
Because of both the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breast-feed if they are receiving FUZEON.
Data
In a lactation study at doses of 200 mg/kg, very low levels of enfuvirtide or enfuvirtide metabolites (amino acids and peptide fragments) were excreted in milk following subcutaneous administration to lactating rats up to 48 hours post-dose on post-partum/lactation days 14 and 18.
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)].
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.
Hepatic Impairment
No dosage adjustments of FUZEON are needed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
Renal Impairment
No dosage adjustments of FUZEON are needed in patients with renal impairment [see Clinical Pharmacology (12.3)].
FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components [see Warnings and Precautions (5.4)].
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.
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.
Post-Injection Bleeding
Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.
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.
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.
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.
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.