Fuzeon

HIV-1 Entry Inhibitors/Fusion Inhibitors

For storage information, see specific product information within the How Supplied section.

Injections may be self-administered after training by a medical professional using aseptic technique. For any questions regarding drug administration, instruct patients to contact a healthcare provider by calling 1-877-438-9366 or visiting the FUZEON website.
Patients should be made fully aware of the high incidence of injection site reactions before initiating therapy. They should be taught to recognize the signs and symptoms of injection site reactions and instructed when to contact their healthcare provider about these reactions.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.[32924]

Reconstitution
Reconstitute vial with 1 mL of Sterile Water for Injection for a resultant concentration of 90 mg/mL.
DO NOT shake the vial, but gently tap the vial for 10 seconds to start dissolving the powder. Gently roll the vial between the hands to reduce the mixing time and to ensure all drug particles are in contact with the diluent with no drug remaining on the vial wall. Then, allow the vial to stand until the powder goes completely into solution; this could take up to 45 minutes.
The reconstituted solution should be clear and colorless, without bubbles or particulate matter. If the product is foamy or jelled, allow more time for it to dissolve.
Storage: Once reconstituted, inject the solution immediately or refrigerate in the original vial for up to 24 hours.
Bring the refrigerated reconstituted solution to room temperature before injection, then inspect again to ensure the contents are fully dissolved and the solution is clear and colorless without bubbles or particulate matter.[32924]
 
Subcutaneous Injection
Administer by subcutaneous injection in the upper arm, abdomen, or anterior thigh at a site different from the preceding injection site and only where there is no current injection site reaction.
Avoid the following injection sites: anatomical areas near where large nerves course close to the skin (e.g., elbow, knee, groin, inferior or medial sections of the buttocks), near skin abnormalities (e.g., moles, scar tissue, bruises, tattoos, burn sites), over blood vessels, or near the navel.[32924]
To minimize local reactions, apply ice or heat after injection or gently massage injection site to better disperse the dose.[42452]

pancreatitis / Delayed / 3.0-3.0
acute respiratory distress syndrome (ARDS) / Early / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
glomerulonephritis / Delayed / 0-1.0
cranial nerve palsies / Delayed / Incidence not known
suicidal ideation / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known

erythema / Early / 91.0-91.0
eosinophilia / Delayed / 1.8-9.1
elevated hepatic enzymes / Delayed / 1.2-4.1
conjunctivitis / Delayed / 2.0-2.0
dyspnea / Early / 0-1.0
peripheral edema / Delayed / 0-1.0
hematuria / Delayed / 0-1.0
hypotension / Rapid / 0-1.0
hematoma / Early / Incidence not known
constipation / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
depression / Delayed / Incidence not known
antibody formation / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
cutaneous amyloidosis / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
angina / Early / Incidence not known
hepatitis / Delayed / Incidence not known
steatosis / Delayed / Incidence not known

injection site reaction / Rapid / 98.0-98.0
pruritus / Rapid / 65.0-65.0
ecchymosis / Delayed / 52.0-52.0
diarrhea / Early / 31.7-31.7
nausea / Early / 22.8-22.8
fatigue / Early / 20.2-20.2
infection / Delayed / 2.7-6.9
weight loss / Delayed / 6.6-6.6
sinusitis / Delayed / 6.0-6.0
abdominal pain / Early / 3.9-3.9
cough / Delayed / 3.9-3.9
myalgia / Early / 2.7-2.7
influenza / Delayed / 2.4-2.4
folliculitis / Delayed / 2.4-2.4
anorexia / Delayed / 2.3-2.3
xerostomia / Early / 2.1-2.1
rash / Early / 0-1.0
vomiting / Early / 0-1.0
chills / Rapid / 0-1.0
fever / Early / 0-1.0
paresthesias / Delayed / Incidence not known
dysgeusia / Early / Incidence not known
anxiety / Delayed / Incidence not known
insomnia / Early / Incidence not known
asthenia / Delayed / Incidence not known

Fuzeon

Rx

Fusion inhibitor
For use with other antiretroviral agents to treat antiretroviral-experienced patients with evidence of ongoing viral replication
98% of patients develop injection site reactions

90 mg subcutaneously twice daily.

2 mg/kg/dose (Max: 90 mg/dose) subcutaneously twice daily.

The US Public Health Service guidelines suggest enfuvirtide 90 mg subcutaneously twice daily in combination with one of the following backbones (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. However, prior to administering an enfuvirtide containing regimen, the US Public Health Service recommends consultation with a clinician experienced in the management of PEP. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

†Indicates off-label use

No dosage adjustments are needed in patients with hepatic impairment.

No dosage adjustments are needed in patients with hepatic impairment.

Tipranavir: (Moderate) Phase 3 trials showed that the coadministration of enfuvirtide increases tipranavir trough concentrations by 45%; however, the mechanism for this increase is unknown. The manufacturer of tipranavir states that tipranavir dosage adjustments are not recommended.

Fuzeon Subcutaneous Inj Pwd F/Sol: 90mg

180 mg/day subcutaneously.

180 mg/day subcutaneously.

4 mg/kg/day (Max: 180 mg/day) subcutaneously.

weight 11 kg or more: 4 mg/kg/day (Max: 180 mg/day) subcutaneously.
weight less than 11 kg: Safety and efficacy have not been established.

weight 11 kg or more: 4 mg/kg/day subcutaneously.
weight less than 11 kg: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Enfuvirtide interferes with the entry of HIV-1 into host cells by inhibiting the fusion of the virus and cell membranes. In order for HIV-1 to enter and infect a human cell, the viral surface glycoprotein gp120 binds to the host CD4+ cell receptor, along with a chemokine co-receptor (CXCR4 or CCR5; both expressed on lymphocytes and mononuclear cells). Then, the viral transmembrane glycoprotein gp41 undergoes a conformational change facilitating the fusion of cellular and viral membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational change required for membrane fusion and subsequent viral entry into target cells. This novel mechanism results in a lack of cross-resistance to enfuvirtide for viral isolates resistant to one or more currently available antiretrovirals.
 
Avoid the use of enfuvirtide in patients with HIV-2, as HIV-2 is intrinsically resistant to enfuvirtide. To identify the HIV strain, The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.

Enfuvirtide is administered as a subcutaneous injection. It is approximately 92% bound to plasma proteins, predominantly to albumin and, to a lesser extent, alpha-1 acid glycoprotein. The CSF concentrations, measured from 2 to 18 hours, in 4 patients with HIV were below the quantifiable limit (0.025 mcg/mL). Enfuvirtide is a peptide and is expected to undergo catabolism to its constituent amino acids. 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 plasma following administration, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.

The mean steady-state volume of distribution following IV administration of a 90 mg dose is 5.5 +/- 1.1 L.

The time to peak serum concentrations (Tmax) is approximately 8 hours (range of 3 to 12 hours) following a single 90 mg subcutaneous injection, with an absolute bioavailability is 84.3% +/- 15.5% compared to a 90 mg intravenous (IV) dose. With twice-daily subcutaneous dosing of 90 mg enfuvirtide in combination with other antiretroviral agents, the median Tmax decreases to 4 hours (range of 4 to 8 hours). Absorption of the 90 mg dose is comparable when injected into the subcutaneous tissue of the abdomen, thigh, or arm. The mean elimination half-life following a 90 mg single subcutaneous dose is 3.8 +/- 0.6 hours with a mean apparent clearance of subcutaneous dosing, in combination with other antiretroviral agents.

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Data regarding administration of enfuvirtide during pregnancy are too limited to rule out any potential association with birth defects; therefore, enfuvirtide-containing regimens should not be initiated in pregnant patients. However, it may be appropriate to continue use of the drug in some virally suppressed pregnant patients. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to enfuvirtide; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding enfuvirtide use during breast-feeding, and excretion into human breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.