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HIV-1 Entry Inhibitors/Fusion Inhibitors
Fusion inhibitorFor use with other antiretroviral agents to treat antiretroviral-experienced patients with evidence of ongoing viral replication98% of patients develop injection site reactions
Fuzeon Subcutaneous Inj Pwd F/Sol: 90mg
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
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.
No dosage adjustments are needed in patients with hepatic impairment.
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.
ReconstitutionReconstitute 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. Subcutaneous InjectionAdminister 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.To minimize local reactions, apply ice or heat after injection or gently massage injection site to better disperse the dose.
Fuzeon:- Discard product if it contains particulate matter, is cloudy, or discolored- Store at 77 degrees F; excursions permitted to 59-86 degrees F- Store in original container- Store reconstituted product in refrigerator (36 to 46 degrees F) and administer within 24 hours
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.  
To better ensure compliance, patients should be given sufficient warning and explanation of injection site reactions before beginning treatment with enfuvirtide. Ninety-eight percent of patients in clinical trials experienced at least 1 injection site reaction during treatment. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis, and reactions are often present at more than one injection site. Patients must be familiar with the enfuvirtide injection instructions in order to know how to inject enfuvirtide appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection. The risk of post-injection bleeding may be higher in patients receiving anticoagulant therapy or persons with hemophilia or other coagulopathy.
An increased rate of bacterial respiratory infection (i.e., pneumonia) was observed in subjects treated with enfuvirtide in the phase III clinical trials, compared to those in the control group. It was unclear if the increased incidence of pneumonia was related to enfuvirtide use; therefore, an observational study was conducted to evaluate the risk of developing pneumonia. During this observational study, a total of 62 of 740 enfuvirtide treated patients (3.2 events/100 patient years) and 61 of 1110 non-enfuvirtide treated patients (1.8 events/100 patient years) experienced a confirmed or probable pneumonia event (hazard ratio 1.34; 95% CI = 0.9—2). Thus, an increased risk of pneumonia cannot be excluded. The manufacturer advises health care providers to carefully monitor patients with HIV infection 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 substance abuse, tobacco smoking, and a prior history of pulmonary disease.
Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. 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 women. However, it may be appropriate to continue use of the drug in some virally suppressed pregnant women. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women 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 women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. 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 women 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 women 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 women 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 woman 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. 
To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. If a mother with HIV opts to breast-feed, the infant 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, health care 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.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy with enfuvirtide may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
pancreatitis / Delayed / 3.0-3.0acute respiratory distress syndrome (ARDS) / Early / 0-1.0Guillain-Barre syndrome / Delayed / 0-1.0glomerulonephritis / Delayed / 0-1.0cranial nerve palsies / Delayed / Incidence not knownsuicidal ideation / Delayed / Incidence not knownrenal failure (unspecified) / Delayed / Incidence not knownrenal tubular necrosis / Delayed / Incidence not known
erythema / Early / 91.0-91.0eosinophilia / Delayed / 1.8-9.1elevated hepatic enzymes / Delayed / 1.2-4.1conjunctivitis / Delayed / 2.0-2.0dyspnea / Early / 0-1.0peripheral edema / Delayed / 0-1.0hematuria / Delayed / 0-1.0hypotension / Rapid / 0-1.0hematoma / Early / Incidence not knownconstipation / Delayed / Incidence not knownneutropenia / Delayed / Incidence not knownthrombocytopenia / Delayed / Incidence not knownperipheral neuropathy / Delayed / Incidence not knowndepression / Delayed / Incidence not knownantibody formation / Delayed / Incidence not knownlymphadenopathy / Delayed / Incidence not knowncutaneous amyloidosis / Delayed / Incidence not knownhypertriglyceridemia / Delayed / Incidence not knownhyperglycemia / Delayed / Incidence not knownangina / Early / Incidence not knownhepatitis / Delayed / Incidence not knownsteatosis / Delayed / Incidence not known
injection site reaction / Rapid / 98.0-98.0pruritus / Rapid / 65.0-65.0ecchymosis / Delayed / 52.0-52.0diarrhea / Early / 31.7-31.7nausea / Early / 22.8-22.8fatigue / Early / 20.2-20.2infection / Delayed / 2.7-6.9weight loss / Delayed / 6.6-6.6sinusitis / Delayed / 6.0-6.0abdominal pain / Early / 3.9-3.9cough / Delayed / 3.9-3.9myalgia / Early / 2.7-2.7influenza / Delayed / 2.4-2.4folliculitis / Delayed / 2.4-2.4anorexia / Delayed / 2.3-2.3xerostomia / Early / 2.1-2.1rash / Early / 0-1.0vomiting / Early / 0-1.0chills / Rapid / 0-1.0fever / Early / 0-1.0paresthesias / Delayed / Incidence not knowndysgeusia / Early / Incidence not knownanxiety / Delayed / Incidence not knowninsomnia / Early / Incidence not knownasthenia / Delayed / Incidence not known
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.
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.