FUZEON

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

Route-Specific Administration

Injectable Administration
-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.
Subcutaneous Administration
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.

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.
-To minimize local reactions, apply ice or heat after injection or gently massage injection site to better disperse the dose.

An increased rate of bacterial pneumonia infection was observed in patients treated with enfuvirtide in the Phase III clinical trials 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 patients with pneumonia required hospitalization and three deaths in the enfuvirtide arm were attributed to pneumonia. Additional clinical trials report the incidence of pneumonia at 2.7% (3.2 events per 100 patient-years) in those subjects receiving enfuvirtide in addition to a background HIV treatment regimen. 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. It is unclear if the increased incidence of pneumonia was related to enfuvirtide use. However, because of this finding, patients with HIV infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Enfuvirtide has been studied in 63 pediatric patients 6-16 years of age with duration of enfuvirtide exposure ranging from 1 dose to 48 weeks of treatment. Adverse experiences seen during clinical trials were similar to those observed in adult patients. However, infections at the injection site, such as cellulitis or abscess, were more frequently seen in adolescents (4 events were reported in 3 of 28 patients), compared to adults. Other infectious adverse events reported in adults include herpes simples (3.5%), influenza-like illness (2.4%), and sepsis.

Injection site reaction (ISR) occurred at least once during clinical trials in 98% of patients in general treated with enfuvirtide, with a majority reporting reactions within the first week of treatment (85% of patients). ISRs involving pain and discomfort were reported in 96% of patients, 11% experiencing severe pain which required prescription analgesics and/or limited usual daily activities. Indurations were reported in 90% of patients, with 39% of indurations being > 25 mm but < 50 mm and 18% being >= 50 mm average diameter. Erythema at the site of injection was reported in 91% of patients, with an average diameter > 50 mm but < 85 mm in 22% and >= 85 mm in 10% of the reported reactions. Nodules and cysts were seen in 80% of patients, 23% were > 3 cm and 0.2% were draining. Pruritus was seen in 65% of patients, with 3% experiencing pruritus refractory to topical treatment or requiring oral or parenteral treatment. Ecchymosis was seen in 52% of patients, > 3 cm but <= 5 cm in 5% and > 5 cm 2% of those affected. Seven percent of patients discontinued enfuvirtide during trials, 4% because of ISRs and 3% because of difficulties with injecting (i.e., injection fatigue and inconvenience). For most patients in clinical trials, the severity of signs and symptoms associated with ISRs did not change during 48 weeks of treatment. On average, ISRs lasted 3 to 7 days in 41% of patients and longer than 7 days in 24%. The number of ISRs present in an individual patient at one time was between 6 and 14 in 26% and more than 14 in 1.3%; infection at the injection site, including abscess and cellulitis. was reported in 1.7% of adults. Post-marketing reports have included incidences of nerve pain (neuralgia and/or paresthesias) lasting up to 6 months associated with the Biojector 2000 Needle-Free device used for injecting enfuvirtide. This particularly occurs when administration is at anatomical sites where large nerves course close to the skin. Bruising and hematoma have also been reported with this device.

Adverse events reported in pediatric patients for enfuvirtide were similar to those noted in adults. In clinical trials, the gastrointestinal events most frequently reported in adult patients receiving enfuvirtide plus background regimen include diarrhea (31.7%), nausea (22.8%), abdominal pain (3.9%), decreased appetite (3.2%), anorexia (2.3%), and xerostomia (2.1%). Other, less common events include constipation, upper abdominal pain, and taste disturbance (dysgeusia).

Hypersensitivity reactions have been reported during treatment with enfuvirtide (<= 1%) and in some cases have recurred upon rechallenge. Such reactions have included, individually and in combination: chills, difficulty breathing/dyspnea, peripheral edema (specifically seen in the feet), elevated hepatic enzymes, fever, hematuria, hypotension, feeling nauseated, vomiting, rigors, and rash (unspecified). Other adverse reactions that may be immune mediated and have been reported in subjects receiving enfuvirtide include primary immune complex reaction, acute respiratory distress syndrome (ARDS), glomerulonephritis, and Guillain-Barre syndrome. Therapy with enfuvirtide 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 enfuvirtide have not been identified.

Adverse events reported in pediatric trials were similar to those noted in adults. Eosinophilia was reported with the use of enfuvirtide. In adult clinical trials, 9.1% of patients had eosinophil counts 1-2 times the upper limit of normal (ULN) and 1.8% of patients had eosinophil counts > 2 times the ULN. Less commonly reported hematologic adverse events include thrombocytopenia and neutropenia.

Adverse events reported in pediatric enfuvirtide trials were similar to those noted in adults. Infrequently reported nervous system or psychiatric adverse events during adult clinical trials include insomnia, depression, anxiety, suicide attempt/suicidal ideation, sixth nerve palsy (cranial nerve palsies), and peripheral neuropathy.

There is a theoretical risk that enfuvirtide use may lead to antibody formation, resulting in 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. Enfuvirtide has not been studied in non-HIV infected individuals.

Adverse events reported in pediatric enfuvirtide clinical trials were similar to those reported in adults. Fatigue (20.2%) was one of the most commonly reported adverse events during adult clinical trials. Weight loss was reported in 6.6% and limb pain was noted in 2.9% of adult patients. Other general adverse events reported less commonly during trials include asthenia, fever, and lymphadenopathy.

Adverse events reported in pediatric enfuvirtide trials were similar to those noted in adults. Respiratory adverse events reported during adult clinical trials include sinusitis (6%) and cough (3.9%). Other, less commonly reported adverse events include pneumopathy and respiratory distress.

Adverse events reported in pediatric enfuvirtide clinical trials were similar to those noted in adults. Pancreatitis was reported in 3% of adult patients during clinical trials. Elevated amylase and lipase concentrations were noted less frequently.

Adverse events reported in pediatric enfuvirtide trials were similar to those noted in adults. Myalgia was reported in 2.7% of adult patients during clinical trials. Elevated creatine phosphokinase (CPK) concentrations were also noted. In adult trials, 6.9% of patients had grade 3 CPK increases and 2.6% had grade 4 CPK increases.

Folliculitis was reported in 2.4% of adult patients during clinical trials; pruritus was less commonly reported. Cutaneous amyloidosis at the injection site has been reported during post-marketing use. Although pediatric-specific ADR incidence rates are not available, adverse events noted during pediatric trials were similar to those reported in adults, with the exception of a higher frequency of infections at the injection site in adolescents.

Adverse events reported in pediatric enfuvirtide trials were similar to those noted in adults. Conjunctivitis was reported in 2% of adult patients during clinical trials.

Renal tubular necrosis, renal insufficiency, and renal failure (unspecified) were infrequently reported during enfuvirtide clinical trials.

Hyperglycemia and hypertriglyceridemia were infrequently reported during enfuvirtide clinical trials.

Unstable angina pectoris was reported infrequently during enfuvirtide clinical trials.

Adverse events reported in pediatric enfuvirtide clinical trials were similar to those noted in adults. Elevated hepatic enzymes have been reported and may be associated with a hypersensitivity reaction. Grade 3 increases in ALT occurred in 4.1% of adult patients and grade 4 increases were noted in 1.2% of adult patients during clinical trials. Toxic hepatitis and hepatic steatosis were less commonly reported during clinical trials.

Unplanned enfuvirtide treatment interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of 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. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. 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 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.

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. Therefore, 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 results kept in the patient's medical record until they become 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 mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii 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 who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients >= 2 years receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Enfuvirtide, also known as T-20, is the first medication in a class of anti-HIV drugs called fusion inhibitors. It is a synthetic 36-amino-acid peptide derived from the HIV-1 envelope glycoprotein gp41, and it interferes with the entry of HIV-1 into cells by inhibiting the fusion of viral and cellular membranes. The drug is indicated to treat HIV infection in antiretroviral-experienced patients with evidence of ongoing viral replication despite ongoing antiretroviral therapy (i.e., show resistance to current HIV treatments). Enfuvirtide should be used in combination with an individualized antiretroviral regimen. It remains active against HIV strains in patients who have previously received and developed resistance to other classes of antiretroviral agents. In clinical trials, patients receiving enfuvirtide in addition to an individualized antiretroviral regimen were less likely to experience virologic failure or relapse compared to those receiving an individualized antiretroviral regimen alone; patients whose virus was sensitive to a greater number of antiretroviral drugs did demonstrate a greater sensitivity to enfuvirtide. During use, at least 98% of patients will develop injection site reactions to varying degrees, with almost 85% of patients developing the reactions within the first week of use. Patients should be appropriately counseled regarding injection site reactions before therapy is initiated. Enfuvirtide is FDA-approved in pediatric patients weighing at least 11 kg.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Enfuvirtide may be used in patients with HIV-1 infection who are treatment-experienced. There are insufficient data to recommend use as initial therapy in antiretroviral-naive patients; data from in vitro studies show HIV-2 to be intrinsically resistant to enfuvirtide.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of advanced human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in treatment-experienced patients with evidence of HIV replication despite ongoing antiretroviral therapy:
Subcutaneous dosage:
Infants, Children, and Adolescents weighing 11 kg or more: 2 mg/kg/dose (Max: 90 mg/dose) subcutaneously twice daily.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
weight less than 11 kg: Safety and efficacy have not been established
weight 11 kg or more: 4 mg/kg/day subcutaneously.
-Children
weight less than 11 kg: Safety and efficacy have not been established
weight 11 kg or more: 4 mg/kg/day (Max: 180 mg/day) subcutaneously.
-Adolescents
4 mg/kg/day (Max: 180 mg/day) subcutaneously.

Patients with Hepatic Impairment Dosing
No dosage adjustments are needed in patients with hepatic impairment.

Patients with Renal Impairment Dosing
No dosage adjustments are needed in patients with renal impairment.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: 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.

Pharmacokinetics: Enfuvirtide is administered as a subcutaneous (SC) injection. It is approximately 92% bound to plasma proteins, predominantly to albumin and, to a lesser extent, a-1 acid glycoprotein. The CSF concentrations, measured from 2-18 hours, in 4 HIV-infected patients 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 2.4-15% of the enfuvirtide AUC.

Affected cytochrome P450 isoenzymes: none


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

Subcutaneous Route
The time to peak serum concentrations (Tmax) is approximately 8 hours (range of 3-12 hours) following a single 90 mg SC injection, with an absolute bioavailability is 84.3% +/- 15.5% compared to a 90 mg intravenous (IV) dose. With twice daily SC dosing of 90 mg enfuvirtide in combination with other antiretroviral agents, the median Tmax decreases to 4 hours (range of 4-8 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 SC dose is 3.8 +/- 0.6 hours with a mean apparent clearance of 24.8 +/- 4.1 ml/hour/kg. In 11 HIV infected patients the mean clearance was 30.6 +/- 10.6 ml/hour/kg after twice daily 90 mg SC dosing, in combination with other antiretroviral agents.


-Special Populations
Pediatrics
Children >= 6 years and Adolescents
Drug exposure in children and adolescents is independent of age, body weight,, surface area, and sexual maturity. Pharmacokinetic data from clinical trials in pediatric patients (6-16 years, n=23), with doses of 2 mg/kg (Max: 90 mg) given twice daily, who were also receiving concomitant medications including antiretroviral agents, revealed enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg twice daily. The mean apparent steady-state clearance was 40 +/- 17 ml/h/kg in pediatric patients as compared to 30.6 +/- 10.6 ml/h/kg in adults.

Hepatic Impairment
Formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with hepatic impairment.

Renal Impairment
Plasma concentration data from patients in clinical trials indicate that the clearance of enfuvirtide is not affected in patients with creatinine clearance > 35 ml/min. In patients with severe renal impairment (CrCl = 11-35 ml/min), the clearance was reduced by 38% compared to those with normal renal function. Patients with end-stage renal disease receiving dialysis showed a 14-28% reduction clearance. Hemodialysis did not significantly affect the clearance of enfuvirtide.