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.

• Adults: Recommended dosage of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen. (
  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 (2.5and 2.6)]

  .
  )
• 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 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 (2.5and 2.6)and Use in Specific Populations (8.4)]

  . Table 1contains dosing recommendations for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.

  Table 1 Pediatric Dosing Recommendations Weighing at Least 11 Kg

  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
  )
• FUZEON must only be reconstituted with 1 mL of Sterile Water for Injection provided in the Convenience Kit. (
  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.
  )
• Reconstituted FUZEON must be injected immediately or kept refrigerated in the original vial. It must be used within 24 hours. (
  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.
  )

Lyophilized powder for injection: 108 mg enfuvirtide per single-dose vial

• Lactation: Breastfeeding is not recommended due to risk of HIV-1 transmission. (
  8.2 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.
  )

• 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 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.
  )
• Biojector^® 2000: Administration of FUZEON with Biojector 2000 may result in neuralgia and/or paresthesia, bruising and hematomas. (
  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.
  )
• 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 Post-Injection Bleeding

  Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.
  )
• Hypersensitivity: FUZEON should be discontinued immediately upon signs and symptoms of systemic hypersensitivity reactions. (
  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.
  )
• 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 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.
  )
• Immune Reconstitution: Patients treated with combination antiretroviral therapy, including FUZEON, may experience immune reconstitution syndrome requiring further evaluation and treatment. (
  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.
  )