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. FUZEON is an HIV-1 gp41 fusion inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with HIV-1 replication despite ongoing antiretroviral therapy. ( 1 )

How Supplied FUZEON (enfuvirtide) for Injection is a white to off-white, sterile, lyophilized powder and it is packaged in a single-dose clear glass vial containing 108 mg of enfuvirtide for the delivery of approximately 90 mg/1 mL when reconstituted with 1 mL of Sterile Water for Injection. FUZEON is available in a Convenience Kit containing 60 single-dose vials of FUZEON (90 mg strength), 60 vials (2 cartons of 30 each) of Sterile Water for Injection (1 mL per vial), 60 reconstitution syringes (3 cc), 60 administration syringes (1 cc), Package Insert, Patient Package Insert, and Injection Instructions (NDC 0004-0381-40). Storage Conditions Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature]. Reconstituted solution should be stored in the original vial under refrigeration at 2º to 8ºC (36º to 46ºF) and used within 24 hours.

Adults: Recommended dosage of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen. ( 2.2 ) 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 ) FUZEON must only be reconstituted with 1 mL of Sterile Water for Injection provided in the Convenience Kit. ( 2.4 ) Reconstituted FUZEON must be injected immediately or kept refrigerated in the original vial. It must be used within 24 hours. ( 2.4 ) 2.1 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. 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 (2.5 and 2.6) ] . 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 (2.5 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. 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 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. 2.5 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. 2.6 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.

FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components [see Warnings and Precautions (5.4) ] . Hypersensitivity to FUZEON or any of its components. ( 4 )

See FDA-Approved Patient Labeling ( Patient Information , Instructions for Use ) To assure safe and effective use of FUZEON, the following information and instructions should be given to patients: Injection Site Reactions Inform patients that injection site reactions occur in almost all patients taking FUZEON. Patients must be familiar with the FUZEON Injection Instructions for instructions on how to appropriately inject FUZEON and how to carefully monitor for signs or symptoms of cellulitis or local infection. Instruct patients when to contact their healthcare provider about these reactions [see Warnings and Precautions (5.1) ] . Administration with Biojector ® 2000 Inform patients that nerve pain (neuralgia and/or paresthesia) 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 [see Warnings and Precautions (5.2) ] . Post-injection Bleeding Advise patients about the risk of post-injection bleeding if they are receiving anticoagulants or have coagulation disorders such as hemophilia [see Warnings and Precautions (5.3) ]. Systemic Hypersensitivity Advise patients of the possibility of a systemic hypersensitivity reaction to FUZEON. Advise patients to discontinue therapy and immediately seek medical evaluation if they develop signs/symptoms of systemic hypersensitivity such as combinations of rash, fever, nausea and vomiting, chills, rigors, and/or hypotension [see Warnings and Precautions (5.4) ] . Pneumonia Advise patients that an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in clinical trials. Advise patients to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness of breath) [see Warnings and Precautions (5.5) ] . Pregnancy Exposure Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiretroviral medicines during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2) ]. Important Dosing and Administration Instructions Inform patients that FUZEON must be taken as part of a combination antiretroviral regimen and that use of FUZEON alone may lead to rapid development of virus resistant to FUZEON and possibly other agents of the same class. Instruct patients and caregivers in the use of aseptic technique when administering FUZEON in order to avoid injection site infections. Appropriate training for FUZEON reconstitution and self-injection must be given by a healthcare provider, including a careful review of the FUZEON Patient Package Insert and FUZEON Injection Instructions . The first injection should be performed under the supervision of an appropriately qualified healthcare provider. It is recommended that the patient and/or caregiver's understanding and use of aseptic injection techniques and procedures be periodically re-evaluated. Instruct patients and caregivers on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Instruct patients and caregivers in the proper techniques for preparation, injection and disposal of needles and syringes (including not recapping needles) in order to avoid needle stick injuries. Advise patients not to reuse needles or syringes, and of safe disposal procedures, including the use of a puncture-resistant container, for disposal of used needles and syringes. Instruct patients on the safe disposal of full containers as per local requirements. Caregivers who experience an accidental needle stick after patient injection should contact a healthcare provider immediately. Inform patients to contact their healthcare provider for any questions regarding the administration of FUZEON. Inform patients not to change the dose or dosing schedule of FUZEON or any antiretroviral medication without consulting their healthcare provider. Inform patients to contact their healthcare provider immediately if they stop taking FUZEON or any other drug in their antiretroviral regimen. Inform patients that they can obtain more information on the self-administration of FUZEON at www.FUZEON.com or by calling 1-877-4-FUZEON (1-877-438-9366).

Carcinogenesis and Mutagenesis Carcinogenicity studies have not been conducted with enfuvirtide. Enfuvirtide was not genotoxic in in vivo and in vitro assays including a bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells, and an in vivo mouse micronucleus assay. Impairment of Fertility In a fertility and early embryonic development study in rats, no effects of enfuvirtide on male or female fertility were observed at enfuvirtide exposures (based on surface area) up to 1.6 times higher than human exposure at the RHD.

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).

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) ].

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.

The following adverse reactions are discussed in greater detail in other sections: Administration with Biojector ® 2000 [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Pneumonia [see Warnings and Precautions (5.5) ] Most common adverse reactions are local injection site reactions, diarrhea, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of FUZEON is based on 2131 subjects who received at least 1 dose of FUZEON during various clinical trials. This includes 2051 adults, 658 of whom received the recommended dose for greater than 48 weeks, and 63 pediatric subjects. Assessment of treatment-emergent adverse events is based on the pooled data from the two randomized, controlled, open-label, multicenter trials in treatment-experienced subjects, T20-301 (TORO 1) and T20-302 (TORO 2). Local Injection Site Reactions Local injection site reactions were the most frequent adverse events associated with the use of FUZEON. In T20-301 and T20-302, 98% of subjects had at least one local injection site reaction (ISR). A total of 7% of subjects discontinued treatment with FUZEON because of ISRs (4%) or difficulties with injecting FUZEON (3%) such as injection fatigue and inconvenience. Eighty-five percent of subjects experienced their first ISR during the initial week of treatment; ISRs continued to occur throughout treatment with FUZEON. For most subjects the severity of signs and symptoms associated with ISRs did not change during the 48 weeks of treatment. The majority of ISRs were associated with erythema, induration, the presence of nodules or cysts, and mild to moderate pain at the injection site ( Table 2 ). In addition, the average duration of individual ISRs was between three and seven days in 41% of subjects and more than seven days in 24% of subjects. Also, the numbers of ISRs per subject at any one time was between six to 14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects. Infection at the injection site (including abscess and cellulitis) was reported in 1.7% of adult subjects. Table 2 Summary of Individual Signs/Symptoms Characterizing Local Injection Site Reactions to Enfuvirtide in Studies T20-301 and T20-302 Combined (% of Subjects) Through 48 Weeks N=663 Event Category Any Severity Grade % of Subjects with Grade 3 Reactions % of Subjects with Grade 4 Reactions Pain/Discomfort Grade 3 = severe pain requiring prescription non-topical analgesics or limiting usual activities. Grade 4 = severe pain requiring hospitalization or prolongation of hospitalization, resulting in death, or persistent or significant disability/incapacity, or life-threatening, or medically significant. 96% 11% 0% Induration 90% 39% >25 but <50 mm 18% ≥50 mm Erythema 91% 22% >50 but <85 mm 10% ≥85 mm Nodules and Cysts 80% 23% >3 cm average diameter 0.2% Draining Pruritus Grade 3 = refractory to topical treatment or requiring oral or parenteral treatment. Grade 4 = not applicable. 65% 3% NA Ecchymosis 52% 5% >3 but ≤5 cm 2% >5 cm Other Adverse Events In T20-301 and T20-302, after study week 8, subjects on background alone who met protocol defined criteria for virological failure were permitted to revise their background regimens and add FUZEON. Exposure on FUZEON+background was 557 patient-years, and to background alone 162 patient-years. Due to this difference in exposure, safety results are expressed as the number of patients with an adverse event per 100 patient-years of exposure. For FUZEON+background, adverse events are also displayed by percent of subjects. The events most frequently reported in subjects receiving FUZEON+background regimen, excluding ISRs, were diarrhea (38 per 100 patient-years or 31.7%), nausea (27 per 100 patient-years or 22.8%), and fatigue (24 per 100 patient-years or 20.2%). These events were also commonly observed in subjects that received background regimen alone: diarrhea (73 per 100 patient-years), nausea (50 per 100 patient-years), and fatigue (38 per 100 patient-years). Treatment-emergent adverse events, regardless of causality and excluding ISRs, from Phase 3 studies are summarized for adult subjects, in Table 3 . Any Grade 2 or above events occurring at ≥2 percent of subjects and at a higher rate in subjects treated with FUZEON are summarized in Table 3 ; events that occurred at a higher rate in the control arms are not displayed. Rates of adverse events for subjects who switched to FUZEON after virological failure were similar. Table 3 Rates of Treatment-Emergent Adverse Events Excludes Injection Site Reactions (≥Grade 2) Reported in ≥2% of Subjects Treated with FUZEON Events listed occurred more frequently in subjects treated with FUZEON (based on rates/100 patient-years). (Pooled Studies T20-301/T20-302 at 48 Weeks) Adverse Event (by System Organ Class) FUZEON+Background Regimen (N=663) FUZEON+Background Regimen (N=663) Background Regimen (N=334) 663 subjects total 557 total patient-years 162 total patient-years % frequency rate/100 patient-years rate/100 patient-years Weight Decreased 6.6% 7.9 6.2 Sinusitis 6.0% 7.2 4.9 Abdominal Pain 3.9% 4.7 3.7 Cough 3.9% 4.7 2.5 Herpes Simplex 3.5% 4.1 3.7 Appetite Decreased 3.2% 3.8 2.5 Pancreatitis 3.0% 3.6 2.5 Pain in Limb 2.9% 3.4 3.1 Pneumonia (see text below) 2.7% 3.2 0.6 Myalgia 2.7% 3.2 1.2 Influenza-Like Illness 2.4% 2.9 1.9 Folliculitis 2.4% 2.9 2.5 Anorexia 2.3% 2.7 1.9 Dry Mouth 2.1% 2.5 1.9 Conjunctivitis 2.0% 2.3 1.9 Less Common Events The following adverse events have been reported in 1 or more subjects; however, a causal relationship to FUZEON has not been established. Immune System Disorders: worsening abacavir hypersensitivity reaction Renal and Urinary Disorders: glomerulonephritis; tubular necrosis; renal insufficiency; renal failure (including fatal cases) Blood and Lymphatic Disorders: thrombocytopenia; neutropenia; fever; lymphadenopathy Endocrine and Metabolic: hyperglycemia Infections: sepsis; herpes simplex Nervous System Disorders: taste disturbance; Guillain-Barre syndrome (fatal); sixth nerve palsy; peripheral neuropathy Cardiac Disorders: unstable angina pectoris Gastrointestinal Disorders: constipation; abdominal pain upper General: asthenia Hepatobiliary Disorders: toxic hepatitis; hepatic steatosis Investigations: increased amylase; increased lipase; increased AST; increased GGT; increased triglycerides Psychiatric Disorders: insomnia; depression; anxiety; suicide attempt Respiratory, Thoracic, and Mediastinal Disorders: pneumopathy; respiratory distress; cough Skin and Subcutaneous Tissue Disorders: pruritus Laboratory Abnormalities Table 4 shows the treatment-emergent laboratory abnormalities that occurred in at least 2 subjects per 100 patient-years and more frequently in those receiving FUZEON+background regimen than background regimen alone from T20-301 and T20-302. Table 4 Treatment-Emergent Laboratory Abnormalities in ≥2% of Subjects Receiving FUZEON Events listed occurred more frequently in subjects treated with FUZEON (based on rates/100 patient-years). (Pooled Studies T20-301 and T20-302 at 48 Weeks) Laboratory Parameters Grading FUZEON+Background Regimen (N=663) FUZEON+Background Regimen (N=663) Background Regimen (N=334) 663 subjects total 557 total patient-years 162 total patient-years % frequency rate/100 patient-years rate/100 patient-years Eosinophilia 1-2 × ULN (0.7 × 10 9 /L) 0.7-1.4 × 10 9 /L 9.1% 10.8 3.7 >2 × ULN (0.7 × 10 9 /L) >1.4 × 10 9 /L 1.8% 2.2 1.8 ALT Grade 3 >5-10 × ULN 4.1% 4.8 4.3 Grade 4 >10 × ULN 1.2% 1.4 1.2 Creatine Phosphokinase (U/L) Grade 3 >5-10 × ULN 6.9% 8.3 8.0 Grade 4 >10 × ULN 2.6% 3.1 8.6 Adverse Events in Pediatric Patients FUZEON has been studied in 63 pediatric subjects 5 through 16 years of age with duration of FUZEON exposure ranging from 1 dose to 134 weeks. Adverse experiences seen during clinical trials 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. 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of FUZEON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Cutaneous amyloidosis at the injection site.

There are no reports of human experience of acute overdose with FUZEON. The highest dose administered to 12 subjects in a clinical trial was 180 mg as a single-dose subcutaneously. There is no specific antidote for overdose with FUZEON. Treatment of overdose should consist of general supportive measures.