Fuzeon Injection

Lyophilized powder for injection: 108 mg enfuvirtide per vial

The following adverse reactions are discussed in greater detail in other sections:

• Administration with Biojector® 2000 [see Warnings and Precautions (5.2)]
• Pneumonia [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

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
* 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. † Grade 3 = refractory to topical treatment or requiring oral or parenteral treatment. Grade 4 = not applicable.
Pain/Discomfort *	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 †	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* (≥Grade 2) Reported in ≥2% of Subjects Treated with FUZEON† (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
* Excludes Injection Site Reactions † Events listed occurred more frequently in subjects treated with FUZEON (based on rates/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* (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
* Events listed occurred more frequently in subjects treated with FUZEON (based on rates/100 patient-years).
Eosinophilia
1-2 X ULN (0.7 × 109/L)	0.7-1.4 × 109/L	9.1%	10.8	3.7
>2 X ULN (0.7 × 109/L)	>1.4 × 109/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.

Postmarketing Experience

The following adverse reaction has been identified during postapproval 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.

Mechanism of Action

Enfuvirtide is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.

Absorption

Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ± 1.5 µg/mL, AUC was 55.8 ± 12.1 µg∙h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ± 15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ± 1.7 µg/mL, Ctrough was 3.3 ± 1.6 µg/mL, AUC0-12h was 48.7 ± 19.1 µg∙h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).

Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.

Distribution

The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ± 1.1 L.

Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 µg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.

The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIV-infected subjects were below the limit of quantification (0.025 µg/mL).

Metabolism/Elimination

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.

Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

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 human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.

Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ± 0.6 h and the mean ±SD apparent clearance was 24.8 ± 4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ± 10.6 mL/h/kg.

Special Populations

Hepatic Impairment

Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.

Renal Impairment

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 – 35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.

No dose adjustment is recommended for patients with impaired renal function.

Gender and Weight

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.

Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.

No dose adjustment is recommended for weight or gender.

Race

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.

Pediatric Patients

The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.

In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 µg∙h/mL, Cmax was 6.3 ± 2.4 µg/mL, Ctrough was 3.1 ± 1.5 µg/mL, and apparent clearance was 40 ± 17 mL/h/kg [see Use in Specific Populations (8.4)].

Geriatric Patients

The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.

Drug Interactions

See also Drug Interactions (7)

Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.

Table 5 Effect of Ritonavir, Saquinavir/Ritonavir, and Rifampin on the Steady-State Pharmacokinetics of Enfuvirtide (90 mg bid)*

Coadministered Drug	Dose of Coadministered Drug	N	% Change of Enfuvirtide Pharmacokinetic Parameters†‡ (90% CI)
			Cmax	AUC	Ctrough
* All studies were performed in HIV-1+ subjects using a sequential crossover design. † ↑= Increase; ↓ = Decrease; = No Effect (↑ or ↓ <10%) ‡ No interactions were clinically significant.
Ritonavir	200 mg, q12h, 4 days	12	↑24 (↑9 to ↑41)	↑22 (↑8 to ↑37)	↑14 (↑2 to ↑28)
Saquinavir/ Ritonavir	1000/100 mg, q12h, 4 days	12		↑14 (↑5 to ↑24)	↑26 (↑17 to↑35)
Rifampin	600 mg, qd, 10 days	12			↓15 (↓22 to ↓7)

Microbiology

Mechanism of Action

Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

Antiviral Activity in Cell Culture

The antiviral activity of enfuvirtide was assessed by infecting different CD4 cell types with laboratory and clinical isolates of HIV-1. The median EC50 value for baseline clinical isolates was 4.10 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 55.9 nM (1.56 to 1675 nM; 7 to 7526 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, F, and G (median EC50 value was 7.01 nM; range 3.78 to 27.9 nM; 17-126 ng/mL), and R5, X4, and dual tropic viruses. Enfuvirtide has no activity against HIV-2.

Enfuvirtide exhibited additive to synergistic effects in cell culture assays when combined with individual members of various antiretroviral classes, including lamivudine, zidovudine, indinavir, nelfinavir, and efavirenz.

Drug Resistance

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in cell culture. Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36 to 38 of the HIV-1 envelope glycoprotein gp41. Phenotypic analysis of site-directed mutants in positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide.

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing a FUZEON containing regimen. Posttreatment HIV-1 virus from 277 subjects experiencing protocol defined virological failure at 48 weeks exhibited a median decrease in susceptibility to enfuvirtide of 33.4-fold (range 0.4-6318-fold) relative to their respective baseline virus. Of these, 249 had decreases in susceptibility to enfuvirtide of greater than 4-fold and all but 3 of those 249 exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45. Mutations or polymorphisms in other regions of the envelope (e.g., the HR2 region or those yet to be identified) as well as co-receptor usage and density may affect susceptibility to enfuvirtide.

Cross-resistance

HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) were susceptible to enfuvirtide in cell culture.