Fuzeon

enfuvirtide

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for 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.

This indication is based on results from two controlled studies of 48 weeks duration. Subjects enrolled were treatment-experienced adults; many had advanced disease. There are no studies of Fuzeon in antiretroviral naive subjects.

Fuzeon Dosage and Administration

Adults

The recommended dose of Fuzeon is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. 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. 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 section 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. Additional detailed information regarding the administration of Fuzeon is described in the Fuzeon Injection Instructions.

Pediatric Patients

Insufficient data are available to establish a dose recommendation of Fuzeon in pediatric patients below the age of 6 years. In pediatric patients 6 years through 16 years of age, the recommended dosage of Fuzeon is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. 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. Fuzeon should not be injected into moles, scar tissue, bruises or the navel. Table 1 contains dosing guidelines for Fuzeon based on body weight. Weight should be monitored periodically and the Fuzeon dose adjusted accordingly.

Table 1 Pediatric Dosing Guidelines

Weight		Dose per bid Injection (mg/dose)	Injection Volume (90 mg enfuvirtide per mL)
Kilograms (kg)	Pounds (lbs)
11.0 to 15.5	24 to 34	27	0.3 mL
15.6 to 20.0	>34 to 44	36	0.4 mL
20.1 to 24.5	>44 to 54	45	0.5 mL
24.6 to 29.0	>54 to 64	54	0.6 mL
29.1 to 33.5	>64 to 74	63	0.7 mL
33.6 to 38.0	>74 to 84	72	0.8 mL
38.1 to 42.5	>84 to 94	81	0.9 mL
≥42.6	>94	90	1.0 mL

Directions for Use

For more detailed instructions, see Fuzeon Injection Instructions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Subcutaneous Administration

Fuzeon must only be reconstituted with 1.1 mL of Sterile Water for Injection provided in the Convenience Kit. After adding sterile water, the vial should be gently tapped for 10 seconds and then gently rolled between the hands to avoid foaming and to ensure all particles of drug are in contact with the liquid and no drug remains on the vial wall. The vial should then be allowed to stand until the powder goes completely into solution, which could take up to 45 minutes. Reconstitution time can be reduced by gently rolling the vial between the hands until the product is completely dissolved. Before the solution is withdrawn for administration, the vial should be inspected visually to ensure that the contents are fully dissolved in solution, and that the solution is clear, colorless and without bubbles or particulate matter. If the Fuzeon is foamy or jelled, allow more time for it to dissolve. If there is evidence of particulate matter, the vial must not be used and should be returned to the pharmacy.

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. The subsequent dose of Fuzeon can be reconstituted in advance and must be stored in the refrigerator in the original vial and 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.

A vial is suitable for single use only; unused portions must be discarded (see Fuzeon Injection Instructions).

Patients should contact their healthcare provider for any questions regarding the administration of Fuzeon. Information about the self-administration of Fuzeon may also be obtained by calling the toll-free number 1-877-4-Fuzeon (1-877-438-9366) or at the Fuzeon website, www.Fuzeon.com. Patients should be taught to recognize the signs and symptoms of injection site reactions and instructed when to contact their healthcare provider about these reactions.

Dosage Forms and Strengths

Lyophilized powder for injection: 108 mg enfuvirtide per vial

Contraindications

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

Warnings and Precautions

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.

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. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.

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.

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.

Non-HIV Infected Individuals

There is a theoretical risk that Fuzeon use may lead to the production of 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. Fuzeon has not been studied in non-HIV infected individuals.

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.

Adverse Reactions

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+Back-ground Regimen (N=663)	Fuzeon+Back-ground 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+Back-ground Regimen (N=663)	Fuzeon+Back-ground 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.

Drug Interactions

See also Clinical Pharmacology (12.3)

Potential for Fuzeon to Affect Other Drugs

Based on the results from an in vitro human microsomal study, enfuvirtide is not an inhibitor of CYP450 enzymes. In an in vivo human metabolism study (N=12), Fuzeon at the recommended dose of 90 mg twice daily did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates.

Potential for Other Drugs to Affect Enfuvirtide

Based on the available data, co-administration of Fuzeon and other drugs which are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide. No dose adjustments are needed when Fuzeon is co-administered with other antiretroviral and non-antiretroviral drugs.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 27 times and 3.2 times the adult human dose on a m2 basis and have revealed no evidence of impaired fertility or harm to the fetus due to enfuvirtide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to Fuzeon and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Fuzeon.

Studies where radio-labeled 3H-enfuvirtide was administered to lactating rats indicated that radioactivity was present in the milk. It is not known whether the radioactivity in the milk was from radio-labeled enfuvirtide or from radio-labeled metabolites of enfuvirtide (i.e., amino acids and peptide fragments).

Pediatric Use

The safety and pharmacokinetics of Fuzeon have been evaluated in the age groups of 6 to 16 years of age supported by evidence from adequate and well-controlled studies of Fuzeon in adults. Limited efficacy data are available in pediatric subjects 6 years of age and older [see Clinical Pharmacology (12.3)].

Sixty-three HIV-1 infected pediatric subjects ages 5 through 16 years have received Fuzeon in two open-label, single-arm clinical trials. Adverse experiences, including ISRs, were similar to those observed in adult subjects.

T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of Fuzeon in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 495 cells/µL and the median baseline HIV-1 RNA was 4.6 log10 copies/mL.

Ten of the 11 study subjects completed 48 weeks of chronic therapy. At week 48, 6/11 (55%) subjects had ≥1 log10 decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.48 log10 copies/mL and +122 cells/µL, respectively.

T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of Fuzeon in treatment-experienced pediatric subjects and adolescents. Fifty-two subjects from 5 through 16 years were enrolled (median age of 12 years). Median baseline CD4 cell count was 117 cells/µL and the median baseline HIV-1 RNA was 5.0 log10 copies/mL.

Thirty-two of the 52 study subjects completed 48 weeks of chronic therapy. At week 48, 17/52 (33%) of subjects had ≥1 log10 decline in HIV-1 RNA, 11/52 (21%) of subjects were below 400 copies/mL of HIV-1 RNA and 5/52 (10%) were below 50 copies/mL. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.17 log10 copies/mL and +106 cells/µL, respectively.

Geriatric Use

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.

Use in Patients with Hepatic Impairment

No dose adjustments of enfuvirtide are needed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Use in Patients with Renal Impairment

No dose adjustments of enfuvirtide are needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

Overdosage

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.

Fuzeon Description

Fuzeon (enfuvirtide) is an inhibitor of the fusion of HIV-1 with CD4 cells. Enfuvirtide is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide. It is composed of naturally occurring L-amino acid residues.

Enfuvirtide is a white to off-white amorphous solid. It has negligible solubility in pure water and the solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL. The empirical formula of enfuvirtide is C204H301N51O64, and the molecular weight is 4492. It has the following primary amino acid sequence:

CH3CO - Tyr - Thr - Ser - Leu - Ile - His - Ser - Leu - Ile - Glu - Glu - Ser - Gln - Asn - Gln - Gln - Glu - Lys - Asn - Glu - Gln - Glu - Leu - Leu - Glu - Leu - Asp - Lys - Trp - Ala - Ser - Leu - Trp - Asn - Trp - Phe - NH2 and the following structural formula:

The drug product, Fuzeon (enfuvirtide) for Injection, is a white to off-white, sterile, lyophilized powder. Each single-use vial contains 108 mg of enfuvirtide for the delivery of 90 mg. Prior to subcutaneous administration, the contents of the vial are reconstituted with 1.1 mL of Sterile Water for Injection giving a volume of approximately 1.2 mL to provide the delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution contains approximately 90 mg of enfuvirtide with approximate amounts of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium carbonate (anhydrous), and sodium hydroxide and hydrochloric acid for pH adjustment as needed. The reconstituted solution has an approximate pH of 9.0.

Fuzeon - Clinical Pharmacology

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 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 geometric mean EC50 value for baseline clinical isolates was 3.52 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 57.9 nM (1.56 to 1680 nM; 7 to 7530 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, E, F, and G (geometric mean EC50 value was 7.7 nM; range 3.9 to 28.6 nM), 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 a

Fusilev

levoleucovorin calcium

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Fusilev

• Fusilev® is a folate analog.


• Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma.


• Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.


• Fusilev is indicated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Limitations of Use

• Fusilev is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

Fusilev Dosage and Administration

Administration Guidelines

Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin.

Fusilev is indicated for intravenous administration only. Do not administer intrathecally.

Co-administration of Fusilev with other agents

Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture.

Fusilev Rescue After High-Dose Methotrexate Therapy

The recommendations for Fusilev rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

Serum creatinine and methotrexate levels should be determined at least once daily. Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev dose should be adjusted or rescue extended based on the following guidelines.

Table 1 Guidelines for Fusilev Dosage and Administration

Clinical Situation	Laboratory Findings	Fusilev Dosage and Duration
Normal Methotrexate Elimination	Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours	7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate Elimination	Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.	Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury	Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).	75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate Fusilev therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, Fusilev rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of Fusilev or prolonged administration may be indicated.

Although Fusilev may ameliorate the hematologic toxicity associated with high-dose methotrexate, Fusilev has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Dosing Recommendations for Inadvertent Methotrexate Overdosage

Fusilev rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and Fusilev rescue increases, Fusilev’s effectiveness in counteracting toxicity may decrease. Fusilev 7.5 mg (approximately 5 mg/m2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of Fusilev should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Fusilev Administration in Combination with 5-Fluorouracil (5-FU)

The following regimens have been used historically for the treatment of colorectal cancer:

1. Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection.


2. Fusilev is administered at 10 mg/m2 by intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.

5-FU and Fusilev should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Fusilev dosages are not adjusted for toxicity.

Reconstitution and Infusion Instructions

Fusilev for Injection

• Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended.


• The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product.


• Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours.


• Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed.


• No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.

Fusilev Injection

• Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product.


• Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours.


• Visually inspect the diluted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed.


• No more than 16 mL of Fusilev Injection (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.

Dosage Forms and Strengths

Fusilev for Injection is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol.

Fusilev Injection, 175 mg is supplied in a single-use vial containing 17.5 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

Fusilev Injection, 250 mg is supplied in a single-use vial containing 25 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

Contraindications

Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions

Rate of Administration

Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin) should be injected intravenously per minute.

Potential for Enhanced Toxicity with 5-Fluorouracil

Fusilev enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of Fusilev and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination.

In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-FU alone or 5-FU in combination with 200 mg/m2 of d,l-leucovorin and 20% when treated with 5-FU in combination with 20 mg/m2 of d,l-leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose d,l-leucovorin/5-FU combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with Fusilev and 5-FU must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-FU and d,l-leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.

Seizures and/or syncope have been reported rarely in cancer patients receiving d,l-leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established.

Potential for interaction with trimethoprim-sulfamethoxazole

The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

Adverse Reactions

Clinical Studies in High-Dose Methotrexate Therapy

Since 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 following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m2 followed by Fusilev rescue for osteosarcoma in 16 patients age 6-21. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate.

Table 2 Adverse Reactions with High-Dose Methotrexate Therapy

Body System/Adverse Reactions	Number (%) of Patients with Adverse Reactions		Number (%) of Courses with Adverse Reactions
	(N =16)		(N = 58)
	All	Grade 3+	All	Grade 3+
Gastrointestinal
Stomatitis	6 (37.5)	1 (6.3)	10 (17.2)	1 (1.7)
Vomiting	6 (37.5)	0	14 (24.1)	0
Nausea	3 (18.8)	0	3 (5.2)	0
Diarrhea	1 (6.3)	0	1 (1.7)	0
Dyspepsia	1 (6.3)	0	1 (1.7)	0
Typhlitis	1 (6.3)	1 (6.3)	1 (1.7)	1 (1.7)
Respiratory
Dyspnea	1 (6.3)	0	1 (1.7)	0
Skin and Appendages
Dermatitis	1 (6.3)	0	1 (1.7)	0
Other
Confusion	1 (6.3)	0	1 (1.7)	0
Neuropathy	1 (6.3)	0	1 (1.7)	0
Renal function abnormal	1 (6.3)	0	3 (5.2)	0
Taste perversion	1 (6.3)	0	1 (1.7)	0
Total number of patients	9 (56.3)		2 (12.5)
Total number of courses	25 (43.1)		2 (3.4)

The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy.

Clinical Studies in Combination with 5-FU in Colorectal Cancer

A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms.

Table 3  Adverse Reactions Occurring in ≥10% of Patients in Either Arm

Adverse Reaction	Levoleucovorin/5FU n=318		d,l-Leucovorin/5FU n=307
Adverse Event N (%)	Grade 1-4	Grade 3-4	Grade 1-4	Grade 3-4
Gastrointestinal Disorders
Stomatitis	229 (72%)	37 (12%)	221 (72%)	44 (14%)
Diarrhea	222 (70%)	61 (19%)	201 (65%)	51 (17%)
Nausea	197 (62%)	25 (8%)	186 (61%)	26 (8%)
Vomiting	128 (40%)	17 (5%)	114 (37%)	18 (6%)
Abdominal Pain1	45 (14%)	10 (3%)	57 (19%)	10 (3%)
General Disorders
Asthenia/Fatigue/Malaise	91 (29%)	15 (5%)	99 (32%)	34 (11%)
Metabolism and Nutrition
Anorexia/Decreased Appetite	76 (24%)	13 (4%)	77 (25%)	5 (2%)
Skin Disorders
Dermatitis	91 (29%)	3 (1%)	86 (28%)	4 (1%)
Alopecia	83 (26%)	1 (0.3%)	87 (28%)	3 (1%)

 1Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

Postmarketing Experience

Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reactions.”

In an analysis where calcium levoleucovorin was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events).

Drug Interactions

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs.

Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.

Fusilev increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Fusilev. It is not known whether Fusilev can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fusilev should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Fusilev, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

[See Clinical Studies (14)]

Geriatric Use

Clinical studies of Fusilev in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects.

In the NCCTG clinical trial of Fusilev in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65.

Overdosage

No data are available for overdosage with levoleucovorin.

Fusilev Description

Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin].

Fusilev for Injection and Fusilev Injection contain levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is:

Its molecular formula is: C20H21CaN7O7  . 5 H2O.

Fusilev for Injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrochloric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See Dosage and Administration (2.6)]

Fusilev Injection is supplied as a sterile solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5).

Fusilev - Clinical Pharmacology

Mechanism of Action

12.1.1 Levoleucovorin effects during high-dose methotrexate therapy

Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

12.1.2 Levoleucovorin effects in combination with 5-fluorouracil

Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.

Pharmacodynamics

Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.

Pharmacokinetics

The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8-tetrahydrofolate was 5.1 and 6.8 hours, respectively.

A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either Fusilev (200 mg/m2 ) or racemic d,l-leucovorin (400 mg/m2), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC0-inf and Cmax were within the standard limit of 80-125% for both l-leucovorin and l-5-methyl-THF. Therefore, the exposure to l-leucovorin and 5-methyl-THF (AUC0-inf and Cmax) was comparable whether it was administered as Fusilev or as d,l-leucovorin. The geometric mean AUC0-inf values for levoleucovorin were 30719 ng.h/mL and 31296 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for levoleucovorin were 10895 ng/mL and 11301 ng/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean AUC0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for Fusilev and d,l-leucovorin, respectively. The geometric mean Cmax values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for Fusilev and d,l-leucovorin, respectively.

Use of Levoleucovorin in combination with 5-fluorouracil

A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether 5-FU (370 mg/m2/day IV bolus) was given in combination with levoleucovorin (250 mg/m2 and 1000 mg/m2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l-leucovorin (500 mg/m2 as a continuous IV infusion for 5.5 days, N=6).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

Animal Toxicology and/or Pharmacology

The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg (2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2 for high-dose methotrexate therapy which represents a 3-log safety margin.

Clinical Studies

High-Dose Methotrexate Therapy

The safety and efficacy of Fusilev rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by Fusilev 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile. [See Adverse Reactions (6)]

Combination with 5-FU in Colorectal Cancer

In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer, three treatment regimens were compared: d,l-leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2. All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.

In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m2 and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.

A randomized controlled trial conducted by the NCCTG in patients with advanced metastatic colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.

Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin.

How Supplied/Storage and Handling

Each 50 mg single-use vial of Fusilev for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol.

50 mg vial of freeze-dried powder – NDC 68152-101-00.

Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light.

Fusilev Injection, 175 mg contains 17.5 mL sterile solution in a single-use vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

175 mg/17.5 mL solution – NDC 68152-102-01

Fusilev Injection, 250 mg contains 25 mL sterile solution in a single-use vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

250 mg/25 mL solution – NDC 68152-102-02

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used.

Manufactured for Spectrum Pharmaceuticals, Inc.

Irvine, CA 92618

Fusilev® is a registered trademark of Spectrum Pharmaceuticals, Inc.

18. Principal Display Panel

Fusilev Vial - Lyophilized

Fusilev Carton - Lyophilized

Fusilev Vial - 175 mg / 17.5 mL

Fusilev Carton - 175 mg / 17.5 mL

Fusilev Vial - 250 mg / 25 mL

Fusilev Carton - 250 mg / 25 mL

Fusilev  levoleucovorin  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 68152-101 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVOLEUCOVORIN CALCIUM (LEVOLEUCOVORIN) LEVOLEUCOVORIN 50 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength HYDROCHLORIC ACID   MANNITOL 50 mg  in 5 mL SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape