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Oforta

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Oforta

Oforta

CLINICAL PHARMACOLOGY

Mechanism of Action

Fludarabine phosphate (2F-ara-AMP) is a synthetic purine nucleotide antimetabolite agent. Upon administration, 2F-ara-AMP is rapidly dephosphorylated in the plasma to 2F-ara-A, which then enters into the cell. Intracellularly, 2F-ara-A is converted to the 5'-triphosphate, 2-fluoro-ara-ATP (2F-ara-ATP). 2F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into DNA. Once incorporated into DNA, 2F-ara-ATP functions as a DNA chain terminator, inhibits DNA polymerase alpha, gamma, and delta, and inhibits ribonucleoside diphosphate reductase. 2F-ara-A also inhibits DNA primase and DNA ligase I. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Pharmacodynamics

Cardiac Electrophysiology

In a randomized, uncontrolled, open-label, parallel study, patients with B-cell CLL were administered a single dose of Oforta™ 40 mg/m2 (n = 42) or intravenous fludarabine phosphate 25 mg/m (n=14). The maximum increase in the baseline-corrected mean change in QTcI (individual-corrected QT interval) following treatment with Oforta™ (fludarabine phosphate tablets) was less than 10 milliseconds.

Pharmacokinetics

Studies with the intravenous product have demonstrated that fludarabine phosphate is converted to the active metabolite, 2F-ara-A. Clinical pharmacology studies have focused on 2F-ara-A pharmacokinetics.

Following administration of the intravenous product, systemic plasma clearance of 2F-ara-A is approximately 117 mL/min to 145 mL/min. After five daily 30 minute intravenous infusions of 25 mg 2F-ara- AMP/m2 to cancer patients, trough concentrations of 2F-ara-A increased by a factor of about 2. The terminal half-life of 2F-ara-A was approximately 20 hours. Plasma protein binding of 2F-ara-A was approximately 19% to 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

2F-ara-A exhibits dose proportional increases in AUC and Cmax after single oral doses of 50 mg, 70 mg or 90 mg of 2F-ara-AMP. Cmax of 2F-ara-A occurs 1 hour to 2 hours after single or multiple oral doses and is approximately 20 % to 30 % of the maximum plasma concentrations produced at the end of a 30 minute intravenous infusion of the same dose. The absolute oral bioavailability of 2F-ara-A is 50 - 65% following single and repeated doses of Oforta™ (fludarabine phosphate tablets) . Similar systemic exposure (AUC) was observed after a single 40 mg/m Oforta™ and a single 25 mg/m2 fludarabine phosphate intravenous dose. The terminal half-life of 2F-ara-A was similar to that following intravenous administration; approximately 20 hours. The Cmax, AUC and terminal half-life of 2F-ara-A are unaffected when administered with a high fat meal, although Tmax is slightly delayed from 1.3 hours to 2.2 hours.

Following intravenous administration, renal clearance of 2F-ara-A represents approximately 40% of the total body clearance of fludarabine phosphate, and total body clearance is inversely correlated with serum creatinine and creatinine clearance. In two patients with median creatinine clearance of 22 mL/min/1.73 m2, 2F-ara-A clearance was reduced by 56%. Dosage adjustment based on creatinine clearance is recommended as follows:

Reduce dose by 20% in patients with mild to moderate renal impairment (creatinine clearance 30 to 70 mL/min/1.73 m2). [See WARNINGS AND PRECAUTIONS]

Reduce dose by 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2). [See WARNINGS AND PRECAUTIONS]

Clinical Studies

Study 1, a single-arm, open-label study of Oforta™ (fludarabine phosphate tablets) was conducted in 78 adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In this multicenter study patients were treated with Oforta™ (fludarabine phosphate tablets) at a dose of 40 mg/m daily for 5 days every 28 days. The patient population median age was 64.5 years and consisted of 72% males and 28% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.9%), Stage I (20.5%), Stage II (32.1%), Stage III (11.5%), and Stage IV (32.1%). The mean number of treatment cycles was 5.1 with a mean daily dose of Oforta™ (fludarabine phosphate tablets) of 38 mg/m2. The overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 51%, including 18% complete responses and 33% partial responses. The overall response rate, according to standardized criteria developed by the International Workshop on CLL (IWCLL criteria), was 46%, including 21% complete responses and 26% partial responses. Data on duration of response was not collected.

In Study 2, a supportive single-arm, open-label study, Oforta™ (fludarabine phosphate tablets) was administered to 81 previously untreated patients with B-CLL. In this multicenter study each patient was treated with Oforta™ (fludarabine phosphate tablets) at a dose of 40 mg/m2 daily for 5 days every 28 days. The patient population median age was 64.0 years and consisted of 63% males and 37% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.7%), Stage I (37.0%), Stage II (37.0%), Stage III (9.9%), and Stage IV (12.3%). The mean number of treatment cycles was 5.9 with a mean daily dose per patient of 71 mg to 74 mg. The overall responses rate, according to NCI criteria, was 80%, including 12% complete responses and 68% partial responses. The overall response rate, according to IWCLL criteria, was 72%, including 37% complete responses and 35% partial responses. The median duration of response was 22.9 months.

Study 3 was a supportive randomized controlled open label study in patients with previously untreated B-CLL that included fludarabine phosphate monotherapy and fludarabine phosphate combination therapy arms. In this study 107 evaluable patients received Oforta™ (fludarabine phosphate tablets) 40mg/m orally daily for 5 days every 28 days. The overall response rate according to modified NCI criteria was 74% and the CR plus nodular PR rate was 41%.

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2 .html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 8/5/2009
This monograph has been modified to include the generic and brand name in many instances.

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