Pentostatin – Nipent®

Pentostatin - Nipent®

Usual Diluents

Dilution Data

Preparation of Intravenous Solution----------------------------------
1. Procedures for proper handling and disposal of anticancer drugs should be followed.
2. Protective clothing including polyethylene gloves must be worn.

3. Transfer 5 mL of sterile water for injection to the vial containing pentostatin and mix thoroughly to obtain complete dissolution of a solution yielding 2 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

4. Pentostatin may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% dextrose injection or 0.9% sodium chloride injection. Dilution of the entire contents of a reconstituted vial with 25 mL or 50 mL provides a pentostatin concentration of 0.33 mg/mL or 0.18 mg/mL, respectively, for the diluted solutions.

5. Pentostatin solution when diluted for infusion with 5% dextrose injection or 0.9% sodium chloride injection does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL.

Hydration: It is recommended that patients receive hydration with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent before pentostatin administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after pentostatin is given.

Stability---------------
Pentostatin vials are stable at refrigerated storage temperature 2° to 8°C (36° to 46°F) for the period stated on the package. Vials reconstituted or reconstituted and further diluted as directed may be stored at room temperature and ambient light but should be used within 8 hours because pentostatin contains no preservatives.     Storage: Store pentostatin vials under refrigerated storage conditions 2° to 8°C (36° to 46°F).

DESCRIPTION
Pentostatin for Injection is supplied as a sterile, apyrogenic, lyophilized powder in single-dose vials for intravenous administration. Each vial contains 10 mg of pentostatin and 50 mg of mannitol. The pH of the final product is maintained between 7.0 and 8.5 by addition of sodium hydroxide or hydrochloric acid.

Pentostatin, also known as 2'-deoxycoformycin (DCF), is a potent inhibitor of the enzyme adenosine deaminase. Pentostatin is known chemically as (R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol, with a molecular formula of C11H16N4O4 and a molecular weight of 268.27.

Pentostatin is a white to off-white solid, freely soluble in distilled water.

CLINICAL PHARMACOLOGY

Mechanism of Action
Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase (ADA). The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells and T-cell malignancies higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity, and this is believed to be due to elevated intracellular levels of dATP which can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. In addition to elevated dATP, these mechanisms may also contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin's antitumor effect, however, in hairy cell leukemia is not known.

Pharmacokinetics/Drug Metabolism
A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration.

In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes, the mean terminal half-life was 5.7 hours, the mean plasma clearance was 68 mL/min/m2, and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%.

A positive correlation was observed between pentostatin clearance and creatinine clearance (CrCl) in patients with creatinine clearance values ranging from 60 mL/min to 130 mL/min.1 Pentostatin half-life in patients with renal impairment (CrCl <50 mL/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CrCl >60 mL/min, n=14), about 6 hours.

INDICATIONS AND USAGE
Pentostatin is indicated as single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.

CONTRAINDICATIONS
Pentostatin is contraindicated in patients who have demonstrated hypersensitivity to pentostatin.

DOSAGE AND ADMINISTRATION
It is recommended that patients receive hydration with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent before pentostatin administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after pentostatin is given.

The recommended dosage of pentostatin for the treatment of hairy cell leukemia is 4 mg/m2 every other week. Pentostatin may be administered intravenously by bolus injection or diluted in a larger volume and given over 20 to 30 minutes. (See Preparation of Intravenous Solution.)

Higher doses are not recommended.

No extravasation injuries were reported in clinical studies.

The optimal duration of treatment has not been determined. In the absence of major toxicity and with observed continuing improvement, the patient should be treated until a complete response has been achieved. Although not established as required, the administration of two additional doses has been recommended following the achievement of a complete response.

All patients receiving pentostatin at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with pentostatin should be discontinued.

If the patient has achieved a partial response, pentostatin treatment should be continued in an effort to achieve a complete response. At any time thereafter that a complete response is achieved, two additional doses of pentostatin are recommended. Pentostatin treatment should then be stopped. If the best response to treatment at the end of 12 months is a partial response, it is recommended that treatment with pentostatin be stopped.

Withholding or discontinuation of individual doses may be needed when severe adverse reactions occur. Drug treatment should be withheld in patients with severe rash, and withheld or discontinued in patients showing evidence of nervous system toxicity.

Pentostatin treatment should be withheld in patients with active infection occurring during the treatment but may be resumed when the infection is controlled.

Patients who have elevated serum creatinine should have their dose withheld and a creatinine clearance determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (creatinine clearance <60 mL/min).

Patients with impaired renal function should be treated only when the potential benefit justifies the potential risk. Two patients with impaired renal function (creatinine clearances 50 to 60 mL/min) achieved complete response without unusual adverse events when treated with 2 mg/m2.

No dosage reduction is recommended at the start of therapy with pentostatin in patients with anemia, neutropenia, or thrombocytopenia. In addition, dosage reductions are not recommended during treatment in patients with anemia and thrombocytopenia if patients can be otherwise supported hematologically. Pentostatin should be temporarily withheld if the absolute neutrophil count falls during treatment below 200 cells/mm3 in a patient who had an initial neutrophil count greater than 500 cells/mm3 and may be resumed when the count returns to predose levels.

Preparation of Intravenous Solution

1. Procedures for proper handling and disposal of anticancer drugs should be followed. Several guidelines on this subject have been published.2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Spills and wastes should be treated with a 5% sodium hypochlorite solution prior to disposal.

2. Protective clothing including polyethylene gloves must be worn.

3. Transfer 5 mL of sterile water for injection to the vial containing pentostatin and mix thoroughly to obtain complete dissolution of a solution yielding 2 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

4. Pentostatin may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% dextrose injection or 0.9% sodium chloride injection. Dilution of the entire contents of a reconstituted vial with 25 mL or 50 mL provides a pentostatin concentration of 0.33 mg/mL or 0.18 mg/mL, respectively, for the diluted solutions.

5. Pentostatin solution when diluted for infusion with 5% dextrose injection or 0.9% sodium chloride injection does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL

Stability
Pentostatin vials are stable at refrigerated storage temperature 2° to 8°C (36° to 46°F) for the period stated on the package. Vials reconstituted or reconstituted and further diluted as directed may be stored at room temperature and ambient light but should be used within 8 hours because pentostatin contains no preservatives.

HOW SUPPLIED
Pentostatin for Injection is supplied as a sterile lyophilized white to off-white powder in single-dose vials containing 10 mg of pentostatin.

NDC 55390-244-01; individually boxed.

Storage: Store pentostatin vials under refrigerated storage conditions 2° to 8°C (36° to 46°F).

HANDLING:

1. Malspeis L, et al. Clinical pharmacokinetics of 2'-Deoxycoformycin. Cancer Treatment Symposia 2:7-15, 1984.

2. Recommendations for the safe handling of parenteral antineoplastic drugs. NIH Publication 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

3. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 253:1590-2, 1985.

4. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1:426-8, 1983.

6. Jones RB, et al. Safe handling of chemotherapeutic agents. A report from the Mount Sinai Medical Center CA. A Cancer Journal for Clinicians 33:258-63, 1983.

7. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 47:1033-49, 1990.