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, USP. 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 and is isolated from fermentation cultures of Streptomyces antibioticus. Pentostatin is known chemically as (R)-3-(2-deoxy-ß-D-erythropentofuranosyl)3,6,7,8 tetrahydroimidazo[4,5d][1,3]diazepin-8-ol with a molecular formula of C11H16N4O4 and a molecular weight of 268.27. The molecular structure of pentostatin is:

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

The following table provides efficacy results for 4 groups (columns) of patients with hairy cell leukemia: patients who initially received pentostatin, patients who initially received alpha-interferon (IFN), and 2 different groups of patients who received pentostatin after proving to be refractory to, or intolerant of IFN therapy. The first 2 groups represent treatment results from the SWOG 8691 study, a large multicenter study comparing pentostatin and IFN in untreated (frontline) patients with confirmed hairy cell leukemia. The third group represents evaluable patients from the SWOG study who crossed over to pentostatin after initially receiving IFN. The fourth group, labeled NCI Phase 2 studies, displays pooled results of 2 noncomparative studies (MD Anderson and CALGB), in which pentostatin was used to treat patients with confirmed IFN-refractory disease.

In the SWOG 8691 study, pentostatin was administered at a dose of 4 mg/m2 every 2 weeks. After 6 months of treatment, patients were evaluated for response. If a complete response was achieved, 2 additional doses of pentostatin were administered and then discontinued. If a partial response was achieved, pentostatin was continued for up to an additional 6 months. Pentostatin was discontinued for stable disease after 6 months or progressive disease after 2 months of therapy. IFN was administered 3 million units subcutaneously 3 times per week. Patients who achieved a complete or partial response after 6 months of treatment continued on IFN for another 6 months. IFN was discontinued if patients did not achieve a complete or partial response after 6 months of initial treatment or progressed after 2 months. This study allowed crossover of patients intolerant of, or refractory to, initial treatment.

Interferon-refractory patients enrolled into the MD Anderson study received pentostatin at a dose of 4 mg/m2 every other week for 3 months and responding patients received 3 additional months. CALGB patients received 4 mg/m2 of pentostatin every other week for 3 months and responding patients were treated monthly for up to 9 additional months. Almost all patients had a PS of 0 to 2 in the Phase 2 and 3 studies.

For each study, a complete response (CR) required clearing of the peripheral blood and bone marrow of all hairy cells, normalization of organomegaly and lymphadenopathy by physical examination, and recovery of hemoglobin to at least 12 g/dL, platelet count to at least 100,000/mm3, and granulocyte count to at least 1500/mm3. A partial response (PR) required that the percentage of hairy cells in the blood and bone marrow decrease by more than 50%, enlarged organs and lymph nodes decrease by more than 50% by physical examination, and hematologic parameters had to meet the same criteria as for complete response. The table below reports the response rate for 2 groups of patients: (1) Evaluable, i.e., patients who could be evaluated for response and (2) Intent-to-Treat, i.e., patients diagnosed with hairy cell leukemia.

The results show that frontline patients treated with pentostatin achieved a significantly higher rate of response than those treated with IFN. The time to recovery of neutrophil and platelet counts was shorter with pentostatin treatment and the estimated duration of response was longer. The response rate in IFN-refractory patients treated with pentostatin was similar to that in pentostatin-treated frontline patients. At a median follow-up duration of 46 months, there was no statistically significant difference in survival between hairy cell leukemia patients initially treated with pentostatin and those initially treated with IFN. However, no definite conclusions regarding survival can be made from these results because they are complicated by the fact that the majority of IFN patients crossed over to pentostatin treatment.

In the Phase 3 SWOG study, 25 patients with hairy cell leukemia died during treatment or follow-up: 18 patients had last received pentostatin (3 of whom had crossed over from IFN), and 7 patients had last received IFN (1 of whom crossed over from pentostatin). Eleven of the 25 deaths occurred within 60 days of the last dose of treatment. Of these, hairy cell leukemia was cited by the investigators as a contributory cause for 1 death in the pentostatin group and 3 deaths in the IFN group. Additionally, infection contributed to the deaths of 3 patients in the pentostatin group and 2 patients in the IFN group. Approximately 4% of hairy cell leukemia patients, in each arm, died more than 60 days after the last dose of either treatment and there was no outstanding cause of death among these patients.

Pentostatin for injection 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.

Pentostatin for injection is contraindicated: In patients who have demonstrated hypersensitivity to pentostatin.

See Boxed Warning.

Patients with hairy cell leukemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to pentostatin treatment have in some cases developed worsening of their condition leading to death, whereas others have achieved complete response. Patients with infection should be treated only when the potential benefit of treatment justifies the potential risk to the patient. Efforts should be made to control the infection before treatment is initiated or resumed.

In patients with progressive hairy cell leukemia, the initial courses of pentostatin treatment were associated with worsening of neutropenia. Therefore, frequent monitoring of complete blood counts during this time is necessary. If severe neutropenia continues beyond the initial cycles, patients should be evaluated for disease status, including a bone marrow examination.

Elevations in liver function tests occurred during treatment with pentostatin and were generally reversible.

Renal toxicity was observed at higher doses in early studies; however, in patients treated at the recommended dose, elevations in serum creatinine were usually minor and reversible. There were some patients who began treatment with normal renal function who had evidence of mild to moderate toxicity at a final assessment (See DOSAGE AND ADMINISTRATION).

Rashes, occasionally severe, were commonly reported and may worsen with continued treatment. Withholding of treatment may be required (See DOSAGE AND ADMINISTRATION).

Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.

Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 studies and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with pentostatin (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (e.g., infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were assessed for severity were either mild or moderate, and diminished in frequency with continued therapy.

The total incidence for all types of infections is considerably higher for both treatment groups in the SWOG 8691 study than is listed in the table above. An intent-to-treat analysis of infections found that 38% of patients treated with pentostatin and 34% of patients treated with IFN averaged 2.4 and 1.9 documented infections during treatment, respectively. The following table lists the different types of infections that were reported as adverse events during the initial phase of the SWOG study. There were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for pentostatin (8%) than for IFN (1%).

The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of pentostatin-treated patients in the initial phase of the SWOG study:

Body as a Whole - Chest Pain, Death, Face Edema, Peripheral Edema

Cardiovascular System - Hemorrhage, Hypotension

Digestive System - Dental Abnormalities, Dyspepsia, Flatulence, Gingivitis

Hematologic System - Agranulocytosis

Laboratory Deviations - Elevated Creatinine

Musculoskeletal System - Arthralgia

Nervous System - Confusion, Dizziness, Insomnia, Paresthesia, Somnolence

Psychobiologic Function - Anxiety, Depression, Nervousness

Respiratory System - Asthma

Skin and Appendages - Skin Dry, Urticaria

The remaining adverse events which occurred in less than 3% of pentostatin for Injection-treated patients during the initial phase of the SWOG study:

Body as a Whole - Flu-like Symptoms, Hangover Effect, Neoplasm

Cardiovascular System - Angina Pectoris, Arrhythmia, A-V Block, Bradycardia, Extrasystoles Ventricular, Heart Arrest, Heart Failure, Hypertension, Pericardial Effusion, Phlebitis, Pulmonary Embolus, Sinus Arrest, Tachycardia, Thrombophlebitis Deep, Vasculitis

Digestive System - Constipation, Dysphagia, Glossitis, Ileus

Hematologic System - Acute Leukemia, Anemia-Hemolytic, Aplastic Anemia

Laboratory Deviations - Hypercalcemia, Hyponatremia

Musculoskeletal System - Arthritis, Gout

Nervous System - Amnesia, Ataxia, Convulsions, Dreaming Abnormal, Dysarthria, Encephalitis, Hyperkinesia, Meningism, Neuralgia, Neuritis, Neuropathy, Paralysis, Syncope, Twitching, Vertigo

Psychobiologic Function - Decrease/Loss Libido, Emotional Lability, Hallucination, Hostility, Neurosis, Thinking Abnormal

Respiratory System - Bronchospasm, Larynx Edema

Skin and Appendages - Acne, Alopecia, Eczema, Petechial Rash, Photosensitivity Reaction

Special Senses - Amblyopia, Deafness, Earache, Eyes Dry, Labyrinthitis, Lacrimation Disorder, Nonreactive Eye, Photophobia, Retinopathy, Tinnitus, Unusual Taste, Vision Abnormal, Watery Eyes

Urogenital System - Amenorrhea, Breast Lump, Impotence, Kidney Function Abnormal, Nephropathy, Renal Failure, Renal Insufficiency, Renal Stone

One patient with hairy cell leukemia treated with pentostatin during another clinical study developed unilateral uveitis with vision loss.

Nineteen (5%) patients withdrew from the Phase 3 SWOG 8691 study because of adverse events; 9 during initial pentostatin treatment, 4 during pentostatin crossover, 5 during initial IFN treatment, and 1 during both initial IFN treatment and pentostatin crossover. In the Phase 2 studies in IFN-refractory hairy cell leukemia, 11% of patients withdrew from treatment with pentostatin due to an adverse event.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pentostatin. 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.

Hematologic System—Febrile Neutropenia, Hemolytic Uremic Syndrome, Thrombotic Thrombocytopenic Purpura, Autoimmune Thrombocytopenia

Respiratory System—Acute Respiratory Failure

Skin and Appendages—Exfoliative Dermatitis

No specific antidote for pentostatin overdose is known. Pentostatin administered at higher doses (20-50 mg/m2 in divided doses over 5 days) than recommended was associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity. In case of overdose, management would include general supportive measures through any period of toxicity that occurs.

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 for injection administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after pentostatin for injection is given.

The recommended dosage of pentostatin for injection for the treatment of hairy cell leukemia is 4 mg/m2 every other week. Pentostatin for injection 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 for injection should be discontinued.

If the patient has achieved a partial response, pentostatin for injection 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 for injection are recommended. Pentostatin for injection 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 for injection 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 for injection 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 CLcr determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (CLcr < 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 (CLcr 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 for injection 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 for injection 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.

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

NDC 67457-288-05

carton containing one vial

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

Preservative Free.

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.

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured by:

NerPharMa srl

V.le Pasteur 10

20014 Nerviano (MI), Italy

Revised: 09/2022

NDC 67457-288-05      10 mg

Pentostatin

for Injection

10 mg/vial

For Intravenous

Administration

MUST BE DILUTED

CAUTION: Cytotoxic Agent

Rx only     Single-Dose Vial

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Made in Italy

Mylan.com

Preservative Free

Sterile and apyrogenic.

Each vial contains: 10 mg of

pentostatin as a lyophilized powder

for reconstitution with 5 mL of

Sterile Water for Injection, USP to

yield a solution containing 2 mg/mL.

Each vial also contains the following

inactives: Mannitol, USP and sodium

hydroxide and/or hydrochloric acid

added to adjust pH.

Usual Dosage: See accompanying

prescribing information.

Each vial delivers the equivalent of

10 mg of pentostatin 2 mg/mL when

reconstituted as directed.

Keep this and all drugs out of the

reach of children.

Store vials under refrigeration

2° to 8°C (36° to 46°F).