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PENTOSTATIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pentostatin, also known as 2'-deoxycoformycin, is an antimetabolite and a purine nucleoside analogue capable of inhibiting adenosine deaminase.

Specific Substances

    1) CI-825
    2) Deoxycoformycin
    3) 2'-Deoxycoformycin
    4) NSC-218321
    5) PD-81565
    6) Pentostatina
    7) Pentostatine
    8) Pentostatinum
    9) CAS 53910-25-1
    1.2.1) MOLECULAR FORMULA
    1) C11-H16-N4-O4 (Prod Info NIPENT(R) IV injection, 2007)

Available Forms Sources

    A) FORMS
    1) Pentostatin is available as intravenous powder for solution in single-dose vials containing 10 mg of pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    B) USES
    1) Pentostatin is used to treat alpha-interferon-refractory hairy cell leukemia in patients with active disease, defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms (Prod Info NIPENT(R) IV injection, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pentostatin is used to treat alpha-interferon-refractory hairy cell leukemia in patients with active disease, defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
    B) PHARMACOLOGY: Pentostatin is a potent inhibitor of the enzyme adenosine deaminase (ADA). Inhibition of ADA leads to cytotoxicity which is believed to be due to elevated intracellular levels of deoxyadenosine 5'-triphosphate (dATP) that block DNA synthesis by inhibiting ribonucleotide reductase. Additionally, pentostatin can inhibit RNA synthesis and cause DNA damage. The exact mechanism for the antitumor effect in patients with hairy cell leukemia is unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) GREATER THAN 10%: Pruritus, rash, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, genitourinary disorder, leukopenia, anemia, granulocytopenia, myalgia, headache, asthenia, fatigue, cough, upper respiratory infection, rhinitis, lung disorder, dyspnea, fever, and chills. UP TO 10%: Chest pain, hypotension, peripheral edema, skin disorder, urticaria, dry skin, gingivitis, dyspepsia, increased serum creatinine, agranulocytosis, thrombocytopenia, arthralgia, paresthesia, insomnia, dizziness, somnolence, confusion, anxiety, nervousness, depression, asthma, pharyngitis, and unspecified infection. OTHER EFFECTS: Acute allergic reaction, nephropathy, renal failure, renal insufficiency, seizures, elevated liver enzymes, and hemolytic anemia.
    2) Although the drug association of some adverse events, such as infections or hematological suppression, is uncertain as they may be associated with the disease itself, other events, such as gastrointestinal symptoms, rash, and elevated liver enzymes may be attributed to the drug.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Exceeding the recommended dose has been associated with a more rapid onset of typical adverse effects. High doses of pentostatin (20 to 50 mg/m(2) in divided doses over 5 days) were associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity.
    0.2.20) REPRODUCTIVE
    A) Pentostatin has been classified as FDA pregnancy category D. There have been no studies on the use of pentostatin during pregnancy or reports of congenital malformations caused by maternal use. However, pentostatin was teratogenic, embryolethal, and maternally toxic in animal studies.
    0.2.21) CARCINOGENICITY
    A) SECONDARY MALIGNANCIES
    1) Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use.
    2) Lymphoid neoplasms have been reported in humans (Crump et al, 1991).

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Hematologic effects, such as neutropenia and thrombocytopenia may occur following pentostatin exposure. Monitor serial CBCs with differential, including platelets, for several weeks following an overdose.
    C) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.
    E) Monitor renal function and hepatic enzymes in patients with significant exposure.
    F) Monitor vital signs frequently. Initiate continuous cardiac monitoring and obtain an ECG in symptomatic patients.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBCs with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    2) INTRATHECAL INJECTION: No clinical reports ARE available, information IS derived from experience with other antineoplastics. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 mL/hr). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms, significant CNS depression, or severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors if patients develop severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBCs with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    H) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    I) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    J) STOMATITIS/MUCOSITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a pentostatin overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    K) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of pentostatin from plasma. Hemodialysis is unlikely to be of value because of the large volume of distribution.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours) and daily monitoring of CBCs with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking pentostatin may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    N) PHARMACOKINETICS
    1) Protein binding: 4%. Vd: 36.1 L. Metabolism: Liver. Renal excretion: Approximately 90% as unchanged pentostatin and/or metabolites. Elimination half-life: 3 to 15 hours (mean 5.7 hours).
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression, primarily other antineoplastics.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. High doses of pentostatin (20 to 50 mg/m(2) in divided doses over 5 days) were associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity.
    B) THERAPEUTIC DOSES: ADULT: 4 mg/m(2) by bolus injection or IV infusion over 20 to 30 min every other week. CHILD: The safety and effectiveness of pentostatin in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Pentostatin is used to treat alpha-interferon-refractory hairy cell leukemia in patients with active disease, defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
    B) PHARMACOLOGY: Pentostatin is a potent inhibitor of the enzyme adenosine deaminase (ADA). Inhibition of ADA leads to cytotoxicity which is believed to be due to elevated intracellular levels of deoxyadenosine 5'-triphosphate (dATP) that block DNA synthesis by inhibiting ribonucleotide reductase. Additionally, pentostatin can inhibit RNA synthesis and cause DNA damage. The exact mechanism for the antitumor effect in patients with hairy cell leukemia is unknown.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) GREATER THAN 10%: Pruritus, rash, nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, genitourinary disorder, leukopenia, anemia, granulocytopenia, myalgia, headache, asthenia, fatigue, cough, upper respiratory infection, rhinitis, lung disorder, dyspnea, fever, and chills. UP TO 10%: Chest pain, hypotension, peripheral edema, skin disorder, urticaria, dry skin, gingivitis, dyspepsia, increased serum creatinine, agranulocytosis, thrombocytopenia, arthralgia, paresthesia, insomnia, dizziness, somnolence, confusion, anxiety, nervousness, depression, asthma, pharyngitis, and unspecified infection. OTHER EFFECTS: Acute allergic reaction, nephropathy, renal failure, renal insufficiency, seizures, elevated liver enzymes, and hemolytic anemia.
    2) Although the drug association of some adverse events, such as infections or hematological suppression, is uncertain as they may be associated with the disease itself, other events, such as gastrointestinal symptoms, rash, and elevated liver enzymes may be attributed to the drug.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Exceeding the recommended dose has been associated with a more rapid onset of typical adverse effects. High doses of pentostatin (20 to 50 mg/m(2) in divided doses over 5 days) were associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In a phase 3 study in patients with hairy cell leukemia, fever was reported in 46% of patients who received frontline therapy with pentostatin (n=180) compared with 59% of patients who received frontline therapy with interferon (n=176). Additionally, fever occurred in 42% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    2) CHILLS: In a phase 3 study in patients with hairy cell leukemia, chill was reported in 19% of patients who received frontline therapy with pentostatin (n=180) compared with 34% of patients who received frontline therapy with interferon (n=176). Additionally, chill occurred in 11% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    3) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, fever developed in 11 (26%) patients (Tsimberidou et al, 2004).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Abnormal vision, amblyopia, conjunctivitis, dry eyes, lacrimation disorder, nonreactive eye, photophobia, retinopathy, and watery eyes have all been reported in less than 3% of patients following pentostatin administration (Prod Info NIPENT(R) IV injection, 2007; Black & Livingston, 1990).
    2) In a clinical study, unilateral uveitis and vision loss occurred in a patient with hairy cell leukemia treated with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Deafness, earache, labyrinthitis, and tinnitus occurred in less than 3% of pentostatin-treated patients during the initial phase of the SWOG study (Prod Info NIPENT(R) IV injection, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, chest pain occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, hypotension occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, peripheral edema occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, cough or increased cough was reported in 20% of patients who received frontline therapy with pentostatin (n=180) compared with 15% of patients who received frontline therapy with interferon (n=176). Additionally, cough or increased cough occurred in 17% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, upper respiratory infection was reported in 13% of patients who received frontline therapy with pentostatin (n=180) compared with 8% of patients who received frontline therapy with interferon (n=176). Additionally, upper respiratory infection occurred in 16% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    C) RHINITIS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, rhinitis was reported in 11% of patients who received frontline therapy with pentostatin (n=180) compared with 15% of patients who received frontline therapy with interferon (n=176). Additionally, rhinitis occurred in 10% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    D) DISORDER OF LUNG
    1) WITH THERAPEUTIC USE
    a) Lung disorder or disease occurred in 12% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    E) ASTHMA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, asthma was reported in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    F) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, pharyngitis was reported in 8% of patients who received frontline therapy with pentostatin (n=180) compared with 11% of patients who received frontline therapy with interferon (n=176). Additionally, pharyngitis occurred in 10% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    G) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, dyspnea was reported in 11% of patients who received frontline therapy with pentostatin (n=180) compared with 13% of patients who received frontline therapy with interferon (n=176). Additionally, dyspnea occurred in 8% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    H) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Acute pulmonary edema leading to death has occurred when pentostatin has been used in combination with chemotherapeutic agents such as fludarabine, carmustine, etoposide, and cyclophosphamide (Prod Info NIPENT(R) IV solution, 1998).
    I) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, bronchospasm developed in one (2%) patient (Tsimberidou et al, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROTOXICITY
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, central nervous system toxicity was reported in 1% of patients who received frontline therapy with pentostatin (n=180). Additionally, central nervous system toxicity occurred in 11% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, headache was reported in 17% of patients who received frontline therapy with pentostatin (n=180) compared with 29% of patients who received frontline therapy with interferon (n=176). Additionally, headache occurred in 13% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, asthenia was reported in 12% of patients who received frontline therapy with pentostatin (n=180) compared with 13% of patients who received frontline therapy with interferon (n=176). Additionally, asthenia occurred in 10% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    D) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, paresthesia occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    E) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, insomnia occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, dizziness occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    G) DROWSY
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, somnolence occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    H) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, confusion occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    I) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, fatigue was reported in 42% of patients who received frontline therapy with pentostatin (n=180) compared with 55% of patients who received frontline therapy with interferon (n=176). Additionally, fatigue occurred in 29% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    b) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, fatigue developed in 7 (17%) patients (Tsimberidou et al, 2004).
    J) ANXIETY
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, anxiety was reported in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    K) FEELING NERVOUS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, nervousness was reported in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    L) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In one study, lethargy, coma, and seizures were reported following pentostatin administration, however, these dose-limiting severe toxicities have been most frequently associated with doses greater than 4 mg/m(2) (Black & Livingston, 1990).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) EOSINOPHILIC GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 43-year-old man developed eosinophilic gastroenteritis while receiving pentostatin therapy for the treatment of newly diagnosed hairy cell leukemia (HCL). Following HCL diagnosis, the patient was given pentostatin 4 mg/m(2) IV every 2 weeks (6 cycles planned), trimethoprim-sulfamethoxazole for PCP prophylaxis, and dolasetron. His peripheral blood eosinophil count started rising after the third dose of pentostatin; by the fifth dose, the patient complained of abdominal pain and heartburn unrelieved by omeprazole. Esophagogastroduodenoscopy revealed findings consistent with eosinophilic gastritis; including a nonobstructive Schatzki ring in the distal esophagus, diffuse patchy erythema in the gastric body and the antrum, and duodenitis in the duodenal bulb. Biopsies showed eosinophilic infiltrates from the distal esophagus to the stomach, antrum, and distal duodenum. Helicobacter pylori or leukemia cell infiltrates were not present. Complete remission was achieved after the 4th cycle of pentostatin therapy. Within 2 weeks of discontinuing pentostatin, his gastrointestinal symptoms and peripheral blood eosinophilia resolved without the use of immunosuppressive therapy. After 2 years of follow-up, the patient remains in complete remission (Shouval et al, 2010).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, nausea and/or vomiting was reported in 63% of patients who received frontline therapy with pentostatin (n=180) compared with 22% of patients who received frontline therapy with interferon (n=176). Additionally, nausea with vomiting occurred in 53% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    b) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, nausea/vomiting, diarrhea, and pancreatitis developed in 9 (21%), 3 (7%), and 3 (7%) patients, respectively (Tsimberidou et al, 2004).
    c) In another phase 2 study of 16 patients (3 therapy naive and 13 pretreated) with splenic marginal zone lymphoma, nausea and vomiting (grade equal or less than 2) developed in one patient (Iannitto et al, 2005).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, diarrhea was reported in 17% of patients who received frontline therapy with pentostatin (n=180) and 17% of patients who received frontline therapy with interferon (n=176). Additionally, diarrhea occurred in 15% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, abdominal pain was reported in 16% of patients who received frontline therapy with pentostatin (n=180) compared with 15% of patients who received frontline therapy with interferon (n=176). Additionally, abdominal pain occurred in 4% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    E) GINGIVITIS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, gingivitis occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    F) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, dyspepsia occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    G) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, anorexia was reported in 13% of patients who received frontline therapy with pentostatin (n=180) compared with 10% of patients who received frontline therapy with interferon (n=176). Additionally, anorexia occurred in 16% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    H) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, stomatitis was reported in 12% of patients who received frontline therapy with pentostatin (n=180) compared with 7% of patients who received frontline therapy with interferon (n=176). Additionally, stomatitis occurred in 5% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes or reversible hepatitis have been reported to occur in up to 19% of those administered pentostatin; usually associated with the use of higher doses (greater than 4 mg/m(2)/dose) (Prod Info NIPENT(R) IV injection, 2007; Black & Livingston, 1990; O'Dwyer et al, 1988a).
    b) In another Phase 2 study of 16 patients (3 therapy naive and 13 pretreated) with splenic marginal zone lymphoma, aminotransferase levels (grade equal or less than 2) increased in a patient after the fourth cycle (AST 3 x n; ALT 4 x n) without other clinical or biochemical signs of liver toxicity. The levels returned to normal after one month (Iannitto et al, 2005).
    B) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes or reversible hepatitis have been reported to occur in up to 19% of those administered pentostatin; usually associated with the use of higher doses (greater than 4 mg/m(2)/dose) (Prod Info NIPENT(R) IV injection, 2007; Black & Livingston, 1990; O'Dwyer et al, 1988a).
    b) In a phase 3 study in patients with hairy cell leukemia, elevated liver enzymes were reported in 2% of patients who received frontline therapy with pentostatin (n=180) and 2% of patients who received frontline therapy with interferon (n=176). Additionally, liver function test elevations occurred in 19% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, nephropathy was reported in less than 3% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure reported following pentostatin administration has been most frequently associated with doses greater than 4 mg/m(2) (Black & Livingston, 1990).
    b) In a phase 3 study in patients with hairy cell leukemia, renal failure was reported in less than 3% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007)
    c) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, renal insufficiency developed in 8 (19%) patients which was reversible in 7 patients (Tsimberidou et al, 2004).
    d) CASE REPORT: A 62-year-old man with cutaneous T-cell lymphoma treated with pentostatin and interferon alpha developed microangiopathic hemolytic anemia and renal failure. He had been treated with pentostatin 5 mg/m(2) on days 1 through 5 and with interferon alpha 3 million units subcutaneously 3 times weekly for 1 week along with amifostine. On day 15 he developed epistaxis, prostration, and headache. Lab results revealed an increased blood urea nitrogen and serum creatinine. Hemolytic anemia with microangiopathic red cell changes and thrombocytopenia was also present (platelet count 93 x 10(9)/L). Needle biopsy of the kidney was performed which showed proliferative glomerulonephritis with thickening of the capillary wall, swelling of endothelial cells, mesangiolysis and leukocyte infiltration. Ultrastructural studies showed the expansion of the subendothelial space by finely granular material. The man was treated with plasma infusions, dialysis, and ventilatory support. He eventually succumbed to multiple organ failure (Antunes et al, 1999).
    C) DISORDER OF THE GENITOURINARY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Genitourinary disorder occurred in 15% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    D) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, increased serum creatinine occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Myelosuppression, including severe or worsening neutropenia, has been reported with pentostatin use in clinical studies (Prod Info NIPENT(R) IV injection, 2007).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, leukopenia was reported in 22% of patients who received frontline therapy with pentostatin (n=180) compared with 15% of patients who received frontline therapy with interferon (n=176). Additionally, leukopenia occurred in 60% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, anemia was reported in 8% of patients who received frontline therapy with pentostatin (n=180) compared with 5% of patients who received frontline therapy with interferon (n=176). Additionally, anemia occurred in 35% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    b) In another phase 2 study of 16 patients (3 therapy naive and 13 pretreated) with splenic marginal zone lymphoma, neutropenia (grade equal or less than 2), anemia, and thrombocytopenia developed in 6, 2, and 1 patients, respectively (Iannitto et al, 2005).
    D) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, agranulocytosis occurred in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, thrombocytopenia was reported in 6% of patients who received frontline therapy with pentostatin (n=180) and 6% of patients who received frontline therapy with interferon (n=176). Additionally, thrombocytopenia occurred in 32% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    b) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, granulocytopenia and thrombocytopenia developed in 15 (36%) and 9 (21%) patients, respectively. In this study, the most common long-term toxicity was CD4 suppression (Tsimberidou et al, 2004).
    c) In another phase 2 study of 16 patients (3 therapy naive and 13 pretreated) with splenic marginal zone lymphoma, neutropenia (grade equal or less than 2), anemia, and thrombocytopenia developed in 6, 2, and 1 patients, respectively (Iannitto et al, 2005).
    F) GRANULOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, granulocytopenia and thrombocytopenia developed in 15 (36%) and 9 (21%) patients, respectively. In this study, the most common long-term toxicity was CD4 suppression (Tsimberidou et al, 2004).
    G) HEMOLYTIC UREMIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 48-year-old woman treated with pentostatin for cutaneous T-cell lymphoma developed thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. She had received pentostatin 5 mg/m(2) for 3 days when she developed abdominal cramps, nausea, vomiting, fever, and chills. Her course continued with severe thrombocytopenia, and microangiopathic hemolytic anemia (hematocrit 21%, platelet count 28,000/microliter). One week later, she became disoriented and suffered from hallucinations. Plasma exchange treatment using fresh frozen plasma was initiated. She continued to decline and plasma exchange was increased to twice daily. Methylprednisolone 100 mg/day was added. Oliguric acute renal failure developed requiring hemodialysis. With this regimen her status gradually improved. Plasma exchange was discontinued after 37 treatments. She remained active and her cutaneous T-cell lymphoma remained stable (Leach et al, 1999).
    b) CASE REPORT: A 62-year-old man with cutaneous T-cell lymphoma treated with pentostatin and interferon alpha developed microangiopathic hemolytic anemia and renal failure. He had been treated with pentostatin 5 mg/m(2) on days 1 through 5 and with interferon alpha 3 million units subcutaneously 3 times weekly for 1 week along with amifostine. On day 15 he developed epistaxis, prostration, and headache. Lab results revealed an increased blood urea nitrogen and serum creatinine. Hemolytic anemia with microangiopathic red cell changes and thrombocytopenia was also present (platelet count 93 x 10(9)/L). Needle biopsy of the kidney was performed which showed proliferative glomerulonephritis with thickening of the capillary wall, swelling of endothelial cells, mesangiolysis and leukocyte infiltration. Ultrastructural studies showed the expansion of the subendothelial space by finely granular material. The man was treated with plasma infusions, dialysis, and ventilatory support. He eventually succumbed to multiple organ failure (Antunes et al, 1999).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, pruritus was reported in 21% of patients who received frontline therapy with pentostatin (n=180) compared with 6% of patients who received frontline therapy with interferon (n=176). Additionally, pruritus occurred in 10% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, rash was reported in 43% of patients who received frontline therapy with pentostatin (n=180) compared with 30% of patients who received frontline therapy with interferon (n=176). Additionally, rash occurred in 26% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    C) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, skin disorder was reported in 4% of patients who received frontline therapy with pentostatin (n=180) compared with 5% of patients who received frontline therapy with interferon (n=176). Additionally, skin disorder occurred in 17% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    D) URTICARIA
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, urticaria was reported in 3% to 10% of patients who received frontline therapy with pentostatin (Prod Info NIPENT(R) IV injection, 2007).
    E) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, dry skin was reported in 3% to 10% of patients who received frontline therapy with pentostatin(Prod Info NIPENT(R) IV injection, 2007).
    F) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, sweating or increased sweating was reported in 8% of patients who received frontline therapy with pentostatin (n=180) compared with 21% of patients who received frontline therapy with interferon (n=176). Additionally, sweating or increased sweating occurred in 10% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    G) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Acne, alopecia, eczema, petechiae, photosensitivity, herpes zoster, seborrhea, and skin abscess have also been associated with pentostatin administration (Prod Info NIPENT(R) IV solution, 1998)
    b) In a phase 2 study of patients (n=42) treated with pentostatin for advanced T-cell lymphoid malignancies, transient flare (increased skin redness or erythema/edema at the site of disease within 1 week after chemotherapy) developed in 9 (21%) patients (Tsimberidou et al, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, arthralgia was reported in 6% of patients who received frontline therapy with pentostatin (n=180) compared with 14% of patients who received frontline therapy with interferon (n=176). Additionally, arthralgia occurred in 3% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a phase 3 study in patients with hairy cell leukemia, myalgia was reported in 19% of patients who received frontline therapy with pentostatin (n=180) compared with 36% of patients who received frontline therapy with interferon (n=176). Additionally, myalgia occurred in 11% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions such as skin rash, pruritus, fever, flushing, edema, and eosinophilia have all occurred in association with pentostatin administration (Iannitto et al, 2005; O'Dwyer et al, 1989). The occurrence of a fatal hypersensitivity vasculitis in association with concomitant pentostatin and allopurinol therapy was reported (Steinmetz et al, 1989).
    b) In a phase 3 study in patients with hairy cell leukemia, allergic reaction was reported in 2% of patients who received frontline therapy with pentostatin (n=180) compared with 1% of patients who received frontline therapy with interferon (n=176). Additionally, allergic reaction occurred in 11% of interferon-refractory, hairy cell leukemia patients who received pentostatin in clinical studies (n=197) (Prod Info NIPENT(R) IV injection, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Pentostatin has been classified as FDA pregnancy category D. There have been no studies on the use of pentostatin during pregnancy or reports of congenital malformations caused by maternal use. However, pentostatin was teratogenic, embryolethal, and maternally toxic in animal studies.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Although teratogenic effects have not been reported with pentostatin, the teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by the majority of practitioners as the most critical for abnormal fetal development. In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations and when given during the second or third trimesters are believed to increase the risk of growth retardation (Glantz, 1994; Doll et al, 1988).
    B) ANIMAL STUDIES
    1) MICE - Teratogenic effects were observed when pregnant mice were administered a single 2 mg/kg (6 mg/m(2)) intraperitoneal injection on day 7 of gestation (Prod Info NIPENT(R) IV injection, 2007)
    2) RATS - When IV pentostatin at doses of 0.1 and 0.75 mg/kg/m(2) (0.6 and 4.5 mg/m(2)) were given to pregnant rats on days 6 through 15 of gestation, there was an increased incidence of skeletal malformations at a dose of 0.75 mg/kg/m(2), omphalocele at 0.05 mg/kg (0.3 mg/m(2)), gastroschisis at 0.75 mg/kg and 1 mg/kg, and a flexure defect of the hindlimbs at 0.75 mg/kg (Prod Info NIPENT(R) IV injection, 2007).
    3) LACK OF EFFECT
    a) RABBITS - In pregnant rabbits given IV pentostatin at doses of 0, 0.005, 0.01, or 0.02 mg/kg/day (0, 0.015, 0.03, or 0.06 mg/m(2)) on days 6 through 18 of gestation, there was no teratogenicity (Prod Info NIPENT(R) IV injection, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified pentostatin as FDA pregnancy category D (Prod Info NIPENT(R) IV injection, 2007)
    B) ANIMAL STUDIES
    1) RATS - Maternal toxicity was observed when IV pentostatin at doses of 0.1 and 0.75 mg/kg/m(2) (0.6 and 4.5 mg/m(2)) was given to pregnant rats on days 6 through 15 of gestation (Prod Info NIPENT(R) IV injection, 2007).
    2) RABBITS - Maternal toxicity, abortions, early deliveries, and deaths occurred in pregnant rabbits given IV pentostatin at doses of 0.005, 0.01, or 0.02 mg/ kg/day (0, 0.015, 0.03, or 0.06 mg/m(2)) on days 6 through 18 of gestation (Prod Info NIPENT(R) IV injection, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No reports describing the use of pentostatin during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known if pentostatin affects the quantity or composition of breast milk (Prod Info NIPENT(R) IV injection, 2007).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DOGS - Fertility studies with pentostatin have not been done in animals; however, mild seminiferous tubular degeneration was observed in a 5-day intravenous toxicity study at doses of 1 and 4 mg/kg in dogs (Prod Info NIPENT(R) IV injection, 2007).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) SECONDARY MALIGNANCIES
    1) Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use.
    2) Lymphoid neoplasms have been reported in humans (Crump et al, 1991).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Studies with pentostatin in animals have not been done (Prod Info NIPENT(R) IV solution, 1998).

Genotoxicity

    A) Pentostatin was not mutagenic in several strains of Salmonella typhimurium, including TA-98, TA-1535, TA-1537, and TA-1538. A repeatable statistically significant response trend was noted in strain TA-100, with or without metabolic activation. In addition, pentostatin (1 to 3 mg per mL for 3 hours) was not mutagenic to V79 Chinese hamster lung cells at the hypoxanthine-guanine-phosphororibosyltransferase (HGPRT) locus, with or without metabolic activation (Prod Info NIPENT(R) IV solution, 1998).
    B) In the in vivo mouse bone marrow micronucleus assay, pentostatin was clastogenic. It also did not induce chromosomal aberrations in V79 Chinese hamster lung cells exposed for 3 hours to 1 to 3 mg per mL, with or without metabolic activation (Prod Info NIPENT(R) IV solution, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Hematologic effects, such as neutropenia and thrombocytopenia may occur following pentostatin exposure. Monitor serial CBCs with differential, including platelets, for several weeks following an overdose.
    C) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.
    E) Monitor renal function and hepatic enzymes in patients with significant exposure.
    F) Monitor vital signs frequently. Initiate continuous cardiac monitoring and obtain an ECG in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours) and daily monitoring of CBCs with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Hematologic effects, such as neutropenia and thrombocytopenia may occur following pentostatin exposure. Monitor serial CBCs with differential, including platelets, for several weeks following an overdose.
    C) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor serum electrolytes in patients with prolonged vomiting and/or diarrhea.
    E) Monitor renal function and hepatic enzymes in patients with significant exposure.
    F) Monitor vital signs frequently. Initiate continuous cardiac monitoring and obtain an ECG in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended. The drug is administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. High doses of pentostatin (20 to 50 mg/m(2) in divided doses over 5 days) were associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity.
    B) THERAPEUTIC DOSES: ADULT: 4 mg/m(2) by bolus injection or IV infusion over 20 to 30 min every other week. CHILD: The safety and effectiveness of pentostatin in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) 4 mg/m(2) by bolus injection or IV infusion over 20 to 30 minutes every other week; given with 500 to 1000 mL of D5W in 0.5 NS or equivalent prior to administration and 500 mL of D5W or equivalent after administration (Prod Info NIPENT(R) intravenous injection, 2009)
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of pentostatin in pediatric patients have not been established (Prod Info NIPENT(R) intravenous injection, 2009).

Minimum Lethal Exposure

    A) Overdose data is limited. High doses of pentostatin (20 to 50 mg/m(2) in divided doses over 5 days) were associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity (Prod Info NIPENT(R) IV injection, 2007).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Although therapeutic serum concentrations of pentostatin have not been established, intravenous administration of 250 mcg/kg for 4 to 5 days resulted in plasma concentrations ranging from 12 to 36 nM (O'Dwyer et al, 1988).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Systemic: Pentostatin is an antimetabolite (Prod Info NIPENT(R) intravenous injection, 2009; O'Dwyer PJ. 1988, 1988). Its exact mechanism of action in hairy cell leukemia is unknown (Prod Info NIPENT(R) intravenous injection, 2009). Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. (Prod Info NIPENT(R) intravenous injection, 2009; Kane et al, 1992; O'Dwyer PJ. 1988, 1988) Inhibition of RNA synthesis may also contribute to the cytotoxic effect (Prod Info NIPENT(R) intravenous injection, 2009; Kane et al, 1992). Although pentostatin arrests cells in the G1 or S phase of cell division, it is also reported to have cell cycle–phase nonspecific actions (including increased DNA strand breaks) (Prod Info NIPENT(R) intravenous injection, 2009; Kane et al, 1992; O'Dwyer PJ. 1988, 1988).

Physicochemical

Physical Characteristics

    A) Pentostatin is a white to off-white solid that is freely soluble in distilled water (Prod Info NIPENT(R) IV injection, 2007).

Ph

    A) 7 to 8.5 (Prod Info NIPENT(R) IV injection, 2007)

Molecular Weight

    A) 268.27 (Prod Info NIPENT(R) IV injection, 2007)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    3) Antunes I, Magina S, & Granjo E: Hemolytic-uremic syndrome induced by pentostatin in a patient with cutaneous T-cell lymphoma. Dermatology 1999; 198:179-180.
    4) Bensinger W, Schubert M, Ang KK, et al: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 2008; 6 Suppl 1:S1-21.
    5) Black DJ & Livingston RB: Antineoplastic Drugs in 1990: a review (part 1). Drugs 1990; 39:489-501.
    6) Black DJ & Livingston RB: Antineoplastic Drugs in 1990: a review (part 1). Drugs 1990a; 39:489-501.
    7) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    8) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    9) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    10) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    11) Crump M, Sutton DM, & Pantalony D: Sezary syndrome in a patient with hairy cell leukemia in remission.. Cancer 1991; 68(4):829-33.
    12) Doll DC, Ringenberg QS, & Yarbro JW: Management of cancer during pregnancy. Arch Intern Med 1988; 148:2058-2064.
    13) Dupuis LL & Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 2003; 5(9):597-613.
    14) Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52(4):e56-e93.
    15) Glantz JC: Reproductive toxicology of alkylating agents. Obstet Gynecol 1994; 49:709-715.
    16) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    17) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    18) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    19) Hensley ML, Hagerty KL, Kewalramani T, et al: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009; 27(1):127-145.
    20) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    21) Iannitto E, Minardi V, Calvaruso G, et al: Deoxycoformycin (pentostatin) in the treatment of splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes. Eur J Haematol 2005; 75(2):130-135.
    22) Kane BJ, Kuhn JG, & Roush MK: Pentostatin: an adenosine deaminase inhibitor for the treatment of hairy cell leukemia.. Ann Pharmacother 1992; 26:939-47.
    23) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    24) Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
    25) Leach JW, Pham T, Diamandidis D, et al: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) following treatment with deoxycoformycin in a patient with cutaneous T-cell lymphoma (Sezary syndrome): a case report. Am J Hematol 1999; 61:268-270.
    26) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    27) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    28) None Listed: ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999; 56(8):729-764.
    29) O'Dwyer PJ, King SA, Eisenhauer E, et al: Hypersensitivity reactions to deoxycoformycin. Cancer Chemother Pharmacol 1989; 23:173-175.
    30) O'Dwyer PJ, Spiers ASD, & Marsoni S: Association of severe and fatal infections and treatment with pentostatin. Cancer Treat Rep 1986; 70:1117-1120.
    31) O'Dwyer PJ, Wagner B, Leyland-Jones B, et al: 2'-deoxycoformycin (pentostatin) for lymphoid malignancies: rational development of an active new drug. Ann Intern Med 1988; 108:733-743.
    32) O'Dwyer PJ, Wagner B, Leyland-Jones B, et al: 2'-deoxycoformycin (pentostatin) for lymphoid malignancies: rational development of an active new drug. Ann Intern Med 1988a; 108:733-743.
    33) O'Dwyer PJ. 1988: 2'-Deoxycoformycin (pentostatin) for lymphoid malignancies. Ann Intern Med 1988; 108:733-43.
    34) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    35) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    36) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    37) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    38) Product Information: KEPIVANCE(TM) IV injection, palifermin IV injection. Amgen Inc, Thousand Oaks, CA, 2005.
    39) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    40) Product Information: NIPENT(R) IV injection, pentostatin IV injection. Hospira, Inc, Lake Forest, IL, 2007.
    41) Product Information: NIPENT(R) IV solution, pentostatin iv solution. SuperGen,Inc., San Ramon, CA, 1998.
    42) Product Information: NIPENT(R) intravenous injection, pentostatin intravenous injection. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    43) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    44) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    45) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    46) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    47) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
    48) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    49) Shouval R, Duffield A, Gocke C, et al: Pentostatin-induced hypereosinophilia with eosinophilic gastroenteritis. Leuk Lymphoma 2010; 51(8):1567-1569.
    50) Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-3205.
    51) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    52) Steinmetz JC, De Conti R, & Ginsburg R: Hypersensitivity vasculitis associated with 2-deoxycoformycin and allopurinol therapy. Am J Med 1989; 86:499.
    53) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    54) Tsimberidou AM, Giles F, Duvic M, et al: Phase II study of pentostatin in advanced T-cell lymphoid malignancies: update of an M.D. Anderson Cancer Center series. Cancer 2004; 100(2):342-349.
    55) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.