Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1585
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Nipent (Injection, Powder, Lyophilized, For Solution)
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It is recommended that patients receive hydration
with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent
before NIPENT administration. An additional 500 mL of 5% Dextrose
or equivalent should be administered after NIPENT is given. The recommended dosage of NIPENT for the treatment of
hairy cell leukemia is 4 mg/mevery other week. NIPENT
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 NIPENT at 6 months should be assessed for
response to treatment. If the patient has not achieved a complete
or partial response, treatment with NIPENT should be discontinued. If the patient has achieved a partial response, NIPENT
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 NIPENT are recommended. NIPENT 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 NIPENT 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. NIPENT 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/m. No dosage reduction is recommended at the start of therapy with NIPENT
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. NIPENT should be temporarily withheld if the absolute
neutrophil count falls during treatment below 200 cells/mmin a patient who had an initial neutrophil count greater than 500
cells/mmand may be resumed when the count returns to
predose levels. Preparation
of Intravenous Solution Stability NIPENT 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 NIPENT contains no preservatives.
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NIPENT (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 knownas 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-��-D-erythropentofuranosyl)3,6,7,8
tetrahydroimidazo[4,5d][1,3]diazepin-8-ol with a molecular formula
of CHNOand 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.
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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 having 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 cellleukemia 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/mof
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/m, 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.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.
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NIPENT is contraindicated in patients who have demonstrated
hypersensitivity to NIPENT.
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NIPENT (pentostatin for injection) is supplied as
a sterile lyophilized white to off-white powder in single-dose vials
containing 10 mg of pentostatin. The vials are packed in individual
cartons. NDC 0409-0801-01. Storage: Store NIPENT vials
under refrigerated storage conditions 2��to 8��C (36��to 46��F).
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WARNING: NIPENT should be administered under the supervision
of a physician qualified and experienced in the use of cancer chemotherapeutic
agents. The use of higher doses than those specified (see DOSAGE AND
ADMINISTRATION) is not recommended. Dose-limiting severe renal, liver,
pulmonary, and CNS toxicities occurred in Phase 1 studies that used
NIPENT at higher doses (20-50 mg/min divided doses over
5 days) than recommended. In a clinical investigation
in patients with refractory chronic lymphocytic leukemia using NIPENT
at the recommended dose in combination with fludarabine phosphate,
4 of 6 patients entered in the study had severe or fatal pulmonary
toxicity. The use of NIPENT in combination with fludarabine phosphate
is not recommended.
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General: Therapy with NIPENT requires regular patient observation
and monitoring of hematologic parameters and blood chemistry values.
If severe adverse reactions occur, the drug should be withheld (see
DOSAGE AND ADMINISTRATION), and appropriate corrective measures should
be taken according to the clinical judgment of the physician. NIPENT treatment should be withheld or discontinued in
patients showing evidence of nervous system toxicity.<br/>Information for Patients: Patients should be advised of the signs and symptoms
of adverse events associated with NIPENT therapy. (See ADVERSE REACTIONS.)<br/>Laboratory Tests: Prior to initiating therapy with NIPENT, renal function
should be assessed with a serum creatinine and/or a creatinine clearance
assay. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Complete blood counts and serum creatinine should be performed before
each dose of NIPENT and at other appropriate periods during therapy
(see DOSAGE AND ADMINISTRATION). Severe neutropenia has been observed
following the early courses of treatment with NIPENT and therefore
frequent monitoring of complete blood counts is recommended during
this time. If hematologic parameters do not improve with subsequent
courses, patients should be evaluated for disease status, including
a bone marrow examination. Periodic monitoring of the peripheral blood
for hairy cellsshould be performed to assess the response to treatment. In addition, bone marrow aspirates and biopsies may be
required at 2 to 3 month intervals to assess the response to treatment.<br/>Drug Interactions: Allopurinol and NIPENT are both associated with skin
rashes. Based on clinical studies in 25 refractory patients who received
both NIPENT and allopurinol, the combined use of NIPENT and allopurinol
did not appear to produce a higher incidence of skin rashes than observed
with NIPENT alone. There has been a report of one patient who received
both drugs and experienced a hypersensitivity vasculitis that resulted
in death. It was unclear whether this adverse event and subsequentdeath resulted from the drug combination. Biochemical
studies have demonstrated that pentostatin enhances the effects of
vidarabine, a purine nucleoside with antiviral activity. The combined
use of vidarabine and NIPENT may result in an increase in adverse
reactions associated with each drug. The therapeutic benefit of the
drug combination has not been established. The combined use of NIPENT and fludarabine phosphate is not recommended
because it may be associated with an increased risk of fatal pulmonary
toxicity (see WARNINGS). 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.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No animal carcinogenicity studies have been conducted with pentostatin. Mutagenesis: Pentostatin
was nonmutagenic when tested in Salmonella
typhimurium strains TA-98, TA-1535, TA-1537, and TA-1538.
When tested with strain TA-100, a repeatable statistically significant
response trend was observed with and without metabolic activation.
The response was 2.1 to 2.2 fold higher than the background at 10
mg/plate, the maximum possible drug concentration. Formulated pentostatin
was clastogenic in the in vivo mouse bone marrow micronucleus assay at 20, 120, and 240 mg/kg.
Pentostatin was not mutagenic to V79 Chinese hamster lung cells at
the HGPRT locus exposed 3 hours to concentrationsof 1 to 3 mg/mL,
with or without metabolic activation. Pentostatin did not significantly
increase chromosomal aberrations in V79 Chinese hamster lung cells
exposed 3 hours to 1 to 3 mg/mL in the presence or absence of metabolic
activation. Impairment
of Fertility: No fertility studies have been conducted in
animals; however, in a 5-day intravenous toxicity study in dogs, mild
seminiferous tubular degeneration was observed with doses of 1 and
4 mg/kg. The possible adverse effects on fertility in humans have
not been determined.<br/>Pregnancy: Pregnancy Category D: (See WARNINGS)<br/>Nursing Mothers: It is not known whether NIPENT is excreted in human
milk. Because many drugs are excreted in human milk, and because of
the potential for serious adverse reactions in nursing infants from
pentostatin, a decision should be made whether to discontinue nursing
or discontinue the drug, taking into account the importance of NIPENT
to the mother.<br/>Pediatric Use: Safety and effectiveness in children or adolescents
have not been established.
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No specific antidote for NIPENT overdose is known.
NIPENT administered at higher doses (20- 50 mg/min 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.
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Pentostatin
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Nipent (Injection, Powder, Lyophilized, For Solution)
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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 NIPENT (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 (eg, 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 NIPENT and 34%
of patients treated with IFN averaged 2.4 and 1.9 documentedinfections
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 NIPENT (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 NIPENT-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 Hemic and Lymphatic 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&Appendages���Skin
Dry, Urticaria The remaining adverse events
which occurred in less than 3% of NIPENT-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 Hemic and Lymphatic 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 NIPENT 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 NIPENT treatment, 4 during NIPENT crossover, 5 during
initial IFN treatment, and 1 during both initial IFN treatment and
NIPENT crossover. In the Phase 2 studies in IFN-refractory hairy cell
leukemia, 11% of patients withdrew from treatment with NIPENT due
to an adverse event.
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See Boxed Warning. Patients
with hairy cell leukemia may experience myelosuppression primarily
during the first few courses of treatment. Patients with infections
prior to NIPENT 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 NIPENT 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 NIPENT 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. Pregnancy Category D Pentostatin can cause fetal harm when administered
to a pregnant woman. Pentostatin was administered intravenously at
doses of 0, 0.01, 0.1, or 0.75 mg/kg/day (0, 0.06, 0.6, and 4.5 mg/m) to pregnant rats on days 6 through 15 of gestation. Drug-related
maternal toxicity occurred at doses of 0.1 and 0.75 mg/kg/day (0.6
and 4.5 mg/m). Teratogenic effects were observed at 0.75
mg/kg/day (4.5 mg/m) manifested by increased incidence
of various skeletal malformations. In a dose range-finding study,
pentostatin was administered intravenously to rats at doses of 0,
0.05, 0.1, 0.5, 0.75, or 1 mg/kg/day (0, 0.3, 0.6, 3, 4.5, 6 mg/m), on days 6 through 15 of gestation. Fetal malformations
that were observed were an omphalocele at 0.05 mg/kg (0.3 mg/m), gastroschisis at 0.75 mg/kg and 1 mg/kg (4.5 and 6 mg/m), and a flexure defect of the hindlimbs at 0.75 mg/kg (4.5
mg/m). Pentostatin was also shown to be teratogenic in
mice when administered as a single 2 mg/kg (6 mg/m) intraperitoneal
injection on day 7 of gestation. Pentostatin was not teratogenic in
rabbits when administered intravenously on days 6 through 18 of gestation
at doses of 0, 0.005, 0.01, or 0.02 mg/kg/day (0, 0.015, 0.03, or
0.06 mg/m); however maternal toxicity, abortions, early
deliveries, and deaths occurred in all drug-treated groups. There
are no adequate and well-controlled studies in pregnant women. If
NIPENT is used during pregnancy, or if the patient becomes pregnant
while taking (receiving) this drug, the patient should be apprised
of the potential hazard to the fetus. Women of childbearing potential
receiving NIPENT should be advised to avoid becoming pregnant.
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NIPENT 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.
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Nipent
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