Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/909
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Eloxatin (Solution, Concentrate)
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ELOXATIN (oxaliplatin injection) is an antineoplastic agent with the molecular
formula CHNOPt and
the chemical name of cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O']
platinum. Oxaliplatin is an organoplatinum complex in which the platinum
atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate
ligand as a leaving group. The molecular weight is 397.3. Oxaliplatin is slightly soluble in
water at 6 mg/mL, very slightly soluble in methanol, and practically
insoluble in ethanol and acetone.
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Mechanism of Action: Oxaliplatin undergoes
nonenzymatic conversion in physiologic solutions to active derivatives
via displacement of the labile oxalate ligand. Several transient
reactive species are formed, including monoaquo and diaquo DACH platinum,
which covalently bind with macromolecules. Both inter- and intrastrand
Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines
(GG), adjacent adenine-guanines (AG), and guanines separated by an
intervening nucleotide (GNG). These crosslinks inhibit DNA replication
and transcription. Cytotoxicity is cell-cycle nonspecific.<br/>Pharmacology: In vivo studies have shown antitumor
activity of oxaliplatin against colon carcinoma. In combination with
5-fluorouracil (5-FU), oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in
several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].<br/>Human Pharmacokinetics: The reactive oxaliplatin
derivatives are present as a fraction of the unbound platinum in plasma
ultrafiltrate. The decline of ultrafilterable platinum levels following
oxaliplatin administration is triphasic, characterized by two relatively
short distribution phases (t; 0.43 hours and
t; 16.8 hours) and a long terminal elimination
phase (t; 391 hours). Pharmacokinetic parameters
obtained after a single 2-hour IV infusion of ELOXATIN at a dose of
85 mg/mexpressed as ultrafilterable platinum were Cof 0.814��g/mL and volume of distribution of 440 L. Interpatient and intrapatient
variability in ultrafilterable platinum exposure (AUC) assessed over 3 cycles was moderate to low (23% and 6%, respectively).
A pharmacodynamic relationship between platinum ultrafiltrate levels
and clinical safety and effectiveness has not been established.<br/>Distribution: At the end of a
2-hour infusion of ELOXATIN, approximately 15% of the administered
platinum is present in the systemic circulation. The remaining 85%
is rapidly distributed into tissues or eliminated in the urine. In
patients, plasma protein binding of platinum is irreversible and is
greater than 90%. The main binding proteins are albumin and gamma-globulins.
Platinum also binds irreversibly and accumulates (approximately 2-fold)
in erythrocytes, where it appears to have no relevant activity. No
platinum accumulation was observed in plasmaultrafiltrate following
85 mg/mevery two weeks.<br/>Metabolism: Oxaliplatin undergoes
rapid and extensive nonenzymatic biotransformation. There is no evidence
of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma
ultrafiltrate samples from patients, including several cytotoxic species
(monochloro DACH platinum, dichloro DACH platinum, and monoaquo and
diaquo DACH platinum) and a number of noncytotoxic, conjugated species.<br/>Elimination: The major route
of platinum elimination is renal excretion. At five days after a
single 2-hour infusion of ELOXATIN, urinary elimination accounted
for about 54% of the platinum eliminated, with fecal excretion accounting
for only about 2%. Platinum was cleared from plasma at a rate (10���17 L/h) that was similar to or exceeded the average human
glomerular filtration rate (GFR; 7.5 L/h). There was no significant
effect of gender on the clearance of ultrafilterable platinum. The
renal clearance of ultrafilterable platinum is significantly correlated
with GFR .<br/>Pharmacokinetics in Special Populations:<br/>Renal Impairment: The AUCof platinum in the plasma ultrafiltrate increases
as renal function decreases. The AUCof platinum
in patients with mild (creatinine clearance, CL50 to
80 mL/min), moderate (CL30 to<50 mL/min) and severe
renal (CL<30 mL/min) impairment is increased by about
60, 140 and 190%, respectively, compared to patients with normal renal
function (CL>80 mL/min) (see PRECAUTIONS and ADVERSE
REACTIONS).<br/>Drug - Drug Interactions: No pharmacokinetic
interaction between 85 mg/mof ELOXATIN and infusional
5-FU has been observed in patients treated every 2 weeks, but increases
of 5-FU plasma concentrations by approximately 20% have been observed
with doses of 130 mg/mof ELOXATIN administered every
3 weeks. In vitro, platinum
was not displaced from plasma proteins by the following medications:
erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel.
In vitro, oxaliplatin is not
metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes.
No P450-mediated drug-drug interactions are therefore anticipated
in patients. Since platinum-containing species are eliminated primarily through
the kidney, clearance of these products may be decreased by co-administration
of potentially nephrotoxic compounds, although this has not been specifically
studied.
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ELOXATIN should not be administered
to patients with a history of known allergy to ELOXATIN or other platinum
compounds.
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ELOXATIN is supplied in
clear, glass, single-use vials with gray elastomeric stoppers and
aluminum flip-off seals containing 50 mg, 100 mg or 200 mg of oxaliplatin
as a sterile, preservative-free, aqueous solution at a concentration
of 5 mg/ml. Water for Injection, USP is present as an inactive ingredient. NDC 0024-0590-10: 50 mg single-use
vial with green flip-off seal individually packaged in a carton. NDC 0024-0591-20: 100 mg single-use
vial with dark blue flip-off seal individually packaged in a carton. NDC 0024-0592-40: 200 mg single-use
vial with orange flip-off seal individually packaged in a carton.
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WARNING: ELOXATIN (oxaliplatin injection)
should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents. Appropriate
management of therapy and complications is possible only when adequate
diagnostic and treatment facilities are readily available. Anaphylactic-like reactions to
ELOXATIN have been reported, and may occur within minutes of ELOXATIN
administration. Epinephrine, corticosteroids, and antihistamines
have been employed to alleviate symptoms (see WARNINGS and ADVERSE
REACTIONS).
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There have been five ELOXATIN
overdoses reported. One patient received two 130 mg/mdoses of ELOXATIN (cumulative dose of 260 mg/m) within
a 24-hour period. The patient experienced Grade 4 thrombocytopenia
(<25,000/mm) without any bleeding, which resolved.
Two other patients were mistakenly administered ELOXATIN instead
of carboplatin. One patient received a total ELOXATIN dose of 500
mg and the other received 650 mg. The first patient experienced dyspnea,
wheezing, paresthesia, profuse vomiting and chest pain on the day
of administration. She developed respiratory failure and severe bradycardia,
and subsequently did not respond to resuscitation efforts. The other
patient also experienced dyspnea, wheezing, paresthesia, and vomiting.
Her symptoms resolved with supportive care. Another patient who
was mistakenly administered a 700 mg dose experienced rapid onset
of dysesthesia. Inpatient supportive care was given, including hydration,
electrolyte support, and platelet transfusion. Recovery occurred
15 days after the overdose. The last patient received an overdose
of oxaliplatin at 360 mg instead of 120 mg over a 1-hour infusion
by mistake. At the end of the infusion, the patient experienced 2
episodes of vomiting, laryngospasm, and paresthesia. The patient
fully recovered from the laryngospasm within half an hour. At the
time of reporting, 1 hour after onset of the event, the patient was
recovering from paresthesia. There is no known antidote for ELOXATIN
overdose. In addition to thrombocytopenia, the anticipatedcomplications
of an ELOXATIN overdose include myelosuppression, nausea and vomiting,
diarrhea, and neurotoxicity. Patients suspected of receiving an overdose
should be monitored, and supportive treatment should be administered.
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oxaliplatin
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Eloxatin (Solution, Concentrate)
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More than 1100 patients
with stage II or III colon cancer and more than 4,000 patients with
advanced colorectal cancer have been treated in clinical studies with
ELOXATIN either as a single agent or in combination with other medications.
The most common adverse reactions in patients with stage II or III
colon cancer receiving adjuvant therapy, were peripheral sensory neuropathy,
neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases
and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.
The most common adverse reactions in previously untreated and treated
patients were peripheral sensory neuropathies, fatigue, neutropenia,
nausea, emesis, anddiarrhea . Combination Adjuvant
Therapy with ELOXATIN and infusional 5-FU/LV in Patients with Stage
II or III Colon Cancer One thousand one hundred and eight patients with stage II or III
colon cancer, who had undergone complete resection of the primary
tumor, have been treated in a clinical study with ELOXATIN in combination
with infusional 5-FU/LV (see CLINICAL
STUDIES). The incidence of grade 3 or 4 adverse events
was 70% on the ELOXATIN combination arm, and31% on the infusional
5-FU/LV arm. The adverse reactions in this trial are shown in the
tables below. Discontinuation of treatment due to adverse events
occurred in 15% of the patients receiving ELOXATIN and infusional
5-FU/LV. Both 5-FU/LV and ELOXATIN are associated with gastrointestinal
or hematologic adverse events. When ELOXATIN is administered in combination
with infusional 5-FU/LV, the incidence of these events is increased. The incidence of death within
28 days of last treatment, regardless of causality, was 0.5% (n=6)
in both the ELOXATIN combination and infusional 5-FU/LV arms, respectively.
Deaths within 60 days from initiation of therapy were 0.3% (n=3)
in both the ELOXATIN combination and infusional 5-FU/LV arms, respectively.
On the ELOXATIN combination arm, 3 deaths were due to sepsis/neutropenic
sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia.
On the 5-FU/LV arm, one death was due to suicide, 2 from Steven-Johnson
Syndrome (1 patient also hadsepsis), 1 unknown cause, 1 anoxic cerebral
infarction and 1 probable abdominal aorta rupture. The following table provides adverse events reported in the adjuvant
therapy colon cancer clinical trial by body system
and decreasing order of frequency in the ELOXATIN and infusional 5-FU/LV
arm for events with overall incidences���5% and for NCI grade
3/4 events with incidences���1%. This table does not include
hematologic and blood chemistry abnormalities; these are shown separately
below. The following table provides
adverse events reported in the adjuvant therapy colon cancer clinical
trial by body system and decreasing order of frequency in the ELOXATIN
and infusional 5-FU/LV arm for events with overall incidences���5% but with incidences<1% NCI grade 3/4 events. Although specific events
can vary, the overall frequency of adverse events was similar in men
and women and in patients<65 and���65 years. However, the
following grade 3/4 events were more common in females: diarrhea,
fatigue, granulocytopenia, nausea and vomiting. In patients���65
years old, the incidence of grade 3/4 diarrhea and granulocytopenia
was higher than in younger patients. Insufficient subgroup sizes
prevented analysis of safety by race. The following additional adverse
events, were reported in���2% and<5% of the patients in
the ELOXATIN and infusional 5-FU/LV combination arm (listed in decreasing
order of frequency): pain, leukopenia, weight decrease, coughing.
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ELOXATIN, used in combination
with infusional 5-FU/LV, is indicated for adjuvant treatment of stage
III colon cancer patients who have undergone complete resection of
the primary tumor. The indication is based on an improvement in disease-free
survival, with no demonstrated benefit in overall survival after a
median follow up of 4 years. ELOXATIN, used in combination with infusional 5-FU/LV, is indicated
for the treatment of advanced carcinoma of the colon or rectum.
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Eloxatin
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