Oxaliplatin Injection is an antineoplastic agent with the molecular formula C8H14N2O4Pt 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 methanol and acetone.
OXOL is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free solution.
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)].
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 intra-strand 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.
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 (t½; 0.43 hours and t½ 16.8 hours) and a long terminal elimination phase (t½; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour IV infusion of oxaliplatin injection at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 μg/mL and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr) 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.
Distribution: At the end of a 2-hour infusion of OXOL, approximately 15% of the administered platinum is present in the systematic 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 plasma ultrafiltrate following 85 mg/m2 every two weeks.
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.
Elimination: The major route of platinum elimination is renal excretion. At five days after a single 2 hour infusion of OXOL, 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.
The AUC0-48hr of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC0-48hr of platinum in patients with mild (creatinine clearance, CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min) and severe renal (CLcr <30 mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CLcr >80 mL/min).
Oxaliplatin in combination with 5-fluouracil (5-FU) and Leucovorin (folinic acid; FA) is indicated for: Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumor.
Treatment of metastatic colorectal colon cancer.
Unresectable advanced or metastatic gastric cancer.
Treatment of unresectable hepatocellular carcinoma (HCC).
For adults only.
The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m2 intravenously repeated every two weeks for 12 cycles (6 months).
The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85 mg/m2 intravenously repeated every 2 weeks.
Dosage given should be adjusted according to tolerability (see Dose Modification Recommendations as follows).
The recommended dosed for oxaliplatin in the treatment of unresectable advanced or metastatic gastric cancer are: 100 mg/m2 intravenously repeated every two weeks in combination with infusional 5-FU and folinic acid.
85 mg/m2 intravenously (FLO regimen every 2 weeks in combination with fluorouracil 2,600 mg/m2 and leucovorin 200 mg/m2.
85 mg/m2 intravenously (Modified FOLFOX regimen) every 2 weeks in combination with fluorouracil 1,000 mg/m2 and leucovorin 200 mg/m2.
130 mg/m2 intravenously (EOX or EOF regimen) every 3 weeks cycle in combination with Epirubicin 50 mg/m2 and Capecitabine 625 mg/m2 or fluorouracil 200 mg/m2.
The recommended dose for oxaliplatin in combination with 5-fluorouracil and folinic acid (FOLFOX) in the treatment of unresectable hepatocellular carcinoma is 85 mg/m2 intravenously, repeated ever two weeks until disease progression or unacceptable toxicity.
Oxaliplatin should always be administered before fluoropyrimidines (5-FU).
Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentrate not less than 0.2 mg/ml.
Oxaliplatin was mainly used in combination with continuous infusion 5-fluorouracil based regimens. For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion were used.
Special Populations: Renal impairment: In gastrointestinal cancer patients with varying degrees of renal impairment, treated with oxaliplatin (2 hour IV infusion every two weeks for a maximum of 12 cycles) in combination with 5FU/FA (FOLFOX4), oxaliplatin showed minimal clinical impact on renal function as assessed by mean creatinine clearance.
The safety results were similar between the patient groups. However, the duration of exposure was shorter in patients with renal impairment. The median exposure was 4, 6 and 3 cycles for mild, moderate and severe renal impairment patients, respectively. In patients with normal renal function, the median exposure was 9 cycles. More patients discontinued treatment due to adverse events in renal impairment groups.
The oxaliplatin initial dose was already reduced to 65 mg/m2 severe renal impairment patients.
In patients with normal renal function or mild to moderate renal impairment, the recommended close of oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended dose should be reduced to 65 mg/m2.
Hepatic insufficiency: Oxaliplatin has not been studied in patients with severe hepatic impairment. No increase in oxaliplatin acute toxicities was observed in the subset of patients with abnormal liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.
Elderly patients: No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-flurouracil in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.
Method of administration: Oxaliplatin is administered by intravenous infusion.
The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml must be infused via a central venous line or peripheral vein over 2 to 6 hours.
Oxaliplatin infusion should always precede that of 5-fluorouracil.
In the event of extravasation, administration must be discontinued immediately.
Instructions for use: Oxaliplatin must be diluted before use. Only the recommended diluent should be used to dilute the concentrate for solution for in fusion product.
Premedication with antiemetics, including 5-HT 3 blockers with or without dexamethasone, is recommended.
For information on 5-fluorouracil and leucovorin, see the respective package inserts.
Dose Modification Recommendations: Prolongation of infusion time for OXOL from 2 hours to 6 hours decreases the Cmax by an estimated 32% and may mitigate acute toxicity. The infusion time for infusional 5-FU and leucovorin do not need to be changed.
For patients who experience persistent Grade 2 neurosensory events that do not 2 resolve, a dose reduction of OXOL to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered.
The infusional 5-FU/LV regimen need not be altered.
A dose reduction of OXOL to 65 mg/m2 and infusional 5-FU by 20% (300 mg/m2 bolus and 500 mg/m2 22 hour infusion) is recommended for patients after recovery from Grade 3/4 gastrointestinal (despite prophylactic treatment) or Grade 3/4 hematologic toxicity (neutrophils <1.5 x 109/L, platelets <100 x 109/L). The next dose should be delayed until neutrophils are >1.5 x 109/L and platelets are >75 x 109/L.
Neurotoxicity scale: The grading scale for paresthesias/dysesthesias was: Grade 1, resolved and did not interfere with functioning; Grade 2, interfered with function but not daily activities; Grade 3, pain or functional impairment that interfered with daily activities; Grade 4, persistent impairment that is disabling or life-threatening.
There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.
Patients with known allergy to oxaliplatin or other platinum compounds.
OXOL should be administered under the supervision of a qualified physician experienced in the used of antineoplastic agents.
Hypersensitivity Reactions: Hypersensitivity and anaphylactic/anaphylactoid reactions to Oxaliplatin have been reported. These allergic reactions were in similar nature and severity to those reported with other platinum-containing compounds, i.e., rash, urticaria, erythema, pruritus and rarely, bronchospasm and hypotension. These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths associated with platinum compounds from this reaction have been reported.
Patients with Renal Impairment: The combination of OXOL and infusional 5-FU/LV should be used with caution in patients with preexisting renal impairment since the primary route of platinum elimination is renal. Clearance of ultrafilterable platinum is decreased
in patients with mild, moderate and severe renal impairment.
Neuropathy: Oxaliplatin is associated with two types of neuropathy: An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain and a feeling of chest pressure have also been observed.
A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias but may also include deficits in proprioception that can interfere with daily activities (e.g. writing, buttoning, swallowing and difficulty walking from impaired proprioception). Persistent neuropathy can occur without any prior acute neuropathy event. These symptoms may improve in some patients upon discontinuation of Oxaliplatin.
Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis (0.7% of study patients), which may be fatal. In case of unexplained respiratory symptoms such as non-productive cough, dsypnea, crackles, or radiological pulmonary infiltrates. Oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
Monitoring: Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count and blood chemistries (including ALT, AST, bilirubin, creatinine) is recommended before each oxaliplatin cycle. Patients receiving oxaliplatin plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require close monitoring.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one seventh the recommended human dose on a body surface are basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. No effect level was not identified. This daily dose is approximately one sixth of the recommended human dose on a body surface area basis.
Use in Pregnancy: Oxaliplatin may cause fetal harm when administered to a pregnant woman. Pregnant rats were administered 1 mg/kg/day oxaliplatin (less than one-tenth the recommended human dose based on body surface area) during gestation days 1-5 (pre-implantation), 6-10 or 11-6 (during organogenesis). Oxaliplatin caused developmental mortality (increase early resorptions) when administered on days 6-10 and 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6-10. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin.
Use in Lactation: It is not known whether Oxaliplatin or its derivatives are 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 oxaliplatin, a decision should be made whether to discontinue nursing or delay the use of the drug, taking into account the importance of the drug to the mother.
Use in Children: The safety and effectiveness of Oxaliplatin in pediatric patients have not been established.
Use in the Elderly: No significant effect of age on the clearance of ultrafilterable platinum has been observed.
Pregnancy: Oxaliplatin may cause fetal harm when administered to a pregnant woman. Pregnant rats were administered 1 mg/kg/day oxaliplatin (less than one-tenth the recommended human dose based on body surface area) during gestation days 1-5 (pre-implantation), 6-10 or 11-6 (during organogenesis). Oxaliplatin caused developmental mortality (increase early resorptions) when administered on days 6-10 and 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6-10. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin.
Nursing Mothers: It is not known whether Oxaliplatin or its derivatives are 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 oxaliplatin, a decision should be made whether to discontinue nursing or delay the use of the drug, taking into account the importance of the drug to the mother.
The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were anemia, diarrhea, fatigue, increase in transaminases and alkaline phosphatase, nausea, neutropenia, peripheral sensory neuropathy, stomatitis, and thrombocytopenia. The most common adverse reactions in previously untreated and treated patients were diarrhea, emesis, fatigue, nausea, neutropenia and peripheral sensory neuropathies.
Cardiovascular: Chest pain, edema, flushing, peripheral edema, thromboembolism.
Central nervous system: Dizziness, fatigue, headache, insomnia, pain, peripheral neuropathy (may be dose limiting), rigors.
Dermatologic: Alopecia, palmar-plantar erythrodysesthesia, skin rash.
Endocrine & metabolic: Dehydration, hypokalemia.
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dysgeusia, dyspepsia, dysphagia (acute), flatulence, gastroesophageal reflux disease, hiccups, mucositis, nausea, stomatitis, vomiting.
Genitourinary: Dysuria.
Hematologic & Oncologic: Anemia, leukopenia, neutropenia, thrombocytopenia.
Hepatic: Increased serum ALT, increased serum AST, increased serum bilirubin.
Hypersensitivity: Hypersensitivity reaction (includes urticaria, pruritus, facial flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, syncope).
Local: Injection site reaction (redness, swelling, pain).
Neuromuscular & skeletal: Arthralgia, back pain.
Ocular: Abnormal lacrimation.
Renal: Increased serum creatinine.
Respiratory: Cough, dyspnea, epistaxis, pharyngitis, pharyngolaryngeal dysesthesia, rhinitis, upper respiratory tract infection.
Miscellaneous: Fever.
Rare but important or life-threatening: Acute renal failure, anaphylactic shock, anaphylactoid reaction, aphonia, ataxia, blepharoptosis, cerebral hemorrhage, colitis, cranial nerve palsy, decreased deep tendon reflex. deafness, decreased visual acuity, diplopia, eosinophilic pneumonitis, fasciculations, febrile neutropenia, hematuria, hemolysis, hemolytic anemia (immune-allergic), hemolytic-uremic syndrome, hemorrhage, hepatic failure, hepatic fibrosis (perisinusoidal), hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease), hepatitis, hepatotoxicity, hypertension, hypomagnesemia, hypoxia. idiopathic noncirrhotic portal hypertension (nodular regenerative hyperplasia), increased INR, increased serum alkaline phosphatase, infusion related reaction (extravasation [including necrosis]), interstitial nephritis (acute), interstitial pulmonary disease, intestinal obstruction, Lhermitte's sign, metabolic acidosis, myoclonus, neutropenic enterocolitis, neutropenic infection (sepsis), optic neuritis, pancreatitis, prolonged prothrombin time, pulmonary fibrosis, prolonged Q-T interval on ECG, purpura, rectal hemorrhage, renal tubular necrosis, reversible posterior leukoencephalopathy syndrome (RPLS), rhabdomyolysis, seizure, sepsis, septic shock, temporary vision loss, thrombocytopenia (immune-allergic), torsades de pointes, trigeminal neuralgia, ventricular arrhythmia, visual field loss.
No pharmacokinetic interaction between 85 mg/m2 of OXOL and infusional 5-FU has been observed in patients treated every 2 weeks, but increase of 5-FU plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of OXOL 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.
Avoid Concomitant Use: Avoid concomitant use of Oxaliplatin with any of the following: BCG (Intravesical); Deferiprone; Dipyrone; Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vaccines (Live).
Increased Effect/Toxicity: Oxaliplatin may increase the levels/effects of: Clozapine; Deferiprone; Fingolimod; Leflunomide; Natalizumab; QTc-Prolonging Agents (Highest Risk); QTc-Prolonging Agents (Moderate Risk); Taxane Derivatives; Tofacitinib; Topotecan; Vaccines (Live).
The levels/effects of oxaliplatin may be increased by: Bupropion; Chloramphenicol (Ophthalmic); Denosumab; Dipyrone; Mifepristone; Ocrelizumab; Palifermin; Pimecrolimus; Promazine; Roflumilast; Tacrolimus (Topical); Trastuzumab.
Decreased Effect: Oxaliplatin may decreased the levels/effects of: BCG (Intravesical); Coccidioides immitis skin test; Fosphenytoin-Phenytoin; Lenograstim; Lipegfilgrastim; Nivolumab; Pidotimod; Sipuleucel-T, Tertomotide; Vaccines (Inactivated); Vaccines (Live).
The levels/effects of oxaliplatin may be decreased by: Echinacea.
PREPARATION OF INFUSION SOLUTION: The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose injection USP.
DILUTION MUST NEVER BE MADE WITH A SODIUM CHLORIDE SOLUTION OR OTHER CHLORIDE-CONTAINING SOLUTIONS.
The concentration over which the physico-chemical stability of OXOL has been demonstrated is 2.0 mg/mL. After dilution in 5% glucose solution, chemical and physical in-use stability has been demonstrated for 12 hours at 25°C or up to 24 hours under refrigeration (2-8°C [36-46°F]).
From a 'microbiological' point of view, this infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of user and would normally not be longer 24 hours at 2° to 8°C unless dilution has taken place in controlled and validated aseptic conditions.
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-FU) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with D5W prior to administration of any concomitant medication.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.
Needles or intravenous administration sets containing aluminum parts that may come in contact with OXOL should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
HANDLING AND DISPOSAL: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from OXOL. The use of gloves is recommended. If a solution of OXOL contacts the skin, wash the skin immediately and thoroughly with soap and water. If OXOL contacts the mucous membranes, flush thoroughly with water.
Store below 30°C. Protect from light. Do not freeze.
L01XA03 - oxaliplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.
Oxol infusion 100 mg/50 mL
1's
Oxol infusion 50 mg/25 mL
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