Oxitan

Oxaliplatin.

Oxaliplatin a cell cycle-phase nonspecific antineoplastic drug belonging to a new class of platinum agent that contains a platinum atom complexed with oxalate and diaminocyclohexane (DACH).
Chemically, oxaliplatin is trans-l-diaminocyclohexane oxalato platinum or cis- [oxalato (trans-/-1,2-diamino cyclohexane) platinum (II)]. The empirical formula of oxaliplatin is C₈H₁₄N₂O₄Pt. The molecular weight of oxaliplatin is 397.3. Oxaliplatin is slightly soluble in water, very slightly soluble in methanol, and practically insoluble in ethanol.
Each mL contains Oxaliplatin 5 mg, Water for Injections q.s.

Pharmacology: 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.
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)].
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_½α; 0.43 hours and t_½β; 16.8 hours) and a long terminal elimination phase (t_½γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour IV infusion of oxaliplatin at a dose of 85 mg/m² expressed as ultrafilterable platinum were C_max of 0.814 μg/mL and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC_{0-48 hr}) 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 oxaliplatin, 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 gammaglobulins. 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 oxaliplatin, 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.

Oxaliplatin in combination with 5-Fluorouracil (5-FU) and 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 cancer.
Unresectable advanced or metastatic gastric cancer.
Treatment of unresectable hepatocellular carcinoma (HCC).

Recommended Dose: 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.
Dosage: Administer oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles): Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL D5W and leucovorin 200 mg/m² IV infusion in D5W both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m² IV infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.
Day 2: Leucovorin 200 mg/m² IV infusion over 120 minutes, followed by 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m² IV infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.
The recommended dose for oxaliplatin in 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 of Oxaliplatin in combination with 5-fluorouracil and folinic acid (FOLFOX) in the treatment of unresectable hepatocellular carcinoma is 85 mg/m² intravenously, repeated every two weeks until disease progression or unacceptable toxicity.
The administration of oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT₃ blockers with or without dexamethasone, is recommended.
Dose Modification Recommendations: Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and laboratory tests. Prolongation of infusion time for oxaliplatin from 2 hours to 6 hours decreases the C_max by an estimated 32% and may mitigate acute toxicities. The infusion times for 5-FU and leucovorin do not need to be changed.
Adjuvant Therapy in Patients with Stage III Colon Cancer: Neuropathy and other toxicities were graded using the NCI CTC scale, version 1.
For patients who experience persistent grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 75 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 oxaliplatin to 75 mg/m² and infusional 5-FU to 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 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 10⁹/L and platelets ≥75 x 10⁹/L.
Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer: Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, version 2.0.
For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 65 mg/m² should be considered. For patients with persistent grade 3 neurosensory events, discontinuing therapy should be considered. The 5-FU/LV regimen need not be altered.
A dose reduction of oxaliplatin to 65 mg/m² and 5-FU (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 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils >1.5 x 10⁹/L and platelets >75 x 10⁹/L.
Dose Modifications in Therapy for Patients with Renal Impairment: In patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m². In patients with severe renal impairment, the initial recommended oxaliplatin dose should be reduced to 65 mg/m².
Mode of Administration: Infusion: The administration of oxaliplatin does not require prehydration.
Oxaliplatin diluted in 250 to 500 mL of a 5% Dextrose Injection to give a concentration not less than 0.2 mg/mL must be infused either by peripheral vein or central venous line over 2 to 6 hours. When oxaliplatin is administered with 5-fluorouracil, the oxaliplatin infusion must precede the administration of 5-fluorouracil.
Preparation of Infusion solution: Do not freeze and protect from light the concentrated solution.
A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection 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 oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Dilution before Infusion: Withdraw the required amount of concentrate from the vial(s) and then dilute with 250 mL to 500 mL of a 5% Dextrose Injection to give an oxaliplatin concentration between not less than 0.2 mg/mL and 0.7 mg/mL. The concentration range for which the physico-chemical stability of oxaliplatin has been demonstrated is 0.2 mg/mL to 0.7 mg/mL.
Administer by IV infusion: After dilution in 5% Dextrose, chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 8°C and for 6 hours at 30°C. 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 the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.
Inspect visually prior to use. Only clear solutions without particles should be used.
The medicinal product is for single use only. Any unused infusion solution should be discarded.
Never use sodium chloride or chloride containing solutions for dilution.
The compatibility of oxaliplatin solution for infusion has been tested with representative, PVC based, administration sets.

Overdosage and Treatment: There is no known antidote for Oxaliplatin overdose. In addition to thrombocytopenia, the anticipated complications of an Oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity. Several cases of overdoses have been reported with Oxaliplatin. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm³) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.
Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.

Oxaliplatin should not be administered to patients with a history of known allergy to oxaliplatin or other platinum compounds.

Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis.

Allergic Reactions: Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.
Neurologic Toxicity: 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.
An acute syndrome of pharyngolaryngeal dysesthesia seen (grade 3/4) in patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms.
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).
Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
Severe Myelosuppression: Grade 3 or 4 neutropenia occurred in patients with colorectal cancer treated with oxaliplatin in combination with 5-flurouracil (5-FU) and leucovorin compared to 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes. Delay oxaliplatin until neutrophils are ≥1.5 × 10⁹/L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from Grade 4 neutropenia or febrile neutropenia.
Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
Hepatotoxicity: Hepatotoxicity is reported. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases.
Cardiovascular Toxicity: QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been observed following oxaliplatin administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin and monitor these electrolytes periodically during therapy. Avoid oxaliplatin in patients with congenital long QT syndrome.
Rhabdomyolysis: Rhabdomyolysis, including fatal cases, has been observed in patients treated with oxaliplatin. Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur.
Recommended Laboratory Tests: Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle. There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring. Thrombocytopenia and immune-mediated thrombocytopenia have been observed with oxaliplatin. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia. In this case, consider discontinuing oxaliplatin.
Patients with Renal Impairment: The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when oxaliplatin is administered to patients with renal impairment. The starting oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance <30 mL/min).
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Children: The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase I and 2 Phase II trials in 235 patients ages 7 months to 22 years with solid tumors and no significant activity observed.
The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were C_max of 0.75±0.24 mcg/mL, AUC_0-48 of 7.52±5.07 mcg·h/mL and AUC_inf of 8.83±1.57 mcg·h/mL at 85 mg/m² of oxaliplatin and C_max of 1.10±0.43 mcg/mL, AUC_0-48 of 9.74±2.52 mcg·h/mL and AUC_inf of 17.3±5.34 mcg·h/mL at 130 mg/m² of oxaliplatin.
Use in the Elderly: No significant effect of age on the clearance of ultrafilterable platinum has been observed.
No adjustment to starting dose was required in patients ≥65 years old.

Pregnancy: Based on direct interaction with DNA, oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with oxaliplatin. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. Advise a pregnant woman of the potential risk to a fetus.
Animal data: Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1-5 (pre-implantation), 6-10, or 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased 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.
Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, oxaliplatin can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with oxaliplatin and for 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with oxaliplatin and for 6 months after the final dose.
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 area 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 × 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.
Lactation: There are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for 3 months after the final dose.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin.
Contraception: Oxaliplatin can cause embryo-fetal harm when administered to a pregnant woman.
Females: Advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for 9 months after the final dose.
Males: Based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for 6 months after the final dose.
Infertility: Based on animal studies, oxaliplatin may impair fertility in males and females.

The following serious adverse reactions are discussed in greater detail in other sections of the monograph: Hypersensitivity reactions; Peripheral Sensory Neuropathy; Severe Myelosuppression; Reversible Posterior Leukoencephalopathy Syndrome; Pulmonary Toxicities; Hepatotoxicity; QT Interval Prolongation and Ventricular Arrhythmias; Rhabdomyolysis; Hemorrhage.
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, and diarrhea.
Thrombocytopenia and bleeding: Thrombocytopenia was frequently reported with the combination of oxaliplatin and infusional 5-FU/LV. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the oxaliplatin combination arm compared to the infusional 5-FU/LV arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages.
Neutropenia: Neutropenia was frequently observed with the combination of oxaliplatin and 5-FU/LV in patients with colon cancer.
Gastrointestinal: Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis were reported.
Dermatologic: Oxaliplatin did not increase the incidence of alopecia compared to 5-FU/LV alone. No complete alopecia was reported.
Intravenous Site Reactions: Extravasation, in some cases including necrosis, has been reported.
Injection site reaction, including redness, swelling, and pain, has been reported.
Anticoagulation and Hemorrhage: There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.
Renal: About 5-10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of grade 3/4 elevations in serum creatinine in the oxaliplatin and 5-FU/LV combination arm was 1% in the previously treated patients.
Hepatic: Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to oxaliplatin combination therapy.
Thromboembolism: The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-FU/LV arm and 6% (1.2% grade 3/4) in the oxaliplatin and infusional 5-FU/LV combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the oxaliplatin and 5-FU/LV combination arm, respectively.
Other Adverse Reactions: Body as a whole: Angioedema, anaphylactic shock.
Cardiovascular disorders: QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes; bradyarrhythmia.
Central and peripheral nervous system disorders: Loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsions.
Hearing and vestibular system disorders: Deafness.
Infections: Septic shock, including fatal outcomes.
Infusion reactions/hypersensitivity: Laryngospasm.
Liver and gastrointestinal system disorders: Severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis, which rarely may progress, focal nodular hyperplasia, esophagitis.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis, including fatal outcomes.
Platelet, bleeding, and clotting disorders: Immuno-allergic thrombocytopenia.
Prolongation of prothrombin time and of INR in patients receiving anticoagulants.
Blood disorders: Secondary leukemia.
Red Blood Cell disorders: Hemolytic uremic syndrome, immuno-allergic hemolytic anemia.
Renal disorders: Acute tubular necrosis, Acute interstitial nephritis and acute renal failure.
Respiratory system disorders: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes).
Vision disorders: Decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation).
Injury, poisoning, and procedural complications: fall-related injuries.

No pharmacokinetic interaction between 85 mg/m² of oxaliplatin and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² of oxaliplatin 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.

Incompatibilities: The diluted medicinal product should not be mixed with other medications in the same infusion bag or infusion line. Under Instruction for use described in for handling and disposal section, oxaliplatin can be coadministered with folinic acid via a Y-line.
Do not mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline drugs or solutions will adversely affect the stability of oxaliplatin.
Do not dilute oxaliplatin with saline or other solutions containing chloride ions (including calcium, potassium or sodium chlorides).
Do not mix with other drugs in the same infusion bag or infusion line.
Do not use injection equipment containing aluminium.
Handling and Disposal: As with other potentially toxic compounds, caution should be exercised when handling and preparing oxaliplatin solutions.
Instructions for handling: The handling of this cytotoxic agent by nursing or medical personnel required every precaution to guarantee the protection of the handler and his surroundings.
The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee integrity of the product, the protection of the environment and in particular the protection of the personnel handling the medicines, in accordance with the hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.
Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area, containers and collection bags for waste.
Excreta and vomit must be handled with care.
Pregnant women must be warned to avoid handling cytotoxic agents.
Any broken container must be treated with the same precautions and considered as contaminated waste. Contaminated waste should be incinerated in suitably labelled rigid containers. See Disposal as follows.
If oxaliplatin concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with water.
If oxaliplatin concentrate or infusion solution should come into contact with mucous membranes, wash immediately and thoroughly with water.
Special precautions for administration: Do not use injection equipment containing aluminium.
Do not administer undiluted.
Only 5% Dextrose Injection is to be used as a diluent. Do not dilute for infusion with sodium chloride or chloride containing solutions.
Do not mix with any other medication in the same infusion bag or administer simultaneously by the same infusion line.
Do not mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of others drugs.
Alkaline drugs or solutions will adversely affect the stability of oxaliplatin.
Instruction for use with folinic acid (as calcium folinate or disodium folinate): Oxaliplatin 85 mg/m² IV infusion in 250 to 500 mL of 5% Dextrose Injection is given at the same time as folinic acid IV infusion in 5% Dextrose Injection, over 2 to 6 hours, using a Y-line placed immediately before the site of infusion. These two drugs should not be combined in the same infusion bag. Folinic acid must not contain trometamol as an excipient and must only be diluted using isotonic 5% Dextrose Injection, never in alkaline solutions or sodium chloride or chloride containing solutions.
Instruction for use with 5-fluorouracil: Oxaliplatin should always be administered before fluoropyrimidines- i.e. 5-fluorouracil.
After oxaliplatin administration, flush the line and then administer 5-fluorouracil.
For additional information on drugs combined with oxaliplatin, see the corresponding manufacturer's summary of product characteristics.
Concentrate for solution for infusion: Inspect visually prior to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused concentrate should be discarded.
Disposal: Any unused medicinal product or waste material should be disposed of according to standard procedures applicable to cytotoxic agents in accordance with local requirements.

Shelf life: 24 Months.
Storage Condition: Store at a temperature below 30°C. Protect from Light. Do not freeze.

Cytotoxic Chemotherapy

L01XA03 - oxaliplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.

S