Oxalee

Oxaliplatin, in combination with infusional 5-fluorouracil (5-FU) and leucovorin is indicated for: Treatment of advanced colorectal cancer.
Adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.

General Dosing Administration: Oxaliplatin lyophilized powder should be reconstituted and diluted prior to IV infusion.
Oxaliplatin is administered by intravenous infusion.
Dosage given should be adjusted according to tolerability.
If severe/life-threatening diarrhea, neurotoxicity or hematological toxicity occurs, a dose adjustment may be required.
Antiemetics (5-HT₃ blockers with or without dexamethasone) should be given during pre- and post-therapy with oxaliplatin since oxaliplatin is highly emetogenic.
Oxaliplatin should always be administered before fluoropyrimidines (i.e., 5-FU).
Oxaliplatin administration does not require prehydration.
Use only the recommended diluents in preparing the solution. (See Incompatibilities under Cautions for Usage).
General Dosing Instruction: Treatment of patients with advanced colorectal cancer: Oxaliplatin should be administered 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.
Day 1: Oxaliplatin 85 mg/m² (as IV infusion diluted in 250 to 500 mL of 5% Dextrose Solution) and leucovorin 200 mg/m² IV infusion in 5% Dextrose Solution both given over 120 minutes (2 hours) at the same time in different bags using a Y-line, followed by 5-FU 400 mg/m² by IV bolus given over 2 to 4 minutes, followed by 5-FU 600 mg/m² diluted in 500 mL 5% Dextrose Solution as a 22-hour continuous IV infusion.
Day 2: Leucovorin 200 mg/m² IV infusion over 120 minutes (2 hours), followed by 5-FU 400 mg/m² by IV bolus over 2 to 4 minutes, followed by 5-FU 600 mg/m² IV infusion in 500 mL 5% Dextrose Solution as a 22-hour continuous IV infusion. (See figure)

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Treatment may be repeated every 2 weeks.
For advanced or metastatic disease, treatment is recommended until disease progression or unacceptable toxicity.
Adjuvant treatment of patients with stage III (Duke's C) colon cancer who have undergone complete resection of primary tumor: Treatment is recommended for a total of 6 months (i.e., 12 cycles), given every 2 weeks, according to the dose schedule described previously for the treatment of patients with advanced colorectal cancer.
Or, as prescribed by a physician.
Dose Modification Recommendations: Oxaliplatin dosage adjustment is recommended according to the duration and severity of toxicities. Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests. Prolongation of infusion time for oxaliplatin from 2 to 6 hours may mitigate acute toxicities. The infusion times for 5-FU and leucovorin do not need to be changed. (See table.)

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Renal Impairment: In patients with normal renal function or mild to moderate renal impairment, the recommended oxaliplatin dose is 85 mg/m².
The initial recommended dose in patients with severe renal impairment should be reduced to 65 mg/ m².

Hypersensitivity to oxaliplatin, other platinum compounds (e.g., cisplatin, carboplatin) or any component in the product.
Patients with peripheral sensory neuropathy with functional impairment prior to first course.
Patients with severely impaired renal function (Cl_cr <30 mL/min).
Patients with myelosuppression prior to starting first course, with baseline neutrophils <2 x 10⁹/L and/or platelet count of <100x 10⁹/L.
Patients who are pregnant or breastfeeding.

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.

General: Patients receiving oxaliplatin should be under the supervision of a physician experienced in chemotherapy. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
As oxaliplatin therapeutic regimen includes the use of 5-FU/leucovorin, the usual cautions, precautions, and contraindications of these drugs should be considered.
Monitoring and Laboratory Tests: Complete blood count with differential, hemoglobin, platelets, and blood chemistries, including ALT, AST, bilirubin, creatinine, magnesium and electrolytes should be performed prior to the start of therapy and before each subsequent course.
There have been reports on prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus 5-FU/LV while on anticoagulants. Patients receiving oxaliplatin plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring.
Patients receiving oxaliplatin combination therapy should be monitored for diarrhea, vomiting, and mucositis, which can lead to severe/life-threatening dehydration. If this occurs, discontinue oxaliplatin until improvement or resolution.
A neurological examination should also be performed before each administration and periodically thereafter.
Allergic Reactions: Grade 3 or 4 hypersensitivity, anaphylactic/anaphylactoid reactions, including allergic reactions to oxaliplatin, has been observed. These allergic reactions (e.g., rash, urticaria, erythema, pruritus, laryngospasm, bronchospasm, and hypotension), 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. The symptoms associated with hypersensitivity reactions reported in previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pain, hypotension, disorientation, and syncope. These reactions are usually managed with epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy. Drug-related deaths associated with anaphylaxis from platinum compounds have been reported. Rechallenge with oxaliplatin is contraindicated.
Cardiovascular: There have been reports of QT prolongation and Torsade de Pointes. QT prolongation, may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal. Caution should be exercised in patients with a history or predisposition for QT prolongation, taking medicinal products known to prolong QT interval and those with electrolyte disturbances (i.e., hypokalemia, hypocalcemia or hypomagnesemia). If QT prolongation occurs, treatment with oxaliplatin should be discontinued.
Gastrointestinal: Oxaliplatin and 5-FU administration may cause diarrhea/emesis in patients. Prophylactic and/or therapeutic antiemetic therapy is given to prevent gastrointestinal toxicity, which manifests as nausea and vomiting.
Dehydration, ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and renal disorders may be associated with severe diarrhea or emesis, particularly when oxaliplatin is combined with 5-FU. Colitis, including Clostridium difficile diarrhea, have been reported.
Cases of intestinal ischemia, duodenal ulcer (DU) and potential complications (i.e., duodenal ulcer hemorrhage and perforation), which can be fatal, have been reported with oxaliplatin use. Discontinue treatment and appropriate measures should be initiated when any of these events occur.
Skin: In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment should be initiated. Extravasation of oxaliplatin may result in local pain and inflammation that may be severe and lead to complications, including necrosis and injection site reaction, including redness, swelling, and pain.
Neuropathy: Oxaliplatin is associated with acute or persistent neuropathy, both of which are principally peripheral sensory neuropathies. The duration and severity of peripheral neuropathy appear to increase with increasing cumulative dosage of oxaliplatin.
Acute 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 presents as transient paresthesia, dysesthesia, and hypoesthesia of the hands, feet, perioral area, or throat. Other symptoms occasionally observed include, jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and throat or chest tightness. In addition, acute motor symptoms, including jaw spasm, muscle spasms, involuntary muscle contractions, ptosis, vocal cord paralysis and cranial nerve dysfunction have been reported.
An acute syndrome of pharyngolaryngeal dysesthesia seen in 1 to 2% (grade 3/4) of 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 infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms.
Persistent Neuropathy: 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). This form of neuropathy can occur without any prior acute neuropathy, and generally progresses with continued cycles. Symptoms may improve over time upon discontinuation of oxaliplatin.
Leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome (PRES) has been observed in clinical trials and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Discontinuation of oxaliplatin and initiation of treatment of hypertension, if present, is recommended in patients developing RPLS. Diagnosis of RPLS is based upon confirmation by brain imaging.
Pulmonary Toxicity: Pulmonary fibrosis and interstitial lung disease has been uncommonly associated with oxaliplatin use. Dyspnea and cough were reported more often in the oxaliplatin combination arm than in the infusional 5-FU/leucovorin alone arm in adjuvant trial. Oxaliplatin should be discontinued in cases of unexplained respiratory symptoms (e.g., non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates) until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
Hepatotoxicity: All patients receiving oxaliplatin should have routine monitoring of their liver function since hepatotoxicity has been noted to occur in patients using oxaliplatin plus 5-FU/leucovorin. Oxaliplatin may cause liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver that is manifested as peliosis, nodular regenerative hyperplasia, and perisinusoidal fibrosis. Cases of hepatic failure, hepatitis, and pancreatitis have also been reported.
Hematologic: Patients must be adequately informed of the risk of neutropenia after oxaliplatin/5-FU administration. There have also been cases of febrile neutropenia reported. If neutropenia or febrile neutropenia occurs, oxaliplatin must be discontinued until improvement or resolution, and the dose of oxaliplatin should be reduced at subsequent cycles, in addition to any 5-FU dose reductions required.
Thrombocytopenia is commonly seen with oxaliplatin combination therapy, although the risk of grade 3 or 4 bleeding is low. Anemia can also occur.
Oxaliplatin should be discontinued immediately at the first signs of any evidence of microangiopathic hemolytic anemia [i.e., rapidly falling hemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen (BUN), or lactate dehydrogenase (LDH)]. Renal failure may not be reversible even though oxaliplatin has been discontinued. In this case, dialysis may be required.
Cases of disseminated intravascular coagulation (DIC), including fatal outcomes, have been reported. Discontinue oxaliplatin if DIC is present and appropriate treatment should be administered.
Musculoskeletal: Rhabdomyolysis, including fatal outcomes, has been reported in patients treated with oxaliplatin. Discontinue treatment if patient experience muscle pain and swelling, in combination with weakness, fever or darkened urine. Appropriate measures should be taken if rhabdomyolysis is confirmed.
Infection and infestations: There have been reports of sepsis, neutropenic sepsis and septic shock, including fatalities, with oxaliplatin use. Discontinue treatment if any of these events occur.
Carcinogenicity, Mutagenicity, Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. However, since oxaliplatin is genotoxic, it should be considered a human carcinogen. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro. Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
Administration of 12 mg/m²/day (approximately one-sixth of the recommended human dose) in female rats caused embryonic mortality, decreased fetal weight and delayed ossifications. Oxaliplatin may increase the risk of genetic defects or fetal malformations.
Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day for 5 days every 28 days for 3 cycles (approximately one-sixth of recommended human dose on a body surface area basis).
Genotoxic effects were observed with oxaliplatin in preclinical studies. It is contraindicated in pregnancy. Men are advised not to father a child during treatment and up to 6 months after treatment with oxaliplatin. Because oxaliplatin may have an irreversible infertility effect, patients should seek advice on sperm conservation.
Effects on Ability to Drive or Use Machines: No studies have been performed. However, oxaliplatin treatment resulting in an increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.
Vision abnormalities, particularly transient vision loss (reversible following therapy discontinuation), were reported with oxaliplatin administration. Transient blindness episodes lasting for periods of seconds or minutes may recur repeatedly during the event duration (usually hours to days). Thus, patients should be warned of the potential effect of these events on the ability to drive or operate machinery.
Renal Impairment: Oxaliplatin is contraindicated in patients with severe renal impairment. In patients with moderate renal impairment, treatment may be initiated with caution at the normally recommended dose. Renal function should also be closely monitored and the dose should be adjusted according to toxicity. There is no need for dose adjustment in patients with mild renal dysfunction.
Hepatic Impairment: In patients with abnormal liver function tests at baseline, no increase in oxaliplatin acute toxicities was observed. No specific dose adjustment for patients with abnormal liver function tests is necessary. Oxaliplatin has not been studied in patients with severe hepatic impairment.
Use in Children: Oxaliplatin is not recommended for use in children. The safety and efficacy of oxaliplatin in children have not been established. Oxaliplatin has been tested in patients 7 months to 22 years old with solid tumors and no significant activity was observed.
Use in Elderly: No significant effect of age on the clearance of ultrafilterable platinum has been observed. However, the incidence of certain adverse effects (i.e., diarrhea, dehydration, hypokalemia, leucopenia, syncope, fatigue) was higher in geriatric patients (≥65 years old) than in younger adults. Patients ≥70 years old have shown a higher risk of thrombocytopenia and stomatitis in clinical studies.

Use in Pregnancy: There are no adequate and well-controlled studies of oxaliplatin in pregnant women. However, based on direct interaction with DNA, oxaliplatin may cause fetal harm when administered to a pregnant woman. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment and for 4 months after 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 there is a potential for serious adverse reactions from oxaliplatin in breastfed infants, breastfeeding is contraindicated during oxaliplatin therapy.

Infections and infestations: Infection, catheter infection, conjunctivitis, infection with normal absolute neutrophil count (ANC), infection with low ANC, unknown infection, upper respiratory tract infection, pneumonia, gingivitis, septic shock, sepsis.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Aggravated neoplasm malignant.
Blood and lymphatic system disorders: Granulocytopenia, leukopenia, lymphopenia, febrile neutropenia, anemia, neutropenia, thrombocytopenia, hyperbilirubinemia, hemolytic anemia, immune-mediated thrombocytopenia, immune-allergic hemolytic anemia, hemolysis, neutropenic sepsis.
Immune system disorders: Allergy/allergic reaction, anaphylactic reactions (including bronchospasm, angioedema, hypotension, sensation of chest pain, and anaphylactic shock), urticaria, hypersensitivity, allergic rhinitis, optic neuritis, Guillain-Barre syndrome.
Metabolism and nutrition disorders: Edema, anorexia, hypokalemia, dehydration, metabolic acidosis, hyperglycemia, hypocalcemia, hyponatremia, hypomagnesemia, peripheral edema.
Psychiatric disorders: Throat tightness, dysphasia, insomnia, depression, anxiety, nervousness, somnolence, dysarthria.
Nervous system disorders: Overall peripheral sensory neuropathy, headache, dysgeusia, sensory disturbance, paresthesia, dizziness, vertigo, muscle weakness, involuntary muscle contractions/fasciculation, intracerebral hemorrhage, loss of deep tendon reflexes, Lhermitte's sign, cranial nerve palsies, convulsion, posterior reversible encephalopathy syndrome (PRES), decrease of visual acuity, neuralgia, cranial nerve dysfunction (including ptosis, diplopia, aphonia, dysphonia, hoarseness, sometimes described as vocal cord paralysis, abnormal tongue sensation/dysarthria, sometimes described as aphasia, trigeminal neuralgia, facial pain, fasciculation, eye pain, decrease of visual acuity, visual field disturbance, transient blindness, amaurosis and amaurosis fugax), jaw spasm, myoclonus, abnormal coordination, abnormal gait, balance disorders.
Eye disorders: Abnormal lacrimation, visual impairment/abnormal vision, visual field disturbance, transient vision loss, tearing.
Ear and labyrinth disorders: Deafness.
Cardiac disorders: Chest tightness, chest pain, tachycardia, dyspnea, ventricular arrhythmia, Torsades de Pointes.
Vascular disorders: Epistaxis, hemorrhage, flushing, deep vein thrombosis/deep thrombophlebitis, hypertension, hypotension, thrombosis, syncope, thromboembolism, rectal bleeding, hemorrhoids, hemoptysis, hot flush, anaphylactic shock, sinusoidal obstruction syndrome/veno-occlusive liver disease, tissue necrosis.
Respiratory, thoracic and mediastinal disorders: Pulmonary embolism, rhinitis, cough, pharyngolaryngeal dysesthesia, pneumonitis, hypoxia, pharyngitis, laryngospasm, pulmonary fibrosis, interstitial lung disease, sinusitis.
Gastrointestinal disorders: Abdominal pain, nausea, diarrhea, vomiting, stomatitis, constipation, dyspepsia, hiccups, flatulence, mouth dryness, rectal pain, gastroesophageal reflux disease, melena, proctitis, intestinal obstruction, enlarged abdomen/abdominal distention, gastrointestinal hemorrhage, colitis, ileus, pancreatitis, tenesmus, intestinal ischemia, duodenal ulcer.
Hepatobiliary disorders: Ascites, hypoalbuminemia, hepatotoxicity, perisinusoidal fibrosis, hepatic failure, hepatitis.
Skin and subcutaneous tissue disorders: Skin disorder, alopecia, skin exfoliation (i.e. hand and food syndrome), rash erythematous, rash, nail disorder, pigmentation changes, pruritus, dry skin, hand and foot syndrome, purpura.
Musculoskeletal and connective tissue disorders: Back pain, myalgia, chills/rigors, arthralgia, bone pain, rhabdomyolysis, muscle spasm, muscle twitching.
Renal and urinary disorders: Urinary frequency, increased creatinine, dysuria, hematuria, urinary incontinence, hemolytic-uremic syndrome, acute renal failure, renal tubular necrosis/acute tubular necrosis, acute interstitial nephritis, urinary tract infection.
Reproductive system and breast disorders: Vaginal hemorrhage.
General disorders and administration site conditions: Fatigue, fever, asthenia, pain, hyperhidrosis/sweating, mucositis, ataxia, extravasation.
Investigations: Weight increase, weight decrease, alkaline phosphatase increased, prolonged prothrombin time and International Normal Ratio (INR), increased transaminases, increased hepatic enzymes, blood bilirubin increased, blood lactate dehydrogenase increased, QT prolongation, decreased neutrophils.
Injury, poisoning and procedural complications: Injection site reaction (redness, swelling, pain), accidental injury, phlebitis, contusion/bruise.
Surgical and medical procedures: Diarrhea-colostomy.

Fluorouracil: Pharmacokinetic interaction with 5-FU is unlikely when recommended dosages and administration schedule are used. Potential pharmacokinetic interaction (20% increase in plasma 5-FU concentrations) during concomitant use of 5-FU and 130 mg/m² of oxaliplatin every 3 weeks.
Anticoagulants: Prolonged time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving oxaliplatin plus 5-FU/leucovorin and requiring oral anticoagulants may require close monitoring.
Nephrotoxic drugs: Nephrotoxic drugs may decrease the clearance of platinum-containing compounds; however, this interaction has not been specifically studied.
Protein-bound drugs: In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.
Drugs that may cause QT prolongation and rhabdomyolysis: Caution is advised when oxaliplatin is co-administered with other drugs known to cause QT prolongation and rhabdomyolysis (see Precautions).

Cytotoxic Chemotherapy

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

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