Oxalee Special Precautions

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.