Renoxtin IV Infusion

Renoxtin, used in combination with infusional 5-fluorouracil/folinic acid, is indicated for:

• Adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
• Treatment of advanced colorectal cancer.

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, 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)].

Administer oxaliplatin in combination with 5-fluorouracil/folinic acid 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 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and folinic acid 200 mg/m² intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m² intravenous bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Folinic acid 200 mg/m² intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m² intravenous bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m² Renoxtin and 5-fluorouracil/folinic acid has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² Renoxtin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied.

It is contraindicated in patients with known allergy to oxaliplatin or other platinum compounds.

Most common adverse reactions (incidence 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported.

Pregnancy Category D. 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. It is not known whether this drug or it 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 discontinue the drug, taking into account the importance of the drug to the mother.

Allergic Reactions: Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Renoxtin has been observed in 2-3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients.

Neurological Toxicity: Neurological toxicity of Renoxtin should be carefully monitored, especially if co-administered with other medications with specific neurological toxicity. A neurological examination should be performed before initiation of each administration, and periodically thereafter. It is not known whether patients with pre-existing medical conditions associated with peripheral nerve damage have a reduced threshold for Renoxtin induced peripheral neuropathy. For patients who develop acute laryngopharyngeal dysaesthesias, during or within 48 hours following the two hour infusion, the next Renoxtin infusion should be administered over six hours. To prevent such dysaesthesia, advise the patient to avoid exposure to cold and to avoid ingesting cold food and/or beverages during or within 48 hours following Renoxtin administration.

Pulmonary Toxicity: Renoxtin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Renoxtin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity: Reactions related to liver sinusoidal obstruction syndrome, including nodular regenerative hyperplasia, have been reported. In the case of abnormal liver function test results or portal hypertension which could not be explained by liver metastases, reactions related to liver sinusoidal obstruction syndrome should be investigated, and very rare cases of drug induced hepatic vascular disorders should be considered.

Cardiovascular Toxicity: QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following Renoxtin 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 Renoxtin and monitor these electrolytes periodically during therapy. Avoid Renoxtin in patients with congenital long QT syndrome.

There is no known antidote for Renoxtin overdose. In addition to thrombocytopenia, the anticipated complications of an Renoxtin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity. Several cases of overdoses have been reported with Renoxtin. 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 Renoxtin that has been administered in a single infusion is 825 mg.

Cytotoxic Chemotherapy

Store in a cool & dry place, protected from light and moisture. Keep out of reach of children.