KNOWLEDGE
Oxaliplatin Injection Leaflet

INDICATIONS AND USAGE:

Oxaliplatin injection, used in combination with infusional 5-fluorouracil/leucovorin, 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

DOSAGE FORMS AND STRENGTHS:

Oxaliplatin Injection, USP is supplied in single-dose vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg per mL.

DOSAGE AND ADMINISTRATION:

Administer Oxaliplatin injection in combination with 5fluorouracil/leucovorin every 2 weeks.

Day 1 : Oxaliplatin injection, 85 mg/m2intravenous infusion in 250-500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m2intravenous 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/m2intravenous bolus given over 2-4 minutes, followed by 5 fluorouracil 600 mg/m2intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Day 2 : leucovorin 200 mg/m2intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2intravenous bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m2intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Reduce the dose of oxaliplatin injection to 75 mg/m2(adjuvant setting) or 65 mg/m2(advanced colorectal cancer) :

if there are persistent grade 2 neurosensory events that do not resolve

after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia. Delay next dose until neutrophils 1.5 x 109/L and platelets 75 x 109/L.

For patients with severe renal impairment (creatinine clearance <30 mL/min), the initial recommended dose is 65 mg/m2.

Discontinue oxaliplatin injection if there are persistent Grade 3 neurosensory events.

Never prepare a final dilution with a sodium chloride solution or other chloride-containing solutions.

ADVERSE REACTIONS:

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Oxaliplatin Injection, USP. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole:angioedema, anaphylactic shock

Cardiovascular disorders:QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes

Central and peripheral nervous system disorders:loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).

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.

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

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:pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)

Vision disorders:decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)

CONTRAINDICATIONS:

Oxaliplatin Injection, USP should not be administered to patients with a history of known allergy to Oxaliplatin Injection, USP or other platinum compounds

WARNINGS AND PRECAUTIONS:

Allergic Reactions

See boxed warning

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin Injection, USP has been observed in 2 to 3% of 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 [see Contraindications (4)]. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

Neurologic Toxicity

Neuropathy

Oxaliplatin Injection, USP 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. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin combination arm was 6.

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 the infusion of Oxaliplatin Injection, USP 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). These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of Oxaliplatin Injection, USP.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (<0.1%) 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 . Diagnosis of RPLS is based upon confirmation by brain imaging

Severe Neutropenia

Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with Oxaliplatin Injection, USP in combination with 5-flurouracil (5-FU) and leucovorin compared to 5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with Oxaliplatin Injection, USP, including fatal outcomes.

Delay Oxaliplatin Injection, USP until neutrophils are ≥1.5 x 109/L. Withhold Oxaliplatin Injection, USP for sepsis or septic shock. Dose reduce Oxaliplatin Injection, USP after recovery from Grade 4 neutropenia or febrile neutropenia.

Pulmonary Toxicity

Oxaliplatin Injection, USP has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the Oxaliplatin Injection, USP plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Oxaliplatin Injection, USP combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin Injection, USP should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity

Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin Injection, USP combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. 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 reported in postmarketing experiences following Oxaliplatin Injection, USP 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 Injection, USP and monitor these electrolytes periodically during therapy. Avoid Oxaliplatin Injection, USP in patients with congenital long QT syndrome .

Rhabdomyolysis

Rhabdomyolysis, including fatal cases, has been reported in patients treated with Oxaliplatin Injection, USP. Discontinue Oxaliplatin Injection, USP if any signs or symptoms of rhabdomyolysis occur.

Use in Pregnancy

Pregnancy Category D

Oxaliplatin Injection, USP may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Injection, USP in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin Injection, USP.

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 Injection, USP cycle.

There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

NONCLINICAL TOXICOLOGY:

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 x 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.

DRUG INTERACTIONS:

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin 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 oxaliplatin injection 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.