Eloxatin (Oxaliplatin) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Laboratory Test Interactions

None known.

Hepatic

Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to ELOXATIN combination therapy (see PRECAUTIONS). The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse events reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients.

Table 22 - Adverse Hepatic Experiences in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy (≥5% of patients)

	ELOXATIN + 5-FU/LV (N=1108)		5-FU/LV (N=1111)
Hepatic Parameter	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Increase in transaminases	57	2	34	1
ALP increased	42	<1	20	<1
Bilirubinaemia	20	4	20	5

Table 23 – Adverse Hepatic – Clinical Chemistry Experience in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients)

	ELOXATIN + 5-FU/LV N=259		irinotecan + 5-FU/LV N=256		ELOXATIN + irinotecan N=258
Clinical Chemistry	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
ALT (SGPT-ALAT)	6	1	2	0	5	2
AST (SGOT-ASAT)	17	1	2	1	11	1
Alkaline Phosphatase	16	0	8	0	14	2
Total Bilirubin	6	1	3	1	3	2

Table 24 – Adverse Hepatic – Clinical Chemistry Experience in Previously Treated Patients (≥5% of patients)

	5-FU/LV (N=142)		ELOXATIN (N=153)		ELOXATIN + 5-FU/LV (N=150)
Clinical Chemistry	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
ALT (SGPT-ALAT)	28	3	36	1	31	0
AST (SGOT-ASAT)	39	2	54	4	47	0
Total Bilirubin	22	6	13	5	13	1

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 ELOXATIN 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 ELOXATIN and 5-FU/LV combination arm, respectively.

Postmarketing Experience

The following events have been reported from worldwide postmarketing experience.

Body as a whole:

• -angioedema, anaphylactic shock

Central and peripheral nervous system disorders:

• -loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations

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.

Hearing and vestibular system disorders:

• -deafness

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 tubulo-interstitial nephropathy leading to acute renal failure.

Respiratory system disorders:

• -pulmonary fibrosis, and other interstitial lung diseases

Vision disorders:

• -decrease of visual acuity, visual field disturbance, optic neuritis

OVERDOSAGE

There have been five ELOXATIN overdoses reported. One patient received two 130 mg/m² doses of ELOXATIN (cumulative dose of 260 mg/m²) within a 24-hour period. The patient experienced Grade 4 thrombocytopenia (<25,000/mm³) without any bleeding, which resolved. Two other patients were mistakenly administered ELOXATIN instead of carboplatin. One patient received a total ELOXATIN dose of 500 mg and the other received 650 mg. The first patient experienced dyspnea, wheezing, paresthesia, profuse vomiting and chest pain on the day of administration. She developed respiratory failure and severe bradycardia, and subsequently did not respond to resuscitation efforts. The other patient also experienced dyspnea, wheezing, paresthesia, and vomiting. Her symptoms resolved with supportive care. Another patient who was mistakenly administered a 700 mg dose experienced rapid onset of dysesthesia. Inpatient supportive care was given, including hydration, electrolyte support, and platelet transfusion. Recovery occurred 15 days after the overdose. The last patient received an overdose of oxaliplatin at 360 mg instead of 120 mg over a 1-hour infusion by mistake. At the end of the infusion, the patient experienced 2 episodes of vomiting, laryngospasm, and paresthesia. The patient fully recovered from the laryngospasm within half an hour. At the time of reporting, 1 hour after onset of the event, the patient was recovering from paresthesia. There is no known antidote for ELOXATIN overdose. In addition to thrombocytopenia, the anticipated complications of an ELOXATIN overdose include myelosuppression, nausea and vomiting, diarrhea, and neurotoxicity. Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered.

CONTRAINDICATIONS

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