ALOXI

1 Dosing Considerations ALOXI should be used only on the day of chemotherapy. Drug accumulation was observed in subjects administered ALOXI on consecutive days or once every two days for three doses. There are limited safety data available regarding repeated dosing of ALOXI (see ACTION AND CLINICAL PHARMACOLOGY/Pharmacokinetics).

No dose adjustment is required for geriatric patients with renal or hepatic impairment. ALOXI has been shown to have similar safety profiles between initial and repeat courses of chemotherapy (see ADVERSE REACTIONS/Clinical Trial Adverse Reactions).

V. dose administered over 30 seconds, approximately 30 minutes before the start of chemotherapy. The efficacy of ALOXI in the prevention of acute nausea and vomiting induced by highly emetogenic chemotherapy was demonstrated mainly in patients who were co-administered prophylactic corticosteroids (see CLINICAL TRIALS).

V. 5 mg) administered as a 15 minute infusion beginning approximately 30 minutes before the start of chemotherapy (see CLINICAL TRIALS). 5 mg capsule administered approximately one hour prior to the start of chemotherapy. ALOXI can be taken with or without food.

3 Administration ALOXI Injection ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discolouration before administration, whenever solution and container permit.

Page 6 of 41

V. pivotal Phase 3 program were headache (9%) and constipation (5%). Dizziness and diarrhea were reported at a rate of 1%. V. was comparable to that observed in adults. 6%). 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. 25 mg. The duration for monitoring adverse events was 14 days after study drug administration for all patients.

Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥1% of patients in these trials (Table 2) adverse events known to be caused by chemotherapy such as blood and lymphatic system disorder were not reported as adverse reactions.

V. V. V. V. n = 194 (%) Any adverse reaction 131 (21%) 77 (19%) 61 (31%) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (<1%) 4 (<1%) 4 (2%) Abdominal Pain 1 (<1%) 2 (<1%) 3 (2%) Appetite decreased 1 (<1%) 1 (<1%) 2 (1%) Insomnia 1 (<1%) 3 (<1%) 3 (2%) Back pain 0 (0%) 1 (<1%) 2 (1%) Dermatitis 0 (0%) 0 (0%) 2 (1%) 1 Adverse events assessed by investigators as ‘definitively, possibly, or probably’ related to study medications.

Page 11 of 41 In patients who continued with open-label IV palonosetron for additional chemotherapy cycles (median: 2, up to 9), overall safety profiles were similar between initial and repeat courses of chemotherapy. 4 Clinical trial Adverse Reactions (Pediatrics).

5 mg. Following is a listing of drug related adverse reactions reported by ≥1% of patients from the clinical trial. V. n = 163 (%) Any adverse reaction 13 (8%) 26 (16%) Headache 6 (4%) 14 (9%) Constipation 1 (<1%) 5 (3%) 1 Adverse events assessed by investigators as ‘definitively, possibly, or probably' related to study medications.

Carcinogenesis and Mutagenesis Statistically significant increased incidences of a variety of different tumours affecting the liver, adrenal gland, mammary gland and other tissues and organs were observed at high doses of palonosetron in a rat carcinogenicity study.

In the mouse study the findings were not attributed to palonosetron treatment (see NON-CLINICAL TOXICOLOGY/Carcinogenicity). Experimental evidence indicates that palonosetron is non-mutagenic (see TOXICOLOGY/Genotoxicity). , congenital QT Syndrome, electrolyte imbalance).

Hypokalemia and hypomagnesemia should be corrected prior to 5-HT3-antagonist administration. In non-clinical studies, palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration (see ACTION AND CLINICAL PHARMACOLOGY/Pharmacodynamics).

At all dose levels tested in the chemotherapy-induced nausea and vomiting pivotal clinical studies, cases of QTc prolongation were reported in the ALOXI treatment groups, although those cases were not considered clinically significant (see ADVERSE REACTIONS/Less Common Clinical Trial Adverse Reactions).

25 mg was below that of moxifloxacin. No clinically significant changes were shown on heart rate, atrioventricular conduction and cardiac repolarization (see ACTION AND CLINICAL PHARMACOLOGY/Pharmacodynamics). Driving and Operating Machinery ALOXI may cause dizziness, somnolence or fatigue.

Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Gastrointestinal As ALOXI may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored following administration.

Hepatic Hepatic impairment does not significantly affect total body clearance of intravenous palonosetron compared to the healthy subjects. However, the terminal half-lives of palonosetron were increased in patients with moderate and severe degrees of hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY/Special Populations and Conditions/Hepatic Insufficiency).

ALOXI is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Page 5 of 41