ALOXI

ALOXI- palonosetron hydrochloride injection
MGI PHARMA

1 INDICATIONS AND USAGE

1.1 Chemotherapy Induced Nausea and Vomiting

ALOXI is indicated for:

• Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses

• Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses

1.2 Postoperative Nausea and Vomiting

ALOXI is indicated for:

• Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

Chemotherapy Induced Nausea and Vomiting

Dosage for Adults — a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

Postoperative Nausea and Vomiting

Dosage for Adults — a single 0.075 mg I.V. dose administered over 10 seconds immediately before induction of anesthesia.

2.2 Instructions for I.V. Administration

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 discoloration before administration, whenever solution and container permit.

3 DOSAGE FORM AND STRENGTHS

Aloxi is supplied as a single-use sterile, clear, colorless solution in glass vials that provide:

• 0.25 mg (free base) per 5 mL

• 0.075 mg (free base) per 1.5 mL

4 CONTRAINDICATIONS

ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Chemotherapy-Induced Nausea And Vomiting

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with Aloxi and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group
Event Aloxi 0.25 mg (N=633) Ondansetron 32 mg I.V.(N=410) Dolasetron 100 mg I.V. (N=194)
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%)
Insomnia 1 (< 1%) 3 (1%) 3 (2%)

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Aloxi to adult patients receiving concomitant cancer chemotherapy:

Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to Aloxi was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

6.2 Postoperative Nausea And Vomiting

The adverse reactions cited in Table 2 were reported in ≥ 2% of adults receiving I.V. Aloxi 0.075 mg immediately before induction of anesthesia in one phase 2 and two phase 3 randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were indistinguishable. Some events are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. Please refer to Section 12.2, thorough QT/QTc study results, for definitive data demonstrating the lack of palonosetron effect on QT/QTc.

Table 2: Adverse Reactions from Postoperative Nausea and Vomiting Studies ≥ 2% in any Treatment Group
Event Aloxi 0.075 mg (N=336) Placebo(N=369)
Electrocardiogram QT prolongation 16 (5%) 11 (3%)
Bradycardia 13 (4%) 16 (4%)
Headache 11 (3%) 14 (4%)
Constipation 8 (2%) 11 (3%)

In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia:

Cardiovascular: 1%: electrocardiogram QTc prolongation, sinus bradycardia, tachycardia; < 1%: blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema; ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo.

Dermatological: 1%: pruritus.

Gastrointestinal System: 1%: flatulence, < 1%: dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia.

General: < 1%: chills.

Liver: 1%: increases in AST and/or ALT< 1%: hepatic enzyme increased

Metabolic: < 1%: hypokalemia, anorexia.

Nervous System: < 1%: dizziness.

Respiratory: < 1%: hypoventilation, laryngospasm.

Urinary System: 1%: urinary retention.

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