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.
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
|Ondansetron 32 mg I.V.
|Dolasetron 100 mg I.V.
|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 postoperative 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.
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
|Electrocardiogram QT prolongation||16 (5%)||11 (3%)|
|Bradycardia||13 (4%)||16 (4%)|
|Headache||11 (3%)||14 (4%)|
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.
The following adverse reactions have been identified during postapproval use of ALOXI. 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.
Very rare cases ( < 1/10,000) of hypersensitivity reactions including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.