Palonosetron Hydrochloride (Page 3 of 6)

8.5 Geriatric Use

Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in Palonosetron Hydrochloride Injection PONV clinical studies, 73 (5%) were ≥ 65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, Palonosetron Hydrochloride Injection efficacy in geriatric patients has not been adequately evaluated.

8.6 Renal Impairment

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.

8.7 Hepatic Impairment

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

8.8 Race

Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.

10 OVERDOSAGE

There is no known antidote to Palonosetron Hydrochloride Injection. Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

11 DESCRIPTION

Palonosetron Hydrochloride Injection is an antiemetic and antinauseant agent. It is a serotonin-3 (5-HT3 ) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3a S)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H benz[de ]isoquinoline hydrochloride. The empirical formula is C19 H24 N2 O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula:

description

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Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

Palonosetron Hydrochloride Injection is a sterile, clear, colorless, non pyrogenic, isotonic, buffered solution for intravenous administration. Palonosetron Hydrochloride Injection is available as 5 mL single use vial. Each 5 mL vial contains 0.25 mg palonosetron base as 0.28 mg palonosetron hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

The pH of the solution in the 5 mL vials is 4.5 to 5.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response.

12.2 Pharmacodynamics

The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical trials. In PONV clinical trials the effect of palonosetron on the QTc interval was no different from placebo. 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.

The effect of palonosetron on QTc interval was evaluated in a double blind, randomized, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of I.V. administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25 mg.

12.3 Pharmacokinetics

After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax ) and area under the concentration-time curve (AUC0-∞ ) are generally dose-proportional over the dose range of 0.3–90 mcg/kg in healthy subjects and in cancer patients. Following single I.V. dose of palonosetron at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean ( ± SD) maximum plasma concentration was estimated to be 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h mcg/L.

Following I.V. administration of palonosetron 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following I.V. administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%.

After intravenous dosing of palonosetron in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

Distribution

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.

Elimination

After a single intravenous dose of 10 mcg/kg [14 C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 0.160 0.035 L/h/kg and renal clearance was 0.067 0.018 L/h/kg. Mean terminal elimination half‑life is approximately 40 hours.

Specific Populations

Pediatric Patients

Single-dose I.V. Palonosetron Hydrochloride Injection pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of Palonosetron Hydrochloride Injection 20 mcg/kg, peak plasma concentrations (CT ) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients < 6 years than in older patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg.

The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg.

Table 3: Pharmacokinetics Parameters in Pediatric Cancer PatientsFollowing Intravenous Infusion of Palonosetron HydrochlorideInjection at 20 mcg/kg over 15 min

a Geometric Mean (CV) except for t1/2 which is median values .

b CT is the plasma palonosetron concentration at the end of the 15 minute infusion.

c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted.

PK Parameter a Pediatric Age Group
<2 y 2 to <6 y 6 to <12 y 12 to <17 y
N=12 N=42 N=38 N=44
CT b , ng/L 9025 (197) 9414 (252) 16275 (203) 11831 (176)
N=5 N=7 N=10
AUC0-∞ , h·mcg/L 103.5 (40.4) 98.7 (47.7) 124.5 (19.1)
N=6 N=14 N=13 N=19
Clearance c , L/h/kg 0.31 (34.7) 0.23 (51.3) 0.19 (46.8) 0.16 (27.8)
Vss c , L/kg 6.08 (36.5) 5.29 (57.8) 6.26 (40.0) 6.20 (29.0)

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