Aloxi®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALOXI® (ALOXI®)

Composition:

Active substance: palonosetron hydrochloride;

5 ml of solution contain palonosetron hydrochloride 250 mcg;

Excipients: mannitol (E 421); disodium edetate; sodium citrate; citric acid, monohydrate; sodium hydroxide; hydrochloric acid, diluted; water for injections.

Pharmaceutical form. Solution for intravenous injection.

Main physicochemical characteristics: clear, colorless solution.

Pharmacotherapeutic group. Antiemetics and antinauseants. Serotonin receptor antagonists (5-HT3). ATC code A04A A05.

Pharmacological Properties.

Pharmacodynamics.

Aloxi® is a selective, high-affinity 5-HT3 receptor antagonist. Its mechanism of action is related to inhibition of the vomiting reflex through blockade of serotonin 5-HT3 receptors at the level of neurons in the central nervous system.

Pharmacokinetics.

Absorption.

The mean elimination half-life after intravenous administration is approximately 40 hours. Mean values of 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 volunteers and in patients with oncological diseases.

After single intravenous administration of 0.75 mg palonosetron once daily in 11 patients with testicular cancer, the mean (± standard deviation (SD)) increase in plasma concentrations from day 1 to day 5 was 42 ± 34%. After intravenous administration of 0.25 mg palonosetron once daily for 3 consecutive days in 12 healthy volunteers, the mean (± SD) increase in plasma concentrations of palonosetron from day 1 to day 3 was 110 ± 45%.

Studies have shown that total exposure (AUC0–∞) following intravenous administration of 0.25 mg palonosetron once daily for 3 consecutive days is comparable to total exposure after a single intravenous dose of 0.75 mg; however, Cmax values after a single 0.75 mg dose are higher.

Distribution.

At recommended doses, palonosetron is widely distributed throughout the body, with a volume of distribution of approximately 6.9–7.9 L/kg. Approximately 62% of the palonosetron dose is protein-bound in plasma.

Biotransformation.

Elimination of palonosetron occurs via two pathways: approximately 40% of the dose is excreted unchanged by the kidneys, and approximately 50% is metabolized, forming two primary metabolites, each with less than 1% of the 5-HT3 receptor antagonistic activity of palonosetron. In vitro metabolism studies have shown that the isoenzyme CYP2D6, and to a lesser extent CYP3A4 and CYP1A2, are involved in the metabolism of palonosetron. However, no clinically significant pharmacokinetic differences have been observed between patients who are poor and extensive metabolizers of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.

Elimination.

After single intravenous administration of a 10 mcg/kg dose of [14C]-palonosetron, approximately 80% of the administered dose was recovered in urine over 144 hours, with unchanged palonosetron accounting for approximately 40% of the administered dose. After single intravenous bolus administration in healthy volunteers, total body clearance of palonosetron was 173 ± 73 mL/min, and renal clearance was 53 ± 29 mL/min. The low total body clearance and large volume of distribution result in a terminal elimination half-life of approximately 40 hours. In 10% of patients, the mean terminal half-life exceeds 100 hours.

Pharmacokinetics in Special Populations.

Elderly Patients.

Age does not affect the pharmacokinetics of palonosetron. Dose adjustment is not required for elderly patients.

Gender.

Patient gender does not influence the pharmacokinetics of palonosetron. Dose adjustment based on gender is not required.

Paediatric Population.

Pharmacokinetic data following single intravenous administration of Aloxi® were obtained in a subgroup of paediatric patients with cancer (n=280), who received the drug at doses of 10 mcg/kg or 20 mcg/kg. Increasing the dose from 10 mcg/kg to 20 mcg/kg resulted in a dose-proportional increase in mean AUC. After single intravenous infusion of Aloxi® at 20 mcg/kg, peak plasma concentrations (Ct), measured at the end of the 15-minute infusion, showed high variability across all age groups, with a tendency toward lower levels in patients under 6 years of age compared to older paediatric patients. The mean elimination half-life was 29.5 hours (range approximately 20 to 30 hours) across all age groups after administration of the 20 mcg/kg dose.

Total body clearance (L/h/kg) in patients aged 12 to 17 years was similar to that observed in healthy adult volunteers. There is no apparent difference in volume of distribution expressed as L/kg.

Renal Impairment.

Dose adjustment is not required for patients with renal impairment. Pharmacokinetic data in patients undergoing hemodialysis are not available.

Hepatic Impairment.

Patients with severe hepatic impairment do not require dose adjustment of palonosetron.

Preclinical Safety Data.

Effects observed in preclinical studies occurred only at doses substantially exceeding the maximum human exposure, suggesting limited relevance to clinical use.

Preclinical studies indicate that palonosetron may block ion channels involved in ventricular depolarization and repolarization, thereby prolonging action potential duration, but only at very high concentrations.

Animal studies do not indicate any direct or indirect harmful effects of this drug on pregnancy, embryonic/fetal development, parturition, or postnatal development of offspring. Data from animal studies regarding placental transfer of the drug are limited (see section "Use during pregnancy or breastfeeding").

Palonosetron is not mutagenic. High doses of palonosetron (each dose producing systemic exposure at least 30 times higher than the therapeutic exposure in humans), administered daily for 2 years, led to increased incidence of liver tumors, endocrine neoplasms (in the thyroid gland and adrenal medulla), and skin tumors in rats, but not in mice. The mechanisms underlying these findings are not fully understood. However, due to the high doses used and the fact that Aloxi® is intended for single-dose use, these findings are not considered relevant to clinical use.

Clinical Characteristics.

Indications.

Prevention of acute nausea and vomiting associated with highly emetogenic or moderately emetogenic chemotherapy in oncology.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Palonosetron is metabolized mainly by the CYP2D6 isoenzyme; CYP3A4 and CYP1A2 isoenzymes play a lesser role in its metabolism. According to in vitro study data, palonosetron at clinically relevant concentrations does not inhibit or induce cytochrome P450 isoenzymes.

Chemotherapeutic medicinal products.

Preclinical studies have shown that palonosetron does not inhibit the antitumor effects of five chemotherapeutic agents investigated (cisplatin, cyclophosphamide, cytarabine, doxorubicin, and mitomycin C).

Metoclopramide.

In a clinical study, no significant pharmacokinetic interaction was observed between palonosetron administered as a single intravenous dose and metoclopramide at steady-state concentration administered orally (a CYP2D6 inhibitor).

CYP2D6 inducers and inhibitors.

Population pharmacokinetic analysis demonstrated no significant effect on palonosetron clearance when administered concomitantly with CYP2D6 inducers (dexamethasone and rifampicin) and CYP2D6 inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline, or terbinafine).

Corticosteroids.

Palonosetron has been safely used concomitantly with corticosteroids.

Serotonergic agents (SSRIs and SNRIs).

Cases of serotonin syndrome have been reported with concomitant use of 5-HT3 antagonists and other serotonergic drugs (including SSRIs and SNRIs).

Other medicinal products.

Palonosetron has been safely used with analgesics, antiemetics/antinausea agents, spasmolytics, and anticholinergic medicinal products.

Special precautions for use

Since palonosetron may increase the transit time of contents through the large intestine, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored after administration of the drug. Two cases of constipation with fecal impaction requiring hospitalization have been reported during treatment with palonosetron at a dose of 750 mcg.

All studied doses of palonosetron did not lead to clinically significant prolongation of the heart rate-corrected QT interval (QTc).

However, as with other 5-HT3 antagonists, this drug should be used with caution in patients who have QT prolongation or are predisposed to its development. Such patients include those with personal or family history of QT prolongation, electrolyte imbalances, congestive heart failure, bradyarrhythmias, conduction system disorders, as well as individuals receiving antiarrhythmic drugs or other medicinal products that may cause QT prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to administration of a 5-HT3 antagonist.

Cases of serotonin syndrome have been reported during treatment with 5-HT3 antagonists, either as monotherapy or in combination with other serotonergic agents (including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)). Appropriate monitoring of patients is recommended to ensure timely recognition of symptoms consistent with serotonin syndrome.

Aloxi® should not be used for the prevention or treatment of nausea and vomiting on days following a chemotherapy session, except when such use precedes another chemotherapy session.

The sodium content of the medicinal product is less than 1 mmol (23 mg) per vial; therefore, Aloxi® is considered practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There are no clinical data on the use of palonosetron during pregnancy. Animal studies do not indicate any direct or indirect harmful effects of this agent on pregnancy, embryonic/fetal development, parturition, or postnatal development of offspring. Currently, animal study data on placental transfer are limited (see section "Preclinical safety data"). There is no experience with the use of palonosetron in human pregnancy; therefore, palonosetron should not be used in pregnant women unless considered necessary by the physician.

Breastfeeding

Since there are no data on the ability of palonosetron to pass into breast milk, breastfeeding should be discontinued during treatment with this agent.

Fertility

There are no data on the effect of palonosetron on fertility.

Ability to influence the speed of reactions while driving vehicles or operating machinery

No studies have been conducted on the effect of the drug on the ability to drive vehicles or operate machinery.

Since palonosetron may cause dizziness, drowsiness, or fatigue, patients should be advised to refrain from driving vehicles or operating machinery.

Administration and Dosage

Aloxi® should only be administered prior to chemotherapy. This medicinal product must be administered by a healthcare professional under appropriate medical supervision.

Dosage.

Adults.

250 mcg of palonosetron is administered as a single intravenous bolus injection approximately 30 minutes before the start of chemotherapy. The administration time of Aloxi® is 30 seconds. The efficacy of Aloxi® in preventing nausea and vomiting associated with highly emetogenic chemotherapy may be enhanced by the additional use of a corticosteroid prior to chemotherapy.

Elderly patients.

Dose adjustment is not required in elderly patients.

Children and adolescents (aged 1 month to 17 years).

Palonosetron at a dose of 20 mcg/kg (maximum total dose should not exceed 1500 mcg) should be administered as a single 15-minute intravenous infusion, starting approximately 30 minutes before the initiation of chemotherapy.

The safety and efficacy of Aloxi® in children under 1 month of age have not been established. There are no data available in this age group. Limited data are available on the use of Aloxi® for the prevention of nausea and vomiting in children under 2 years of age.

Hepatic impairment.

Dose adjustment is not required in patients with hepatic impairment.

Renal impairment.

Dose adjustment is not required in patients with renal impairment.

There are no available data on the use of this medicinal product in patients with end-stage renal disease on hemodialysis.

Administration method.

For intravenous use.

Children.

This medicinal product is intended for use in children aged 1 month to 17 years.

Overdose.

There have been no reports of overdose to date.

In clinical trials in adults, doses up to 6 mg were administered. In the group receiving the highest dose, the incidence of adverse reactions was similar to that observed in other groups; no dose-dependent adverse reactions were observed. In the unlikely event of overdose, supportive treatment is recommended. Studies on the utility of dialysis have not been conducted; however, due to the large volume of distribution of the drug, dialysis is unlikely to be effective in treating an overdose of Aloxi®.

Paediatric population.

There have been no reports of overdose during clinical trials involving the paediatric population.

Adverse reactions

During clinical studies with a dose of 250 mcg (total number of participants – 633), the most frequently observed adverse reactions considered at least possibly related to Alocsi® were headache (9%) and constipation (5%).

The adverse reactions (ARs) listed below were observed during clinical studies and were considered possibly or probably related to the use of Alocsi®. They were classified by frequency as follows: frequently (≥ 1/100 to < 1/10) or infrequently (≥ 1/1000 to < 1/100). Reactions occurring very rarely (< 1/10,000) have been reported during the post-marketing surveillance period.

Within each frequency group, adverse reactions are listed in order of decreasing severity.

° Data obtained during the post-marketing surveillance period.

* Including: burning sensation, skin induration, discomfort, and pain.

Pediatric population

In clinical studies involving pediatric patients for the prevention of nausea and vomiting caused by moderately emetogenic and highly emetogenic chemotherapy, 402 patients received a single dose of palonosetron (3, 10, or 20 mcg/kg). With the use of palonosetron, both common and uncommon adverse reactions were reported; however, the incidence of any reported adverse reaction did not exceed 1%.

Adverse reactions were evaluated in pediatric patients who received palonosetron prior to chemotherapy with up to 4 cycles.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

After opening the vial, the solution should be used immediately, and any unused solution should be discarded.

Storage conditions.

Store at a temperature not exceeding 25 ºC, in places inaccessible to children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products.

Packaging.

5 mL in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorization Holder.

Helsinn Birex Pharmaceuticals Ltd., Ireland.

Address of manufacturer and location of its operations/Address of marketing authorization holder.

Damastown, Mulhuddart, Dublin 15, Ireland.