Palonosetron

Palonosetron is a selective, high-affinity antagonist of the 5-HT3 receptor, with little or no affinity for other receptors. It is pharmacologically related to other 5-HT3 antagonists but is structurally different, and its terminal half-life is long.

Mechanism of Action

• 5-HT3 receptor blockade: 5-HT3 receptors lie on the nerve terminals of the vagus in the periphery and in the chemoreceptor trigger zone of the area postrema. Palonosetron blocks them.
• Chemotherapy trigger: cytotoxic drugs are thought to release serotonin from enterochromaffin cells of the small intestine by damaging the gut lining. The serotonin stimulates vagal and splanchnic nerve receptors that project to the medullary vomiting centre, and 5-HT3 receptors in the area postrema, starting the vomiting reflex.
• Delayed symptoms: the pivotal studies were not designed to assess efficacy in delayed-onset nausea and vomiting, and Aloxi should not be used for nausea and vomiting in the days after chemotherapy unless another chemotherapy dose is given.
• Clinical studies: in studies of moderately emetogenic chemotherapy (compared with ondansetron or dolasetron, without dexamethasone) and of highly emetogenic chemotherapy (compared with ondansetron, with prophylactic dexamethasone in 67% of patients), palonosetron was non-inferior to the comparators in the acute phase of emesis.
• Cardiac electrophysiology: at all dose levels tested, palonosetron did not cause clinically relevant QTc prolongation.

Pharmacokinetics

The figures below come from the solution for injection SmPC. For absorption after oral dosing of the capsules, see the SmPC of the soft capsules.

• Exposure: after intravenous administration, plasma concentrations first fall and then decline slowly, with a mean terminal elimination half-life of about 40 hours. Maximum concentration and area under the curve are generally dose-proportional from 0.3 to 90 micrograms/kg in healthy subjects and cancer patients.
• Distribution: widely distributed, with a volume of distribution of about 6.9 to 7.9 L/kg; about 62% is bound to plasma proteins.
• Metabolism: about 50% is metabolised to two primary metabolites with less than 1% of the 5-HT3 antagonist activity of palonosetron. CYP2D6 is mainly involved, and CYP3A4 and CYP1A2 to a lesser extent. Pharmacokinetics do not differ significantly between poor and extensive CYP2D6 metabolisers. Palonosetron does not inhibit or induce cytochrome P450 enzymes at clinically relevant concentrations.
• Elimination: by two routes. After a single intravenous dose of 10 micrograms/kg of radiolabelled palonosetron, about 80% of the dose was recovered in urine within 144 hours, about 40% of the dose as unchanged palonosetron. Total body clearance was 173 ± 73 mL/min and renal clearance 53 ± 29 mL/min.
• Special populations: no dose adjustment is needed in the elderly or in hepatic or renal impairment (see Administration and Dosage).

Solution for injection (250 micrograms)

• Adults: prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy; prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.
• Children and adolescents from 1 month of age: prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy, and prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

Soft capsules (500 micrograms)

• Adults: prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

• Hypersensitivity to the active substance or to any of the excipients (both forms).

The adverse reaction data below are from the SmPC of the solution for injection (adult clinical studies with 250 micrograms, 633 patients); for the soft capsules consult their own SmPC. The most frequent reactions at least possibly related to Aloxi were headache (9%) and constipation (5%). Frequencies are shown only for the categories reported in the studies: common and uncommon from clinical trials, very rare from post-marketing experience.

Common (≥1/100 to <1/10): headache; dizziness; constipation; diarrhoea.

Uncommon (≥1/1,000 to <1/100): hyperkalaemia, metabolic disorders, hypocalcaemia, hypokalaemia, anorexia, hyperglycaemia, decreased appetite; anxiety, euphoric mood; somnolence, insomnia, paraesthesia, hypersomnia, peripheral sensory neuropathy; eye irritation, amblyopia; motion sickness, tinnitus; tachycardia, bradycardia, extrasystoles, myocardial ischaemia, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles; hypotension, hypertension, vein discolouration, vein distended; hiccups; dyspepsia, abdominal pain, upper abdominal pain, dry mouth, flatulence; hyperbilirubinaemia; allergic dermatitis, pruritic rash; arthralgia; urinary retention, glycosuria; asthenia, pyrexia, fatigue, feeling hot, influenza-like illness; raised transaminases, QT prolongation on the electrocardiogram.

Very rare (<1/10,000): hypersensitivity, anaphylaxis, anaphylactic or anaphylactoid reactions and shock; injection site reaction (burning, induration, discomfort and pain).

Children and adolescents: in clinical trials 402 patients received a single dose of 3, 10 or 20 micrograms/kg, and no reaction occurred in more than 1%. Headache was common; uncommon reactions were dizziness, dyskinesia, QT prolongation on the electrocardiogram, conduction disorder, sinus tachycardia, cough, dyspnoea, epistaxis, allergic dermatitis, pruritus, skin disorder, urticaria, pyrexia, infusion site pain, infusion site reaction and pain. Reactions were assessed over up to 4 chemotherapy cycles.

Important serious reactions are the very rare hypersensitivity reactions, including anaphylaxis and shock.

The figures below are from the SmPC of the solution for injection.

• Cytochrome P450: palonosetron is metabolised mainly by CYP2D6, with minor contributions from CYP3A4 and CYP1A2. In vitro it does not inhibit or induce cytochrome P450 enzymes at clinically relevant concentrations.
• CYP2D6 inducers and inhibitors: a population pharmacokinetic analysis showed no significant effect on palonosetron clearance of inducers (dexamethasone, rifampicin) or of a range of inhibitors, including amiodarone, cimetidine, quinidine, ritonavir and terbinafine as well as several antidepressant and antipsychotic medicines.
• Metoclopramide: no significant pharmacokinetic interaction with steady-state oral metoclopramide, a CYP2D6 inhibitor.
• Chemotherapy: in preclinical studies palonosetron did not inhibit the antitumour activity of cisplatin, cyclophosphamide, cytarabine, doxorubicin or mitomycin C.
• Corticosteroids: palonosetron has been given safely with corticosteroids. Adding a corticosteroid before chemotherapy may enhance its efficacy in highly emetogenic chemotherapy.
• Serotonergic medicines (SSRIs and SNRIs): serotonin syndrome has been reported after combined use with 5-HT3 antagonists.
• QT-prolonging medicines and anti-arrhythmic agents: use caution (see Special Instructions).
• Other medicines: palonosetron has been given safely with analgesics, antiemetics or antinauseants, antispasmodics and anticholinergic medicines.
• Food: the soft capsules can be taken with or without food.

Aloxi is used only before chemotherapy is given. The solution for injection is administered by a healthcare professional under appropriate medical supervision. The soft capsules are taken by mouth.

Solution for Injection

• Adults: 250 micrograms as a single intravenous bolus about 30 minutes before the start of chemotherapy, injected over 30 seconds. In highly emetogenic chemotherapy, adding a corticosteroid before chemotherapy may enhance efficacy.
• Children and adolescents (1 month to 17 years): 20 micrograms/kg (maximum total dose 1,500 micrograms) as a single 15-minute intravenous infusion starting about 30 minutes before chemotherapy. Safety and efficacy in children under 1 month have not been established and there are no data; data in children under 2 years are limited.

Soft Capsules

• Adults: 500 micrograms by mouth about one hour before the start of chemotherapy, with or without food.
• Children: safety and efficacy have not been established. The available data are described in sections 5.1 and 5.2 of the SmPC, but no dose recommendation can be made.

Special Populations

• Elderly: no dose adjustment (both forms).
• Hepatic impairment: no dose adjustment (both forms).
• Renal impairment: no dose adjustment (both forms). No data are available for patients with end-stage renal disease on haemodialysis.

Constipation and Intestinal Obstruction

Palonosetron may increase large bowel transit time, so patients with a history of constipation or signs of subacute intestinal obstruction should be monitored after administration. Two cases of constipation with faecal impaction needing hospitalisation were reported with palonosetron 750 micrograms.

QT Prolongation

At all dose levels tested palonosetron did not cause clinically relevant QTc prolongation, and a thorough QT/QTc study in healthy volunteers confirmed this. As with other 5-HT3 antagonists, caution is advised in patients who have or are likely to develop QT prolongation: a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances, or use of anti-arrhythmic agents or other medicines that prolong the QT interval or cause electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected before a 5-HT3 antagonist is given.

Serotonin Syndrome

Serotonin syndrome has been reported with 5-HT3 antagonists, alone or together with other serotonergic medicines such as SSRIs and SNRIs. Patients should be observed for serotonin syndrome-like symptoms.

Use Only Around Chemotherapy

Aloxi should not be used to prevent or treat nausea and vomiting in the days after chemotherapy unless it is linked to another chemotherapy administration.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development, and only limited animal data exist on placental transfer. Palonosetron should not be used in pregnant women unless the physician considers it essential.
• Breastfeeding: there are no data on excretion in breast milk, so breastfeeding should be discontinued during therapy.
• Fertility: there are no data on the effect of palonosetron on fertility.

Excipients

The solution for injection contains less than 1 mmol (23 mg) of sodium per vial, so it is essentially sodium-free. Each soft capsule contains 7 mg of sorbitol; see the capsule SmPC for the related warning.

Effect on Driving

No studies have been performed. Palonosetron may cause dizziness, somnolence or fatigue, so patients should be cautioned when driving or operating machines.

Neither the solution for injection nor the soft capsules need special storage conditions. The solution is supplied in a type I glass vial with a chlorobutyl siliconised rubber stopper and an aluminium cap, in packs of one 5 mL vial. After a vial is opened, the solution must be used immediately and any unused solution discarded.

Solution for injection: 5 years. Soft capsules: 4 years. After a vial of the solution is opened, use it immediately and discard any unused solution.

Prescription only (Rx). The solution for injection is subject to restricted medical prescription (Annex II B) and is given by a healthcare professional under medical supervision, so it is supplied to the hospital or clinic that administers it. The soft capsules are subject to medical prescription and are taken by the patient about one hour before chemotherapy, so they are supplied to the patient or to the treating clinic on prescription.