Netupitant/Palonosetron

Akynzeo pairs two antiemetics that act on different pathways of chemotherapy-induced vomiting. Chemotherapy releases serotonin from enterochromaffin cells of the small intestine, and serotonin then activates 5-HT3 receptors on vagal afferents to start the vomiting reflex. Delayed vomiting has been linked to substance P acting on neurokinin 1 (NK1) receptors, which are widely distributed in the central and peripheral nervous systems. Palonosetron blocks the first pathway and netupitant the second.

Mechanism of Action

• Netupitant: a selective antagonist of human substance P/neurokinin 1 (NK1) receptors. In vitro and in vivo studies show that it inhibits responses mediated by substance P. It crosses the blood–brain barrier: after a 300 mg dose, NK1 receptor occupancy in the striatum was 92.5% at 6 hours and still 76.0% at 96 hours.
• Palonosetron: a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.
• Fosnetupitant (infusion forms): the infusion forms contain fosnetupitant in place of netupitant; the amount in one vial (235 mg) corresponds to 197.5 mg of netupitant.
• Clinical effect: in two pivotal studies, oral Akynzeo given with dexamethasone prevented acute and delayed nausea and vomiting after highly and moderately emetogenic chemotherapy.
• Cardiac safety: in an ECG study at supratherapeutic doses (netupitant 600 mg with palonosetron 1.5 mg) the largest placebo- and baseline-corrected QTc increase was 7.0 ms (one-sided upper 95% confidence limit 8.8 ms), with no clinically important effect on ECG parameters.

Pharmacokinetics

The figures below are those given in the SmPC for the capsules; the SmPC for the infusion forms covers the intravenous route.

• Absorption: oral netupitant appears in plasma between 15 minutes and 3 hours after a dose and peaks at about 5 hours; its absolute bioavailability has not been measured in humans but is estimated to exceed 60%. Exposure rises more than in proportion to dose between 10 and 300 mg, is higher in women than in men (Cmax 1.31-fold, AUC 1.02-fold) and rises slightly after a high-fat meal (AUC 1.1-fold, Cmax 1.2-fold). Oral palonosetron is well absorbed (absolute bioavailability 97%) and peaks at about 5 hours; a high-fat meal does not change its exposure.
• Distribution: netupitant has a large central volume of distribution (486 L) and is more than 99% bound to plasma proteins (its metabolites M1 and M3 likewise, M2 more than 97%). Palonosetron has a volume of distribution of about 8.3 L/kg and is about 62% protein bound.
• Metabolism: netupitant is metabolised mainly by CYP3A4, with smaller contributions from CYP2D6 and CYP2C9, to three pharmacologically active metabolites (desmethyl M1, N-oxide M2 and OH-methyl M3). About half of palonosetron is metabolised, mainly by CYP2D6 with minor CYP3A4 and CYP1A2 roles, to two metabolites (N-oxide and 6-S-hydroxy) with less than 1% of its activity; exposure does not differ significantly between poor and extensive CYP2D6 metabolisers.
• Elimination: netupitant is eliminated in a multi-exponential fashion with a mean apparent half-life of 88 hours in cancer patients; less than 1% of a dose is excreted unchanged in urine and about 71% of a radiolabelled dose was recovered in faeces. Palonosetron has a terminal half-life of about 37 hours in healthy volunteers and 48 hours in cancer patients; about 40% of a dose is excreted unchanged in urine, and 85–93% of the radioactivity appears in urine.
• Special populations: netupitant exposure (AUC0–∞) was 19% higher in mild and 143% higher in moderate hepatic impairment than in healthy subjects, but no dose adjustment is needed; palonosetron clearance is not significantly affected. Renal excretion of netupitant is negligible, and palonosetron exposure after intravenous dosing rises by about 28% in severe renal impairment. Neither substance has been evaluated in end-stage renal disease.

The SmPCs for the capsules and for the powder for infusion give the same indications. Akynzeo is indicated in adults for:

• Highly emetogenic chemotherapy: prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy.
• Moderately emetogenic chemotherapy: prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

• Hypersensitivity to the active substances or to any of the excipients.
• Pregnancy.

The common reactions are headache (3.6%), constipation (3.0%) and fatigue (1.2%); all other reactions in the SmPC table are uncommon or rare.

Common (≥1/100 to <1/10): headache, constipation, fatigue.

Uncommon (≥1/1,000 to <1/100): neutropenia, leucocytosis, decreased appetite, insomnia, dizziness, vertigo, first-degree atrioventricular block, cardiomyopathy, conduction disorder, tachycardia, hypertension, hiccups, abdominal distension, abdominal pain, diarrhoea, dyspepsia, flatulence, nausea, alopecia, urticaria, asthenia, increased liver transaminases, increased blood alkaline phosphatase, increased blood creatinine, QT prolongation on the ECG.

Rare (≥1/10,000 to <1/1,000): cystitis, leukopenia, lymphocytosis, hypokalaemia, acute psychosis, altered mood, sleep disorder, hypoaesthesia, somnolence, conjunctivitis, blurred vision, tinnitus, arrhythmia, second-degree atrioventricular block, left and right bundle branch block, mitral valve incompetence, myocardial ischaemia, ventricular extrasystoles, flushing, hypotension, dry mouth, dysphagia, eructation, haemorrhoids, coated tongue, vomiting, erythema, pruritus, rash, back pain, pain in an extremity, feeling hot, non-cardiac chest pain, abnormal taste of the medicinal product, and increases in blood bilirubin, creatine phosphokinase MB, blood urea, myoglobin, neutrophil count and troponin, with ST-segment depression or ST-T abnormality on the ECG.

Cardiac rhythm and conduction findings (QT prolongation, atrioventricular and bundle branch block, arrhythmia) appear among the uncommon and rare reactions, and serotonin syndrome has been reported with 5-HT3 antagonists (see Special Instructions).

Netupitant is a substrate and a moderate inhibitor of CYP3A4. Palonosetron is cleared mainly through CYP2D6 and does not inhibit or induce cytochrome P450 enzymes at clinically relevant concentrations. No clinically relevant pharmacokinetic interaction was seen between oral netupitant and oral palonosetron.

• Dexamethasone: netupitant raised dexamethasone exposure about 2.4-fold, so the oral dexamethasone dose is reduced by about 50% when the two are given together.
• Chemotherapy metabolised by CYP3A4: exposure to docetaxel and etoposide rose by 37% and 21%, with no consistent effect on cyclophosphamide. Patients should be monitored for increased toxicity of CYP3A4-substrate chemotherapy such as docetaxel and irinotecan, and netupitant may also affect the efficacy of chemotherapy that needs CYP3A4 activation.
• Strong CYP3A4 inhibitors (ketoconazole): raised netupitant AUC 1.8-fold and Cmax 1.3-fold without changing palonosetron. Use with caution.
• Strong CYP3A4 inducers (rifampicin): lowered netupitant AUC 5.2-fold and Cmax 2.6-fold. Avoid the combination.
• Oral CYP3A4 substrates with a narrow therapeutic range: use with caution with ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl and quinidine.
• Benzodiazepines: midazolam exposure rose about 2.4-fold and erythromycin exposure about 1.3-fold, which was not considered clinically important, but the effect of higher levels of midazolam and other CYP3A4-metabolised benzodiazepines (alprazolam, triazolam) should be considered.
• Serotonergic medicines: serotonin syndrome has been reported when 5-HT3 antagonists are combined with SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRIs (venlafaxine, duloxetine).
• Hormonal contraceptives: ethinylestradiol exposure was unchanged and levonorgestrel AUC rose 1.4-fold; an effect on contraceptive efficacy is unlikely.
• P-glycoprotein, UGT2B7 and BCRP: netupitant inhibits P-gp in vitro. Digoxin Cmax rose 1.09-fold in healthy volunteers, and the effect may be larger in cancer patients, particularly with abnormal renal function, so caution is advised with digoxin, dabigatran and colchicine. Caution is also advised with oral UGT2B7 substrates (zidovudine, valproic acid, morphine). The clinical relevance of BCRP inhibition is not established.
• QT-prolonging medicines: caution with medicines that prolong the QT interval or cause electrolyte abnormalities (see Special Instructions).
• Food and herbal products: grapefruit products may raise netupitant levels (CYP3A4 inhibition) and St John’s wort may lower them (CYP3A induction); avoid both. The capsules can be taken with or without food.

Akynzeo is given with each cycle of chemotherapy; in the studies it was combined with dexamethasone. The capsule is swallowed whole, with or without food. It must not be opened, because it holds four separate components (three tablets and one soft capsule) that have to be taken together.

Recommended Dose

• Hard capsules (300 mg/0.5 mg): one capsule about 1 hour before the start of each chemotherapy cycle.
• Powder for concentrate for solution for infusion (235 mg/0.25 mg): the content of one vial, reconstituted and diluted, given intravenously (preferably through a running infusion) over 30 minutes, started about 30 minutes before each chemotherapy cycle. The line is flushed with the same carrier solution at the end. Reconstitution and dilution are described in section 6.6 of the SmPC.
• Oral suspension in sachet (300 mg/0.5 mg) and concentrate for solution for infusion (235 mg/0.25 mg per 20 mL vial): covered by the same product information; their preparation and use are set out in their own SmPCs.
• Dexamethasone: the recommended oral dexamethasone dose is reduced by about 50% when it is given with Akynzeo.

Special Populations

• Elderly: no dose adjustment. Caution over 75 years, because of the long half-lives of the active substances and limited experience.
• Renal impairment: no adjustment from mild to severe impairment. Not studied in end-stage renal disease needing haemodialysis; use there should be avoided.
• Hepatic impairment: no adjustment in mild or moderate impairment (Child-Pugh score 5–8). Data are limited in severe impairment (Child-Pugh score ≥9), where netupitant exposure may be higher; use with caution.
• Children and adolescents: safety and efficacy have not been established; no data are available.

Constipation

Palonosetron may lengthen large-bowel transit time. Patients with a history of constipation or signs of subacute intestinal obstruction should be monitored after administration.

Serotonin Syndrome

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

QT Prolongation

The ECG study showed no clinically important effect, but because the product contains a 5-HT3 antagonist, caution is needed with medicines that prolong the QT interval and in patients who have or may develop QT prolongation: a personal or family history, electrolyte abnormalities, congestive heart failure, bradyarrhythmia, conduction disturbances, or treatment with anti-arrhythmic or other QT-prolonging medicines. Hypokalaemia and hypomagnesaemia should be corrected before administration.

Chemotherapy and Other CYP3A4 Substrates

Netupitant is a moderate CYP3A4 inhibitor and can increase exposure to chemotherapy metabolised by CYP3A4 (for example docetaxel), so patients should be monitored for increased toxicity, including with irinotecan. Caution is also needed with orally taken medicines of narrow therapeutic range that are metabolised mainly by CYP3A4.

Severe Hepatic Impairment

Data are limited and netupitant exposure may be higher; use with caution.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. A pregnancy test should be done in all pre-menopausal women before treatment. Women of childbearing potential must not be or become pregnant during treatment and must use effective contraception during therapy and for up to one month afterwards. Netupitant caused reproductive toxicity, including teratogenic effects in rabbits without a safety margin; animal data do not indicate harm with palonosetron.
• Breastfeeding: it is unknown whether either substance passes into human milk, and a risk to the infant cannot be excluded. The product should not be used during breastfeeding; breastfeeding should be stopped during treatment and for 1 month after the last dose.
• Fertility: netupitant had no effect on fertility in animals; degeneration of the seminiferous epithelium was seen in rats given palonosetron.

Excipients

• Each capsule contains 7 mg of sorbitol (E420) and 20 mg of sucrose. The additive effect of other sorbitol- or fructose-containing medicines and of dietary sorbitol or fructose should be taken into account, and sorbitol in oral medicines may affect the bioavailability of other oral medicines taken at the same time. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take the capsules.
• The capsules may contain a trace of lecithin derived from soya; patients with known hypersensitivity to peanut or soya should be monitored closely for allergic reactions. They contain less than 1 mmol (23 mg) of sodium per capsule.
• Each vial of the powder for infusion contains about 24.8 mg of sodium, and about 202 mg once diluted in sodium chloride 9 mg/mL (0.9%) solution.

Effect on Driving

Akynzeo has a moderate influence on the ability to drive and use machines. It may cause dizziness, somnolence or fatigue, and patients with these symptoms should not drive or use machines.

• Hard capsules: no special storage conditions.
• Powder for concentrate for solution for infusion: store in a refrigerator at 2–8 °C, with the vial kept in the outer carton to protect it from light. The cold chain is kept from supply to administration. After reconstitution and dilution the solution is kept below 25 °C (see Shelf Life).
• The sachet and the concentrate for solution for infusion have their own storage conditions in the SmPC.

• Hard capsules and powder for infusion (unopened): 5 years.
• Reconstituted and diluted solution: dilute immediately after reconstitution. Chemical, physical and microbiological in-use stability has been shown for 24 hours at 25 °C; store the solution below 25 °C.

Prescription only (Rx). The capsules and the oral suspension are taken by the patient before chemotherapy, so they are supplied to the patient or to the treating clinic on prescription. The infusion forms are given in a hospital or clinic, so they are supplied to the hospital or clinic that administers them, with cold-chain delivery at 2–8 °C for the powder for infusion.