Akynzeo (Netupitant and palonosetron) is a fixed-dose combination product indicated for the treatment of acute and delayed chemotherapy-induced vomting.

Akynzeo (Netupitant and palonosetron) Uses:

• Chemotherapy-induced nausea and vomiting:

  • preventing early and delayed nauseous and diarrhoeal reactions during the first and later cancer treatment regimens, including but not limited to severely emetogenic chemotherapy (in combination with dexamethasone).

Akynzeo (Netupitant and palonosetron) Dose in Adults

Akynzeo Dose in the treatment of Highly emetogenic chemotherapy (including cisplatin-based):

• P/O:
  • On day 1: 1 capsule 1 hour before chemotherapy.

Note:

• Dexamethasone is another component of the antiemetic regimen and should be taken orally in doses of 12 milligrammes on day 1 and 8 milligrammes once a day on days 2-4 of chemotherapy.

Treatment with the Akynzeo Dose for chemotherapy that uses anthracyclines and cyclophosphamide and chemotherapy that is not thought to be very emetogenic:

• P/O:
  • On day 1: 1 Capsule one hour before chemotherapy  (Gralla 2014; Hesketh 2017; Roila 2016).
• Note:
  • On day one, the antiemetic regimen also calls for taking 12 mg of dexamethasone orally 30 minutes before treatment (only).

Use in children:

Not indicated

Akynzeo Pregnancy Risk Category: Not assigned

• In some studies on animal reproduction, adverse reactions were seen when using the components of this mixture product.
• Information regarding the use of palonosetron and netupitant during pregnancy is not available.

Use of palonosetron and netupitant during breastfeeding:

• It is unknown if netupitant and palonosetron are present or not in breast milk.
• The manufacturer advises that you weigh the dangers to the baby, the advantages for the mother, and the advantages of nursing while undergoing treatment.

Akynzeo Dose in Kidney Disease:

• CrCl 30 to 60 mL per min:
  • No dose change is required.
• ESRD:
  • Skip using (has not been reviewed).
• CrCl less than 30 mL per min:
  • Avoid using.

Akynzeo Dose in Liver disease:

• Mild or moderate impairment (Child-Pugh classes A and B):
  • No dosage adjustment is necessary.
• Severe impairment (Child-Pugh class C):
  • Avoid use.

Side Effects of Akynzeo (Netupitant and palonosetron):

• Dermatologic:

  • Erythema

• Central Nervous System:

  • Headache
  • Fatigue

• Neuromuscular & Skeletal:

  • Weakness

• Gastrointestinal:

  • Dyspepsia
  • Constipation

Contraindications to Akynzeo (Netupitant and palonosetron):

• There are no contraindications in the US manufacturer's labeling.

Canadian labeling:

• Hypersensitivity to netupitant, palonosetron or any other component of the formulation
• Pregnancy.
• Use pimozide, Terfenadine or Astemizole in conjunction

Warnings and precautions

• Hypersensitivity

  • Palonosetron, a component of this product, has been associated with hypersensitivity. This could include anaphylaxis.

• Hepatic impairment

  • In extreme liver impairment, avoid use.

• Serotonin syndrome:

  • Serotonergic medications (such as SSRIs and SNRIs), mirtazapine, fentanyl, lithium, tramadol, and methylene blue are the ones that cause serotonin syndrome the most frequently.
  • Some incidents resulted in death.
  • Most 5-HT receptor antagonist-induced occurrences of serotonin syndrome occurred in post-anaesthesia settings or infusion facilities.
  • Another 5-HT3 antagonist overdose was associated with serotonin syndrome.
  • Examine patients for agitation, hallucinations, or coma, which are serotonin syndrome indications and symptoms.
  • Neuromuscular changes (such as tremor, stiffness, myoclonus, and hyperreflexia); autonomic instability (such as tachycardia or labile blood pressure; diaphoresis and flushing, hypothermia.
    seizures and gastrointestinal problems (such as nausea, vomiting, and diarrhoea).
  • Stop using 5HT receptor antagonists if serotonin syndrome is evident, and start supportive care instead.

• Renal impairment

  • Use should be avoided in cases of serious renal impairment and kidney failure.
  • For moderate to mild impairment, dosage modification is not necessary.

Monitoring parameters:

• Check for hypersensitivity and serotonin syndrome symptoms and indicators.

How to administer Akynzeo (Netupitant and palonosetron)?

P/O:

• Before chemotherapy, administer 1 hour.
• May administer with or without food.

Mechanism of action of Akynzeo (Netupitant and palonosetron):

• Acute and delayed chemotherapy-induced emesis are inhibited by the substance P/neurokinin antagonist (NK), netupitant.
• It augments the antiemetic activities of corticosteroids and 5-HT3 receptor antagonists.
• Palonosetron, a selective 5-HT3 receptor antagonist, inhibits serotonin on the terminals of vagal nerves in the peripheral vagus and centrally in the chemoreceptor trigger area.
• Palonosetron blocks communication between 5-HT3 and NK receptors.
• More effectively than either drug alone, the combination of netupitant and palonosetron inhibits the substance P response (Aapro 2014).

Netupitant:

Time to peak:

• ~4 to 5 hours

Absorption:

• Within 15 mins to 3 hours

Metabolism:

• Extensively hepatic via CYP3A4 (major), CYP2C9 (minor) and CYP2D6 (minor).
• Forms active metabolites M1, M2, and M3

Excretion:

• Feces (~71%).
• Urine (~4%).

Protein binding:

• >97 percent for major metabolites.
• >99.5 percent for netupitant.

Half-life elimination:

• 80 ± 29 hours

Palonosetron:

Absorption:

• Well absorbed.

Time to peak:

• ~5 hours

Protein binding:

• ~62 percent.

Metabolism:

• 50% metabolized to relatively inactive metabolites (N-oxide-palonosetron and 6-S-hydroxy-palonosetron).
• CYP2D6, 3A4 & 1A2 contribute to metabolism.

Excretion:

• Feces (5 percent-8 percent).
• Urine (85 percent -93 percent; 40 percent as unchanged drug).

Bioavailability:

• P/O:
• ~97 percent.

Half-life elimination:

• 50 ± 16 hours

International Brands of Netupitant and palonosetron:

• Akynzeo
• Aqynzio

Netupitant and palonosetron Brand Names in Pakistan:

No Brands Available in Pakistan.