Granisetron (Sancuso) is a 5-HT-3 receptor antagonist that is used in the treatment and prevention of chemotherapy-induced vomiting.

Granisetron Uses:

• Chemotherapy-associated nausea and vomiting:

  • Prevention of nausea and vomiting linked with early and repeat courses of emetogenic chemotherapy, including high-dose cisplatin (injection and tablets);
  • prevention of nausea and vomiting linked with anthracycline/cyclophosphamide chemotherapy regimens;
  • prevention of nausea and vomiting associated with moderately and/or highly emetogenic chemotherapy regimens for the duration of five days (transdermal).

• Radiation-associated nausea and vomiting:

  • Prevention of nausea and vomiting because of radiation therapy, including full-body radiation and fractionated abdominal radiation (tablets).

• Off Label Use of Granisetron in Adults:

  • Prevention of postoperative nausea and vomiting

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Granisetron (Sancuso) Dose in Adults

Note: Granisol oral solution is not available in the US for the past year.

Granisetron (Sancuso) Dose in the Prevention of chemotherapy-associated nausea and vomiting:

• Oral: 2 mg one time every day 1 hour before chemotherapy or 1 mg two times a day; the first 1 mg dose should be given 1 hour before chemotherapy (with the second 1 mg dose after 12 hours). Administer only on the day(s) chemotherapy is given.
• IV: 10 mcg/kg within 30 minutes before chemotherapy; only on the day(s) chemotherapy is given.
• SubQ (extended-release injection):
  • mildly emetogenic chemotherapy or anthracycline/cyclophosphamide chemotherapy:
    • 10 mg at least half an hour before chemotherapy on day 1 (in combination with IV dexamethasone on day 1 and [for anthracycline/cyclophosphamide chemotherapy] oral dexamethasone on days 2 to 4); do not administer more than once every 7 days.
    • May also be given in combination with an NK receptor antagonist antiemetic regimen.
• Transdermal patch:
  • Prophylaxis of chemotherapy-related emesis:
    • Apply 1 patch at least 24 hours before chemotherapy; may be applied 2 days prior to chemotherapy.
    • Remove patch after at least 24 hours of chemotherapy completion. Maximum duration: Patch may be worn up to 7 days, depending on chemotherapy duration.

• Adult guideline recommendations:

  • American Society of Clinical Oncology: High emetic risk:

    • IV: 1 mg or 10 mcg/kg on the day(s) of chemotherapy (antiemetic regimen also includes dexamethasone and aprepitant or fosaprepitant)
    • Oral: 2 mg on the day(s) of chemotherapy (antiemetic regimen also includes dexamethasone and aprepitant or fosaprepitant)

  • Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO):

    • Highly emetic chemotherapy:
      • IV: 1 mg or 10 mcg/kg (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant) before chemotherapy on the first day
      • Oral: 1 mg or 2 mg (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant) before chemotherapy on the first day
    • Moderately emetic chemotherapy:
      • IV: 1 mg or 10 mcg/kg (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant for AC chemotherapy regimen]) before chemotherapy on the first day
      • Oral: 1 mg or 2 mg (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant for AC chemotherapy regimen]) before chemotherapy on the first day
    • Low emetic risk:
      • IV: 1 mg or 10 mcg/kg before chemotherapy on the first day
      • Oral: 1 mg or 2 mg before chemotherapy on the first day

Granisetron (Sancuso) Dose in the Prophylaxis of radiation therapy-associated emesis:

• Oral: 2 mg once daily within 1 hour of radiation therapy.

Granisetron (Sancuso) Dose in the Prevention of postoperative nausea and vomiting (off-label):

• IV: 0.35 to 3 mg (5 to 20 mcg/kg) given at the end of surgery.

Granisetron (Sancuso) Dose in Childrens

Note: Granisol oral solution is not available in the US for the past one year.

Granisetron (Sancuso) Dose in the prevention of Chemotherapy-induced nausea and vomiting (CINV):

Pediatric Oncology Group of Ontario (POGO) guidelines: Note: POGO guidelines do not recommend a maximum dose as most studies did not cap the dose.

• Highly-emetogenic chemotherapy:

  • Infants <6 months:
    • IV: 40 mcg/kg as a single everyday dose before chemotherapy; used in combination with dexamethasone
  • Infants ≥6 months, Children, and Adolescents:
    • IV: 40 mcg/kg as a single everyday dose before chemotherapy; used in combination with dexamethasone and aprepitant (if no known or suspected drug interactions)

• Moderately-emetogenic chemotherapy:

  • Infants, Children, and Adolescents:

    • IV: 40 mcg/kg as everyday dose before chemotherapy; used in combination with dexamethasone.
    • For patients less than or equal to 6 months of age who cannot be given dexamethasone, use granisetron in combination with aprepitant (if no known or suspected drug interactions).
    • Oral: 40 mcg/kg/dose every 12 hours; used in combination with dexamethasone on the day of chemotherapy.
    • For patients ≥6 months of age who cannot be given dexamethasone, use granisetron in combination with aprepitant (if no known or suspected drug interactions).

• Low-emetogenic chemotherapy:

  • Infants, Children, and Adolescents:

    • IV: 40 mcg/kg as a single daily dose before chemotherapy
    • Oral: 40 mcg/kg/dose every 12 hours on chemotherapy days

Granisetron (Sancuso) Dose in the prevention of postoperative nausea and vomiting:

• Children and Adolescents:

• • IV: 40 mcg/kg as a single dose;
  • The maximum dose: 0.6 mg/dose;
  • The perfect administration time in pediatric patients is not clear; in adults, the administration is suggested at the end of surgery; in a granisetron pediatric PONV trial, doses were given before the surgical incision.

Note: QT prolongation has been seen at this dose in pediatric patients 2 to 16 years of age; monitor carefully.

Pregnancy Risk Factor B

• Animal reproductive studies have not shown any harmful events.
• Ex vivo perfusion studies showed that granisetron enters the placenta in an dose-dependent manner.
• Studies in the past have shown that the pharmacokinetics for the transdermal system might be different in pregnant women.
• It was also found that granisetron plasma levels and the relief of symptoms such as nausea and vomiting during pregnancy were related.
• Some dosage forms (injection) may contain benzyl alcohol.

Use during breastfeeding:

• It isn't known if breast milk contains granisetron.
• The manufacturer states that the decision to discontinue or continue breastfeeding should take into consideration the risks to infants, the benefits to the mother and the maternal condition.

Dose in Kidney Disease:

• IV, Oral, Transdermal: No dosage adjustment necessary.

• SubQ (extended-release injection):

  • CrCl ≥60 mL/minute: No dosage adjustment necessary.
  • CrCl 30 to 59 mL/minute: 10 mg on day 1 of chemotherapy; do not administer more frequently than once every 14 days.
  • CrCl <30 mL/minute: Avoid use.

Dose in Liver Disease:

• Total clearance may be reduced by ~50% in patients with hepatic impairment. However, intersubject variability limits the interpretation of kinetic studies.
• IV, Oral, Transdermal:
  • No dose modifications required (standard doses are well-tolerated).
• SubQ (extended-release injection):
  • There are no dosage modifications given in the manufacturer’s labeling.

Common Side Effects of Granisetron (Sancuso):

• Central Nervous System:

  • Headache

• Gastrointestinal:

  • Nausea
  • Constipation
  • Vomiting

• Neuromuscular & Skeletal:

  • Weakness

Less Common Side Effects Of Granisetron (Sancuso):

• Cardiovascular:

  • Prolonged Q-T Interval On ECG
  • Hypertension

• Central Nervous System:

  • Dizziness
  • Insomnia
  • Drowsiness
  • Anxiety
  • Agitation
  • Central Nervous System Stimulation

• Dermatologic:

  • Alopecia
  • Skin Rash

• Gastrointestinal:

  • Diarrhea
  • Decreased Appetite
  • Dyspepsia
  • Abdominal Pain
  • Dysgeusia

• Hematologic & Oncologic:

  • Leukopenia
  • Anemia
  • Thrombocytopenia

• Hepatic:

  • Increased Serum ALT
  • Increased Serum AST

• Miscellaneous:

  • Fever

Contraindications to Granisetron (Sancuso):

Allergy to granisetron, any component of the formulation, or other 5-HT3 receptor antagonists

Canadian labeling: Additional contraindications not in US labeling

• Use of apomorphine in combination

Warnings and precautions

• ECG effects

  • Selective 5-HT-3 antagonists, such as granisetron have been shown to cause dose-dependent increases of ECG intervals (e.g. PR, QRS durations, QT/QTc and JT), which usually occur within 1 to 2 hours following IV administration.
  • These changes are usually not clinically related. However, arrhythmia can occur when combined with other agents that prolong these intervals.
  • If used with QT prolonging agents (e.g. Class I and III antiarrhythmics), clinically significant QT interval prolongation can occur, resulting in torsade des pointes.
  • Multiple tests have shown that 5-HT antagonists can prolong the QT interval to variable degrees.
  • Patients at high risk for QT prolongation or ventricular arrhythmia should be restrained. Patients with cardiac disease, electrolyte abnormalities and patients who are being treated with cardiotoxic chemotherapy may also be at higher risk.
  • The 5-HT-3 antagonists may cause a decrease in heart rate.
  • IV formulations of 5-HT-3 inhibitors are more involved with ECG interval changes than oral formulations.

• Gastrointestinal effects:

  • All formulations can cause constipation, but tablets and extended-release subcutaneous injections are more common.
  • Extended-release subcutaneous injections have been used to treat constipation and fecal impaction.
  • Extended-release subcutaneous injections may mask progressive ileus or gastric distention (assess the risks and benefits for patients who have had recent abdominal surgery).
  • Check for constipation or reduced bowel activity in patients at high risk of gastrointestinal obstruction.
  • Granisetron is not intended to stimulate the gastric or intestinal peristalsis. It should not be used in place of nasogastric suction.

• Hypersensitivity

  • Patients who are hypersensitive to other 5-HT-3 antagonists have reported anaphylactic reactions with granisetron (cross-reactivity has been reported).
  • Granisetron may be exposed for up to seven days due to its extended-release properties.
  • Pay attention to hypersensitivity symptoms.

• Injection site reactions:

  • Subcutaneous extended-release formulations can cause reactions at the injection site.
  • There have been reports of infections at the injection site (median onset 9 days); antibiotics were used until they resolved completely.
  • Around one-third of patients experience bruising or hematomas (average onset: two days); they may be delayed (5 days) after administration.
  • It has been reported that serious bruising can also be caused.
  • Patients receiving anticoagulant or Antiplatelet treatment are more at risk of serious bruising/hematoma at their injection site.
  • Sometimes, injection site bleeding can last for up to 5 days.
  • Usually, injection site tenderness or pain was reported and lasted 5 to 7 business days.
  • Patients who experienced tenderness or pain that interfered with their activity or caused discomfort at rest were rare. Some patients required pain medication.
  • Injection site nodules occurred in less than 1/5 of patients. They usually last for 15 to 21 day.
  • For at least two weeks following administration, examine for any injection site reactions.
  • Rotate the injection site if there is still an injection site reaction after the next dose.

• Serotonin syndrome:

  • Serotonin syndrome has been linked to 5-HT-3 receptor antagonists. This is most commonly when they are used in combination with serotonergic agents such as SSRIs and SNRIs.
  • Some of these cases were fatal.
  • The majority of reports about serotonin syndrome were due to the 5-HT-3 receptor antagonist. These reports occurred in a postanaesthetic setting, or in an infusion centre.
  • Serotonin syndrome was also reported in the wake of an overdose on another 5-HT-3 antagonist.
  • Serotonin syndrome symptoms include mental changes such as agitation, hallucinations and delirium, and autonomic instability.
  • Serotonin syndrome can be treated with supportive management.

• Long QT syndrome:

  • Patients with congenital QT syndrome (or other risk factors for QT prolongation) should be treated with caution.

Granisetron: Drug Interaction

Monitoring parameters:

• Examine for constipation and for reduced bowel activity.
• Check for signs/symptoms of allergic reaction. Monitor patients for signs of serotonin syndrome

Extended-release subcutaneous injection:

• Check for injection site reactions for at least 2 weeks after administration.

How to administer Granisetron (Sancuso)?

Oral:

• You should give the dose at least one hour before you start radiation or chemotherapy.

IV:

• You can either administer it intravenously over 30 seconds, or slow for 5 minutes.

SubQ (extended release injection):

• This product is for subcutaneous use only.
• The injection should be given as a single dose at the upper arm back or in the abdomen (at least 1 inch from the umbilicus).
• Avoid using it on areas that are irritated, inflamed or swollen.
• Slowly inject the product for 20-30 seconds. If the product is thick, pushing on the syringe will not cause faster ejection.
• Before administering the medication, a topical anesthetic can be applied to the injection site.
• If particulate matter is found or discoloration is suspected, do not give up.
• Take out of the refrigerator at least one hour before administering.
• Sometimes injection site reactions can occur. If the injection site reaction does not resolve before the next dose is administered, you should change injection site.

Transdermal (Sancuso).

• Apply patch to the upper arm's dry, clean skin.
• Avoid using on red, irritated or damaged skin.
• Before applying, immediately remove the patch from the pouch.
• The patch should not be cut. Protect the patch area with clothing for at least 10 days after application. Granisetron can be damaged by sunlight.
• Avoid heating the transdermal area with heat (e.g. heating pad); avoid prolonged heat exposure (may increase plasma concentrations).

Mechanism of action of Granisetron:

It blocks serotonin centrally in the chemoreceptor trigger area and peripherally at vagal nerve terminals.

The onset of action:

• IV: 1 to 3 minutes

Duration:

• Oral, IV: Generally up to 24 hours;
• SubQ (extended-release): Remains detectable in the plasma for 7 days

Absorption:

• Oral: Tablets and oral solution are bioequivalent;
• Transdermal patch: ~66% over 7 days

Distribution: It is distributed widely throughout the body. Protein binding:

• ~65%

Metabolism:

• Hepatic via CYP1A1 and CYP3A4 N-demethylation, oxidation, and conjugation;
• some metabolites may have 5-HT-3 antagonist activity

Half-life elimination:

• Oral: 6 hours;
• IV: Mean range: 5 to 9 hours;
• SubQ (extended-release): ~24 hours

Time to peak, plasma:

• Transdermal patch: Maximum systemic concentrations: ~48 hours after application (range: 24 to 168 hours);
• SubQ (extended-release): ~24 hours

Excretion:

• Urine (11% to 12% as unchanged drug, 48% to 49% as metabolites);
• feces (34% to 38% as metabolites)

International Brand Names of Granisetron:

• Sancuso
• Sustol
• APO-Granisetron
• Kytril
• NAT-Granisetron
• Anavo
• Degrani
• Emegran
• Emetovoid
• Frezitron
• Gomsetron
• Gramet
• Granesis
• Granicip
• Granil
• Graniset
• Granison
• Granitron
• Granitryl
• Granon
• Granored
• Grantron
• Gratril
• Gratril OD
• Helminar
• Kevatril
• Kyotil
• Kytril
• Kytron
• Nisetron
• Opigran
• Sancuso
• Sancuso Patch
• Setron
• Sulingqiong
• Trilemes
• Vomitran

Granisetron Brand Names in Pakistan: