Ondansetron

Ondansetron is a potent and highly selective antagonist of the serotonin 5-HT3 receptor. The exact way it controls nausea and vomiting is not known. It does not change plasma prolactin concentrations.

Mechanism of Action

• Blocking the vomiting reflex: cytotoxic chemotherapy and radiotherapy can release serotonin (5-HT) in the small intestine and start the vomiting reflex by activating 5-HT3 receptors on vagal afferent nerves. Ondansetron blocks the start of this reflex.
• Central pathway: activation of vagal afferents can also release serotonin in the area postrema, on the floor of the fourth ventricle, and promote vomiting through a central mechanism. The antiemetic effect is therefore probably due to antagonism of 5-HT3 receptors on neurons in both the central and the peripheral nervous system.
• Postoperative nausea and vomiting: the mechanism is not known; it may share pathways with nausea and vomiting caused by cytotoxic drugs.
• QT interval: ondansetron prolongs the QT interval in a dose-dependent manner. In a placebo- and moxifloxacin-controlled crossover study in 58 healthy adults, 32 mg infused intravenously over 15 minutes gave a maximum mean difference in QTcF from placebo, after baseline correction, of 19.6 ms (upper limit of the 90% confidence interval 21.5 ms).

Pharmacokinetics

• Absorption: after oral dosing ondansetron is absorbed passively and completely from the gut and undergoes first-pass metabolism. Peak plasma concentrations are reached about 1.5 hours after a dose. Above 8 mg, exposure rises more than in proportion to the dose, probably because first-pass metabolism is reduced at higher oral doses. Mean bioavailability after an 8 mg tablet in healthy men is about 55–60%; food raises it slightly, antacids do not.
• Distribution: disposition is similar after oral, intramuscular and intravenous dosing, with an elimination half-life of about 3 hours and a steady-state volume of distribution of about 140 litres. Intramuscular and intravenous exposure are equivalent. Plasma protein binding is 70–76%.
• Metabolism: ondansetron is cleared mainly by hepatic metabolism through several enzyme routes, including CYP3A4, CYP2D6 and CYP1A2. Absence of CYP2D6 (the debrisoquine polymorphism) has no effect on its kinetics.
• Elimination: less than 5% of the absorbed dose is excreted unchanged in the urine. The pharmacokinetics do not change with repeated dosing.
• Special populations: in surgical patients aged 1 to 4 months, weight-normalised clearance was about 30% slower than at 5 to 24 months but comparable to that at 3 to 12 years; the mean half-life was 6.7 hours at 1–4 months against 2.9 hours at 5–24 months and at 3–12 years, partly explained by the higher total body water and volume of distribution of water-soluble drugs in infants. In moderate or severe hepatic impairment, clearance is significantly reduced and the half-life significantly prolonged.

The Zofran SmPCs for the tablets and for the solution for injection give the same indications.

• Chemotherapy and radiotherapy (adults): control of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.
• Postoperative nausea and vomiting (adults): prevention and treatment. The tablets are used for prevention; for treating established postoperative nausea and vomiting the tablet SmPC refers to the solution for injection.
• Chemotherapy (children from 6 months): control of chemotherapy-induced nausea and vomiting.
• Postoperative nausea and vomiting (children from 1 month): oral ondansetron has not been studied for this use, and the SmPC recommends the solution for injection.

• Hypersensitivity to ondansetron, to any other 5-HT3 receptor antagonist (for example granisetron or dolasetron), or to any of the excipients.
• Concomitant use with apomorphine, because profound hypotension and loss of consciousness have been reported when ondansetron was given with apomorphine hydrochloride.

Headache is the only very common reaction. Frequencies apply at the standard recommended doses: very common to uncommon reactions come from clinical trials (allowing for placebo rates), and rare and very rare ones mainly from post-marketing data. The profile in children and adolescents was comparable to that in adults.

Very common (≥1/10): headache.

Common (≥1/100 to <1/10): sensation of flushing or warmth; constipation; local reactions at the intravenous injection site (solution for injection).

Uncommon (≥1/1,000 to <1/100): seizures; movement disorders, including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia (observed without conclusive evidence of persistent clinical sequelae); arrhythmias; chest pain with or without ST-segment depression; bradycardia; hypotension; hiccups; asymptomatic increases in liver function tests (seen frequently in patients receiving cisplatin chemotherapy).

Rare (≥1/10,000 to <1/1,000): immediate hypersensitivity reactions, sometimes severe, including anaphylaxis (cross-sensitivity with other selective 5-HT3 antagonists may occur); vertigo, mainly during rapid intravenous administration; transient visual disturbances such as blurred vision, mainly during intravenous administration; QTc prolongation, including torsade de pointes.

Very rare (<1/10,000): transient blindness, mainly during intravenous administration (most cases resolved within 20 minutes; most patients had received chemotherapy including cisplatin, and some cases were reported as cortical in origin); toxic skin eruption, including toxic epidermal necrolysis.

Not known: myocardial ischaemia.

The most important serious reactions are anaphylaxis, QT prolongation with torsade de pointes and myocardial ischaemia (see Special Instructions).

There is no evidence that ondansetron induces or inhibits the metabolism of other medicines it is commonly given with. Specific studies found no pharmacokinetic interaction with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol.

• Apomorphine: contraindicated, because of reports of profound hypotension and loss of consciousness.
• QT-prolonging medicines and medicines that cause electrolyte disturbances: use caution. Giving ondansetron with medicines that prolong the QT interval may cause additional QT prolongation (see Special Instructions).
• Strong CYP3A4 inducers (phenytoin, carbamazepine, rifampicin): oral clearance of ondansetron was increased and plasma concentrations were reduced.
• Serotonergic medicines (SSRIs, SNRIs, buprenorphine): serotonin syndrome, with altered mental state, autonomic instability and neuromuscular abnormalities, has been reported. If the combination is clinically justified, monitor the patient.
• Enzyme inhibition or deficiency: ondansetron is metabolised by several cytochrome P-450 enzymes (CYP3A4, CYP2D6, CYP1A2), so inhibition or reduced activity of one of them, such as genetic CYP2D6 deficiency, is normally compensated by the others and should give little or no change in overall clearance or dose requirement.
• Food and antacids: food slightly increases bioavailability; antacids do not.

The regimen is chosen according to the severity of emesis, because the emetogenic potential of cancer treatment varies with the doses and combinations of chemotherapy and radiotherapy used. The tablets are swallowed whole with a little water. The solution for injection is given by intravenous or intramuscular injection, or by intravenous infusion after dilution (see section 6.6 of its SmPC for dilution).

Chemotherapy and Radiotherapy in Adults, Tablets

• Emetogenic chemotherapy or radiotherapy: 8 mg by mouth 1 to 2 hours before treatment, then 8 mg by mouth every 12 hours for up to 5 days.
• Highly emetogenic chemotherapy: a single 24 mg oral dose together with 12 mg of dexamethasone sodium phosphate by mouth, one or two hours before chemotherapy. After the first 24 hours, 8 mg twice daily by mouth may be continued for 5 days after a treatment cycle.

Chemotherapy and Radiotherapy in Adults, Solution for Injection

• Emetogenic chemotherapy or radiotherapy: in the first 24 hours, a single 8 mg dose by slow intravenous injection (over at least 30 seconds) or by intramuscular injection, immediately before treatment, followed by 8 mg by mouth every 12 hours. To protect against delayed or prolonged vomiting after the first 24 hours, continue 8 mg by mouth twice daily for 5 days after a treatment cycle.
• Highly emetogenic chemotherapy (for example high-dose cisplatin): one of the following regimens in the first 24 hours, chosen according to the intensity of the emetogenic treatment:
  • a single 8 mg dose by slow intravenous injection (at least 30 seconds) or intramuscularly, immediately before chemotherapy;
  • 8 mg by slow intravenous injection or intramuscularly immediately before chemotherapy, followed by two further 8 mg doses 4 hours apart, or by a constant infusion of 1 mg per hour for 24 hours;
  • an initial intravenous dose of up to 16 mg, diluted in 50–100 mL of saline or another compatible infusion fluid and infused over at least 15 minutes immediately before chemotherapy, which can be followed by two further 8 mg doses 4 hours apart by slow intravenous injection or intramuscularly.
• No dose above 16 mg should be given by injection or infusion, because the risk of QT prolongation rises with the dose.
• Adding a single intravenous dose of 20 mg of dexamethasone sodium phosphate before chemotherapy can enhance efficacy in highly emetogenic chemotherapy. After the first 24 hours, oral ondansetron 8 mg twice daily for 5 days protects against delayed or prolonged vomiting.

Chemotherapy in Children from 6 Months and Adolescents

• The dose can be calculated by body surface area or by body weight. Weight-based dosing gives a higher total daily dose than body-surface-area dosing. There are no controlled clinical trial data on preventing delayed or prolonged chemotherapy-induced nausea and vomiting, or on radiotherapy-induced nausea and vomiting in children.
• By body surface area: 5 mg/m² as a single intravenous dose immediately before chemotherapy (the intravenous dose must not exceed 8 mg). Oral dosing can start 12 hours later and continue for up to 5 days: for a body surface area below 0.6 m², 2 mg by mouth 12 hours later and then 2 mg every 12 hours; for 0.6 m² or more, 4 mg by mouth 12 hours later and then 4 mg every 12 hours.
• By body weight: 0.15 mg/kg as a single intravenous dose immediately before chemotherapy (not above 8 mg), with two further intravenous doses at 4-hour intervals. Oral dosing can start 12 hours later and continue for up to 5 days, at 2 mg or 4 mg every 12 hours depending on a weight split at 10 kg (the SmPC tables give the exact boundary).
• The total dose over 24 hours must not exceed the adult dose of 32 mg. The 2 mg dose cannot be made from the 4 mg tablets, which are not designed to be split into two equal halves.
• The intravenous doses are given with the solution for injection, diluted in 5% dextrose or 0.9% sodium chloride (or another compatible infusion fluid) and infused over at least 15 minutes.

Postoperative Nausea and Vomiting

• Adults, prevention: 16 mg by mouth one hour before anaesthesia (tablets), or a single 4 mg dose by intramuscular injection or slow intravenous injection at induction of anaesthesia (solution for injection).
• Adults, treatment of established nausea and vomiting: a single 4 mg dose by intramuscular or slow intravenous injection.
• Children from 1 month and adolescents: oral use has not been studied. A single dose of 0.1 mg/kg, up to a maximum of 4 mg, by slow intravenous injection (at least 30 seconds), before, during or after induction of anaesthesia for prevention, or the same dose to treat established nausea and vomiting. There are no data on treating established postoperative nausea and vomiting in children under 2 years.

Special Populations

• Elderly: no change to the oral dose or frequency. For the injection, patients aged 65 to 74 years can follow the adult regimens, with every intravenous dose diluted in 50–100 mL of saline or another compatible fluid and infused over more than 15 minutes. From 75 years, the initial intravenous dose must not exceed 8 mg, all intravenous doses are diluted and infused over more than 15 minutes, and two further 8 mg doses may follow, more than 4 hours apart. Experience with postoperative nausea and vomiting in elderly patients is limited.
• Renal impairment: no change to the daily dose, dose frequency or route.
• Hepatic impairment: in moderate or severe impairment, the total daily dose must not exceed 8 mg, whether given by mouth or intravenously.
• Poor metabolisers of sparteine or debrisoquine: the elimination half-life is unchanged, so no change in daily dose or frequency is needed.

QT Prolongation

Ondansetron prolongs the QT interval in a dose-dependent manner, and cases of torsade de pointes have been reported after marketing. Avoid ondansetron in patients with congenital long QT syndrome. Give it with caution to patients who have or may develop QTc prolongation, including those with electrolyte disturbances, congestive heart failure or bradyarrhythmias, and those taking other medicines that prolong the QT interval or cause electrolyte disturbances. Correct hypokalaemia and hypomagnesaemia before giving ondansetron.

Hypersensitivity

Hypersensitivity reactions have been reported in patients who were hypersensitive to other selective 5-HT3 receptor antagonists. Respiratory events should be treated symptomatically, and doctors should pay particular attention to them as precursors of hypersensitivity reactions.

Myocardial Ischaemia

Myocardial ischaemia has been reported in patients treated with ondansetron. In some cases, especially after intravenous administration, symptoms began immediately after the dose. Patients should be told the signs and symptoms of myocardial ischaemia.

Serotonin Syndrome

Serotonin syndrome has been reported after ondansetron was given with other serotonergic medicines, including SSRIs, SNRIs and buprenorphine. If the combination is clinically justified, patients should be monitored.

Bowel Transit and Tonsil Surgery

Ondansetron increases large bowel transit time, so patients with signs of subacute intestinal obstruction should be watched after administration. After adenotonsillectomy, preventing nausea and vomiting with ondansetron could mask occult bleeding, so these patients should be monitored carefully.

Children Given Hepatotoxic Chemotherapy

Paediatric patients receiving ondansetron with hepatotoxic chemotherapy should be monitored for any change in liver function. When the dose is calculated in mg/kg and three doses are given 4 hours apart, the total daily dose is higher than with a single 5 mg/m² dose followed by an oral dose. The two regimens have not been compared in clinical trials, but comparison across trials suggests similar efficacy.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential should have a pregnancy test before treatment and be warned that Zofran can harm the development of the foetus. Sexually active women of childbearing potential should use an effective contraceptive method (one giving pregnancy rates below 1%) during treatment and for two days after stopping.
• First trimester: epidemiological studies suggest that ondansetron causes orofacial malformations when used in the first trimester. In a cohort of 1.8 million pregnancies, first-trimester use was associated with a higher risk of oral clefts (3 additional cases per 10,000 treated women; adjusted relative risk 1.24, 95% confidence interval 1.03–1.48). Studies of cardiac malformations give conflicting results. Ondansetron must not be used during the first trimester of pregnancy.
• Other pregnancy data: reproduction studies in rats and rabbits showed no foetal harm at about 6 and 24 times the maximum recommended human oral dose of 24 mg per day (by body surface area). Safety data in pregnancy are limited and the epidemiological findings are inconsistent; post-marketing reports of congenital malformations are insufficient to establish a causal relationship.
• Breastfeeding: it is not known whether ondansetron passes into human milk, and there are no data on effects in breastfed infants or on milk production. It passes into the milk of lactating animals, so mothers taking ondansetron should not breastfeed.
• Fertility: the SmPC advises women of childbearing potential to consider using contraception.

Lactose in the Tablets

The tablets contain anhydrous lactose (81.875 mg in the 4 mg tablet and 163.75 mg in the 8 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

The SmPC states that Zofran has no influence on the ability to drive and use machines.

The tablets must not be stored above 30 °C. The ampoules must be kept in the outer carton to protect them from light and not stored above 30 °C. Neither form needs refrigeration. The tablets come in double aluminium blisters in packs of 6, 15 or 500.

3 years for the tablets and 3 years for the solution for injection. Do not use after the expiry date on the pack.

Prescription only (Rx). The film-coated tablets are taken by the patient, so they are supplied to the patient or to the treating clinic on prescription. The solution for injection is given by intravenous or intramuscular injection or by intravenous infusion, so it is supplied to the hospital or clinic that administers it.