Ondansetron

Registered South African indications: 

• Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy
• Prevention and treatment of post-operative nausea and vomiting

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
  - ≤12 weeks
  - >12 weeks (For the indication of post-operative nausea and vomiting)
• Congenital long QT syndrome
• Coadministration with apomorphine

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with apomorphine

Cautions

South African manufacturer recommendations

• Hypersensitivity to other selective serotonin (5-HT3) receptor antagonists
• Pregnancy (>12 weeks)
• Breastfeeding
• Severe renal impairment
• Moderate to severe hepatic impairment
• Elderly
• Risk factors for QT prolongation
  - Patients who have or may develop prolongation of QTc
• Electrolyte abnormalities
• Congestive cardiac failure
• Bradydysrhythmias
• Hypokalaemia
• Hypomagnesaemia
• Adenotonsillar surgery
• Intestinal obstruction
• Coadministration with hepatotoxic chemotherapeutic agents in children
• Coadministration with QT prolongation agents
• Coadministration with agents that cause electrolyte abnormalities
• Coadministration with selective serotonin reuptake inhibitors (SSRIs)
• Coadministration with serotonin noradrenaline reuptake inhibitors (SNRIs)
• Galactose intolerance e.g. galactosaemia (tab)
• Lapp lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)
• Phenylketonuria (dsp)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Hypersensitivity to other selective serotonin (5-HT3) receptor antagonists
• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Elderly (≥75 years)
• Risk factors for QT prolongation
  - Patients who have or may develop prolongation of QTc
• Congenital long QT syndrome
• Electrolyte abnormalities
• Congestive cardiac failure
• Bradyarrhythmias
• Hypokalaemia
• Hypomagnesaemia
• Adenotonsillar surgery
• Subacute intestinal obstruction
• Patients on a controlled sodium diet (certain formulations)
• Coadministration with hepatotoxic chemotherapeutic agents in children
• Coadministration with QT prolongation agents
• Coadministration with agents that cause electrolyte abnormalities
• Coadministration with selective serotonin reuptake inhibitors (SSRIs)
• Coadministration with serotonin noradrenaline reuptake inhibitors (SNRIs)
• Galactose intolerance (tab)
• Lapp lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)
• Phenylketonuria (dsp)

Forms avail. in SA and covered in this monograph: tab, inj, dsp

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and vomiting will occur

Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy -  mild to moderately emetogenic

Initial management

• IV: 8mg, given as a slow infusion over not less than 2-3min immediately before treatment

OR

• IM: 8mg, given as a slow injection over not less than 30sec immediately before treatment

OR

• Oral (tab,dsp): Initial: 8mg, as a single dose 1-2hrs before treatment 

Maintenance
- Where delayed or prolonged emesis is expected after the first 24hrs

• Oral (tab,dsp): 8mg, 12hrly; Treatment duration: Up to 5 days

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Higher doses may be required in some patients, particularly those on high dose cisplatin and the doses should be adjusted according to the severity of the emetogenic challenge. In these patients, the below dose schedules have been shown to be effective

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Management of nausea and vomiting induced by cytotoxic chemotherapy - highly emetogenic

Initial management

• IV/IM: 8mg, given as a slow IV infusion or IM injection before chemotherapy; Then 8mg, 4hrly

OR

• IV: 1mg/hr, as a constant infusion for up to 24hrs

OR

• IV: 16mg, as a single dose infused over not less than 15min immediately before chemotherapy

Maintenance
- Delayed or prolonged emesis after the first 24 hours

• Oral (tab): Maintenance: 8mg, 12hrly, Treatment duration: Up to 5 days

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A single dose greater than 16mg should not be given due to dose-dependent increased risk of QT prolongation

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The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone phosphate 20mg administered 30-45mins prior to the first ondansetron dose prior to chemotherapy

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The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge

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Prevention and treatment of post-operative nausea and vomiting (PONV)

• IV: 4mg, given as a slow infusion over 2-5min or longer, immediately before induction of anaesthesia, or post-operatively if the patient symptomatic
• IM: 4mg, given as a slow injection, immediately before induction of anaesthesia, or post-operatively if the patient symptomatic

OR

• Oral (tab, dsp): 16mg, as a single dose 1hr prior to induction of anaesthesia

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For treatment of established PONV, administration by injection is recommended

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Repeat dosing for patients who continue to experience nausea and/or vomiting post-operatively has not been studied

---

While recommended as a fixed dose for all, few patients above 80kg or below 40kg have been studied

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International manufacturer recommendations

Management of nausea and vomiting induced by cytotoxic chemotherapy -  mild to moderate emetogenic

Prescribers intending to use ondansetron in the prevention of delayed nausea and vomiting associated with chemotherapy or radiotherapy should take into consideration current practice and appropriate guidelines

Oral only

• Oral (tab, dsp): Initial:  8mg, 1-2hrs before chemotherapy or radiotherapy; Followed by: 8mg, 12hrly; Treatment duration: 5 days

IV - with switch to oral

Initial management

• IV: 8mg, given as a slow injection over not less than 30sec immediately before treatment OR IV: 8mg, given as a slow infusion over 15min immediately before treatment 

Maintenance
- To protect against delayed or prolonged emesis after the first 24 hours

• Oral (tab,dsp): 8mg, 12hrly, Treatment duration: 5 days

Management of nausea and vomiting induced by cytotoxic chemotherapy -  highly emetogenic

Oral only

• Oral (tab, dsp): Up to 24mg, 1-2hrs before chemotherapy (additional agent required)

IV - with switch to oral

Initial management

IV: 8mg, as a single dose by slow injection over not less than 30sec immediately before chemotherapy

OR

IV: 8mg, as a slow injection over not less than 30sec or as a short-time IV infusion over 15min immediately before chemotherapy; Followed by two: IV: 8mg, no less than 4hrly OR IV: 1mg/hr, as an infusion for up to 24hrs

OR

• IV: Up to 16mg, given as an infusion over not less than 15min immediately before chemotherapy; Followed by two: IV: 8mg, 4hrly by slow injection over not less than 30sec

Maintenance
- To protect against delayed or prolonged emesis after the first 24 hours

• Oral (tab,dsp): 8mg, 12hrly, Treatment duration: 5 days

---

IV: A single dose >16mg must not be given due to dose dependent increase of QT-prolongation risk

---

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemo/radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge

---

IV: The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20mg administered prior to chemotherapy

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Post-operative nausea and vomiting (PONV)
- Prevention of PONV

• IV: 4mg, as a single dose by slow injection at induction of anaesthesia

OR

• Oral (tab, dsp): 16mg, as a single dose 1hr prior to anaesthesia

- Treatment of established PONV

• IV: 4mg, as a single dose by slow injection at induction of anaesthesia

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For treatment of established PONV: Intravenous or intramuscular administration is recommended

Paed. forms avail. in SA and covered in this monograph: tab, inj, dsp

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy

Younger than 4 years

• Not established for use 

Over 4 years

• IV: Initial: 5mg/m², as an infusion over 15min immediately before cancer chemotherapy; Maintenance: Oral: 4mg, 12hrly; Treatment duration: Up to 5 days

Prevention and treatment of post-operative nausea and vomiting (PONV)
- Prevention in those having surgery performed under general anaesthesia
- Treatment of established PONV

Younger than 2 years

• Not established for use 

Older than 2 years

• IV: 0.1mg/kg, as a slow infusion over 2-5min or longer prior to, at or after induction of anaesthesia; Max single dose: 4mg

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Repeat dosing for for those who continue to experience nausea and/or vomiting has not been studied, and should thus not be give​n​​​​​​

---

There is limited data on the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting in children <2 years 

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International manufacturer recommendations

Chemotherapy-induced nausea and vomiting 

Younger than 6 months

• Not established for use

Between 6 months and 17 years

• IV: Administer immediately before chemotherapy as a single intravenous dose of 5mg/m²

	Day 1		Day 2-6
Body surface area (m2)	Initial dose (immediately before chemotherapy)	Repeat doses (12hrs after initial dose)	Dose
<0.6	IV: 5mg/m2	-	-
≥0.6	IV: 5mg/m2	Oral (tab, dsp): 4mg	Oral (tab, dsp): 4mg, 12hrly

OR

	Day 1		Day 2-6
Weight (kg)	Initial dose (immediately before chemotherapy)	Repeat doses (Max: 2 doses)	Dose
≤10	IV: 0.15mg/kg (Up to 3 doses)	IV: 0.15mg/kg, 4hrly	-
>10	IV: 0.15mg/kg (Up to 3 doses)	IV: 0.15mg/kg, 4hrly	Oral (tab, dsp): 4mg, 12hrly

Older than 17 years

• See adult dosage

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Ondansetron syrup is not registered for use in South Africa, therefore recommendations for its use where applicable could not be made

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Max single IV dose: 8mg; Max dose: 32mg/24hrs 

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Oral dosing can commence 12 hours after the IV initial dose and may be continued for up to 5 days

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Weight-based dosing results in higher total daily doses compared to BSA-based dosing

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There are no data from controlled clinical trials on the use of ondansetron in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy-induced nausea and vomiting in children

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Post-operative nausea and vomiting (PONV)
- Prevention in those having surgery performed under general anaesthesia

Younger than 1 month

• Not established for use

Between 1 month and 17 years 

• IV: 0.1mg/kg, as a single dose by slow injection over 30sec prior to, at or after induction of anaesthesia by slow IV injection; Max single dose: 4mg

- Treatment of PONV after surgery

Younger than 2 years

• No information available

Older than 2 years

• IV: 0.1mg/kg, as a single dose by slow injection over 30sec prior to, at or after induction of anaesthesia by slow IV injection; Max single dose: 4mg

- Treatment of established PONV

IV: 0.1mg/kg, as a slow injection; Max single dose: 4mg

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There are no data on the use of ondansetron injection for the treatment of post-operative vomiting in children under 2 years of age

Pregnancy

South African manufacturer recommendations

• ≤12 weeks: Contraindicated
• >12 weeks: For the indication of post-operative nausea and vomiting: Contraindicated  
• >12 weeks: Caution; not recommended
• Ondansetron is contraindicated for post-operative nausea and vomiting during pregnancy, as well as during the first 12 weeks of pregnancy irrespective of the indication due to the risk
• Use during the first 12 weeks of pregnancy can be associated with an increased risk of developing oral cleft palate and/or lip to the foetus
• Women of childbearing potential to use contraception while taking ondansetron and for 2 days after stopping treatment
• Healthcare professionals must ensure that female patients of childbearing age are adequately counselled on the teratogenicity of the treatment with ondansetron

International manufacturer recommendations

• ≤12 weeks: Caution; not recommended
• >12 weeks: Caution
• Based on human experience from epidemiological studies, use during the first 12 weeks of pregnancy can be associated with an increased risk of developing oral cleft palate and/or lip to the foetus. Data regarding cardiac malformations showed conflicting results
• In one cohort study including 1.8million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)). The available epidemiological studies on cardiac malformations show conflicting results
• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• However, ondansetron should not be used during the first trimester of pregnancy
• Women of childbearing potential should consider the use of contraception

Breastfeeding

• Caution; not recommended
• Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron should not breastfeed their babies

Fertility

• There is no information on the effects of ondansetron on human fertility

Renal Impairment

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; no dose adjustment recommended
  There is limited information available for daily dosage or frequency of dosing, or route of administration for severe renal impairment

International manufacturer recommendations

• No dose adjustment recommended 

Hepatic Impairment

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; dose adjustment recommended

Hepatic Impairment	Dose
Mild	No adjustment necessary
Moderate to severe	IV/Oral: Max: 8mg/24hrs

Elderly

South African manufacturer recommendations

• Caution; dose adjustment recommended 
  65-74 years: IV: Up to 16mg, as an infusion over 15min for the prevention of chemotherapy induced nausea and vomiting (CINV); Max single dose: 16mg
  ≥75 years: IV: 8mg, as an infusion over 15min for the prevention of CINV; Max single dose: 8mg
  Repeat IV doses given not less than 4hrs apart
  All IV doses should be diluted in 50-100ml saline or other compatible fluid and infused over ≥15 minutes

International manufacturer recommendations

• 65-74 years: No dose adjustment recommended 
  All IV doses should be diluted in 50-100ml saline or other compatible fluid and infused over ≥15 minutes
• ≥75 years: Caution; dose adjustment recommended 
  IV: Initial: 8mg, as an infusion over 15min; Then 8mg, 4hrly, by infusion if needed (Max: 2 doses); Max single dose: 8mg
  All IV doses should be diluted in 50-100ml saline or other compatible fluid and infused over ≥15 minutes

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Extrapyramidal reactions
• Dyskinesia
• Dizziness
• Depression

Cardiovascular Disorders

• Chest pain with or without ST segment depression
• Cardiac arrhythmias
• Bradycardia
• QT prolongation
• Torsades de Pointes
• Flushing
• Hypotension

Respiratory Disorders

• Hiccups

Gastrointestinal Disorders

• Constipation

Hepatobiliary Disorders

• Increased hepatic function tests

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions around the injection site

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Anaphylaxis

Sensory Disorders

• Transient visual disturbances
• Transitory blindness

• Potent CYP3A4 inducers, e.g. phenytoin, carbamazepine rifampicin
• Patients with CYP2D6 genetic deficiency
• Apomorphine
• QT prolonging agents 
• Serotonergic agents, e.g. selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs)
• Antiarrhythmic agents
• Beta blockers
• Tramadol
• Hepatotoxic chemotherapy agents

None routine. Specific cases may require

• ECG
• Electrolytes

Tablet 8mg - EML (Hospital)

Tablet dispersible 4mg - EML (Tertiary)

Injection 4mg - EML (Hospital)

Injection 8mg - EML (Tertiary)

Administration directions

IM injection

• Administered in not less than 30 seconds
• Should be administered undiluted

IV injection

• For unpreserved ampoule formulations, single use is recommended and any remaining solution should be appropriately discarded
• Administered by slow IV infusion in not less than 2-3 minutes
• Infused over a minimum of 15 minutes with 50-100ml compatible diluent
• IV admixtures should be inspected for clarity, particulate matter, precipitate discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, or discolouration or leakage should not be used
• In keeping with good pharmaceutical practice dilutions of ondansetron injection in intravenous solutions should be prepared at the time of infusion

Compatible diluents for IV infusion

• Sodium chloride intravenous infusion BP 0,9% m/v
• Glucose intravenous infusion BP 5% m/v
• Mannitol intravenous infusion BP 10% w/v
• Ringers intravenous infusion
• Potassium chloride 0,3% m/v and sodium chloride 0,9% m/v intravenous infusion BP
• Potassium chloride 0,3% m/v and glucose 5% m/v intravenous infusion BP

Dispersible tablet

• To be placed on the top of the tongue, where it will disperse within seconds, then to be swallowed
• Do not attempt to push the tablet through the lidding foil, rather peel back the lidding foil gently and remove the tablet

Special warnings

• Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions
• Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron administration

Ondansetron is a highly selective (5HT3) serotonin receptor antagonist that acts both centrally in the medullary chemoreceptor zone and peripherally in the gastrointestinal tract at vagal nerve terminals to reduce nausea and vomiting.

Tablet 4mg

• Aspetron fct (Mylan)
• Austell Ondansetron (Austell)
• Cipla-Ondansetron (Cipla)
• Vomiz (Zydus)
• Zofer (Ranbaxy)
• Zofran (Sandoz South Africa) originator

Tablet 8mg

• Aspetron fct (Mylan)
• Austell Ondansetron (Austell)
• Cipla-Ondansetron (Cipla)
• Vomiz (Zydus)
• Zofer (Ranbaxy)
• Zofran (Sandoz South Africa) originator

Tablet rapitab 4mg

• Ondansetron Cipla (Cipla)
• Zofer (Ranbaxy)
• Zofran zydis 4mg (Sandoz South Africa) originator

Tablet rapitab 8mg

• Zofer (Ranbaxy)
• Zofran zydis 8mg (Sandoz South Africa) originator

Injection (per 2ml) 4mg

• Alepet (Accord)
• Aspen Ondansetron (Pharmacare)
• Danset (Specpharm)
• Emistop (Pharma Dynamics)
• Mylan Ondansetron (Mylan)
• Nausetron (Brimpharm)
• Ondansetron 4mg/2ml PharmC (Pharmacorp)
• Ondansetron Cipla  (Zydus)
• Ondansetron Fresenius (Fresenius)
• Vomiz (Zydus)
• Sabax Ondansetron (Adcock)
• Zofer (Ranbaxy)
• Zofran (Sandoz South Africa) originator

Injection (per 4ml) 8mg

• Alepet (Accord)
• Aspen Ondansetron (Pharmacare)
• Danset (Specpharm)
• Emistop (Pharma Dynamics)
• Mylan Ondansetron (Mylan)
• Nausetron (Brimpharm)
• Ondansetron 8mg/4ml PharmC (Pharmacorp
• Ondansetron Fresenius (Fresenius)
• Sabax Ondansetron (Adcock)
• Vomiz (Zydus)
• Zofer (Ranbaxy)
• Zofran (Sandoz South Africa) originator
• Zydus-Ondansetron (Zydus)