Ondansetron 2mg|Ml Solution For Injection
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ondansetron 2mg/ml Solution for Injection
Ondansetron
Read all of this leaflet carefully before you are given this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet:
1. What Ondansetron Injection is and what it is used for
2. What you need to know before you are given Ondansetron Injection
3. How you are given Ondansetron Injection
4. Possible side effects
5. How to store Ondansetron Injection
6. Contents of the pack and other information
1. What Ondansetron Injection is and what it is used for
Ondansetron belongs to a group of medicines known as ‘antiemetics and antinauseants’. These prevent feelings of sickness (nausea) or being sick (vomiting) that may occur after certain medical or surgical treatments.
Your doctor or nurse may give you Ondansetron Injection to prevent you from, or to treat you for, feeling or being sick when you:
are on chemotherapy and radiotherapy that can cause nausea and vomiting, undergo surgical treatment.
2. What you need to know before you are given Ondansetron Injection
Please take the time to read the following information carefully as this may stop you from being able to have Ondansetron 2mg/ml Solution for Injection.
You should not be given Ondansetron Injection:
- if you are allergic to ondansetron or any of the other ingredients of this medicine (listed in section 6).
- if you are using apomorphine (used to treat Parkinson’s disease)
Warnings and precautions
Talk to your doctor, pharmacist or nurse before you are given Ondansetron Injection
if you have ever been allergic (hypersensitive) to similar medicines known as 5HT3 receptor antagonists if you have liver disease
if you are suffering from severe constipation or have a blockage in your gut
if you have had surgery on your gut
if you have had surgery on your adenoids or tonsils
if you have had heart problems, including an uneven heart beat (arrhytmias)
if you have problems with the levels of salts in your blood, such as potassium, sodium and magnesium If any of the above apply to you, talk to your doctor , nurse or pharmacist who will decide what to do.
Other medicines and Ondansetron Injection
Tell your doctor , pharmacist or nurse if you are taking or have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines.
Tell your doctor, pharmacist or nurse if you are taking or have recently taken or might take any of the following:
• Tramadol. The effect of tramadol on pain relief may be reduced whilst you are receiving Ondansetron Injection.
• Phenytoin and carbamazepine (usually used to treat epilepsy)
• Rifampicin (a type of antibiotic, often used for the treatment of tuberculosis)
• Medicines that affect the heart (such as haloperidol or methadone)
• Medicines used to treat an uneven heart beat (anti-arrhytmics)
• Beta-blocking medicines (used to treat heart problems, eye problems, anxiety or for prevention of migraines)
• Cancer medicines (especially anthracyclines)
• Medicines used to treat infections (erythromycin, ketoconazole)
• Medicines of the type SSRI (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety (such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram)
• Medicines of the type SNRI (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety (such as venlafaxine, duloxetine)
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before being given this medicine.
Ondansetron may pass into mothers’ milk. Therefore breast-feeding is not recommended in mothers receiving Ondansetron Injection.
Driving and using machines
Ondansetron Injection should not affect your ability to drive or use machinery.
Ondansetron Injection contains sodium
Ondansetron Injection contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium free’.
3. How you are given Ondansetron Injection
A doctor has prescribed these injections for you. The injection will usually be given by a doctor or nurse. You should check with your doctor or pharmacist if you have any questions.
Ondansetron Injection should start to work soon after it is administered. If you continue to feel sick or to be sick, tell your doctor or nurse.
For patients receiving chemotherapy and/or radiotherapy that causes nausea or vomiting
Adults (including the elderly)
• The recommended dose is between 8 - 32mg a day.
• The recommended dose is 8mg administered as a slow i ntravenous injection (into a vein) or an intramuscular injection (into a muscle) immediately before you are treated with ch emotherapy or radiotherapy, followed by an 8mg tablet after 12 hours.
If your chemotherapy or radiotherapy may cause severe nausea or vomiting, you may be given:
• 8mg by slow intravenous or intramuscular injection immediately before your treatment.
• 8mg by slow intravenous or intramuscular injection immediately before your treatment, followed by two further intravenous or intramuscular doses of 8mg two to four hours apart, or by a constant infusion (a ‘drip’) of 1mg/hour for up to 24 hours.
• 16mg infused (by a ‘drip’) over not less than 15 minutes immediately before chemotherapy.
To pr event further nausea and vomiting, you may be given Ondansetron tablets for up to 5 days after chemotherapy or radiotherapy.
Children (aged over 6 months and adolescents)
• The intravenous dose will be determined by a doctor (depending on your child’s height and weight).
The initial intravenous dose will be given immediately before chemotherapy and will be followed by ondansetron given by mouth twelve hours later. Oral treatment according to body height and weight may be given for up to 5 days after chemotherapy. The oral dose will be determined by a doctor.
To prevent or treat nausea and vomiting after an operation
Adults
• Prevention (before surgery): 4mg may be given by intramuscular or slow intravenous injection before the surgery.
• Treatment (after surgery): 4mg may be given by intramuscular or slow intravenous injection.
Children (aged 1 month and adolescents)
• Prevention (before surgery): slow intravenous injection at a dose of 0.1mg/kg up to a maximum of 4mg before the surgery.
• Treatment (after surgery): slow intravenous injection at a dose of 0.1mg/kg up to a maximum of 4mg. Patients with Liver Disease
In patients with moderate or severe liver problems, a total daily dose of 8mg should not be exceeded.
If you have more Ondansetron Injection than you should
Your doctor or nurse will give you or your child Ondansetron Injection so it is unlikely that you or your child will receive too much. If you think you or your child have been given too much or have missed a dose, tell your doctor or nurse.
If you miss a dose of Ondansetron Injection
Ondansetron injections will be given to you by a doctor or nurse, so if you think that you may have missed a dose, let them know.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
If you experience any of the following side effects, you should let your doctor know immediately:
Rare: may affect up to 1 in 1,000 people
If the following side effects happen soon after being given your injection it may mean that you are having an allergic reaction to the injection:
sudden chest tightness or wheeziness swelling of the eyelids, face or lips
skin rash - red spots or hives (skin lumps) collapse
Other side effects
Very common: may affect more than 1 in 10 people
headache
Common: may affect up to 1 in 10 people
feeling of warmth in the head or stomach
flushing of the face
constipation
changes to liver function test results (if you are given Ondansetron Injection with a medicine called cisplatin, otherwise this sideeffect is uncommon)
irritation and redness at the site of injection
Uncommon: may affect up to 1 in 100 people
upward rolling of the eyes
abnormal muscular stiffness, bodily movements or shaking fits
chest pain
irregular or slow heart beat low blood pressure hiccups
Rare: may affect up to 1 in 1,000 people
dizziness or light-headedness visual disturbances (e.g. blurred vision) disturbance in heart rhythm
Very rare: may affect up to 1 in 10,000 people
temporary blindness, which usually comes back within 20 minutes Reporting of side effects
If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
By reporting side effects you can help provide more information on the safety of this medicine
5. How to store Ondansetron Injection
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP:. The expiry date refers to the last day of that month.
Do not store above 25°C. Keep the ampoules in the outer carton in order to protect from light.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.
6. Contents of the pack and other information
What Ondansetron Injection contains
- The active substance is ondansetron (as hydrochloride dihydrate). Each 2ml glass ampoule contains 2ml of aqueous solution containing 4mg ondansetron. Each 5ml glass ampoule contains 4ml of aqueous solution containing 8mg ondansetron.
- The other ingredients are citric acid monohydrate, sodium citrate, hydrochloric acid, sodium chloride, water for injections.
What Ondansetron Injection looks like and contents of the pack
Ondansetron Injection is a colourless, clear solution for injection. It is available in packs of 5 x 2ml glass ampoules containing 2ml solution or in packs of 1or 5 x 5ml glass ampoules containing 4ml solution.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder
Teva UK Limited, Eastbourne, BN22 9AG, UK
Manufacturer
Teva Operations Poland Sp. z.o.o, ul. Mogilska 80, 31-546 Krakow, Poland.
Teva Pharmaceutical Works Private Limited Company, H-2100 Godollo, Tanasics Mihaly. ut 82. Hungary. Pliva Hrvatska d.o.o. (Pliva Croatia Ltd.) Prilaz baruna Filipovica 25, 10000 Zagreb, Croatia
This medicinal product is authorised in the Member States of the EEA under the following names: United Kingdom Ondansetron 2mg/ml Solution for Injection
Lithuania Setronon 4mg/2ml injekcinis tirpalas / Setronon 8mg/4ml injekcinis tirpalas
This leaflet was last revised in September 2016.
PL 00289/1402 PA 237/62/1
* Only the paragraph containing the details of the current batch release site will be included in the printed version of the PIL
The following information is intended for medical or healthcare professionals only:
1. NAME OF THE MEDICINAL PRODUCT
Ondansetron 2mg/ml Solution for Injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 2ml glass ampoule contains 2ml of aqueous solution containing 4mg ondansetron (as hydrochloride dihydrate).
Each 5ml glass ampoule contains 4ml of aqueous solution containing 8mg ondansetron (as hydrochloride dihydrate).
Excipient(s) with known effect
Each ml of solution for injection contains 3.343 mg sodium.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for Injection.
Ondansetron 2mg/ml Solution for Injection is a colourless, clear solution for injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV). Paediatric population:
Ondansetron is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged >6 months, and for the prevention and treatment of PONV in children aged >1 month.
4.2 Posology and method of administration
Chemotherapy and radiotherapy induced nausea and vomiting (CINV and RINV):
Adults:
The emetogenic potential of cancer treatment v aries acco rding to t he d oses an d co mbinations o f chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge. The route of administration and dose of Ondansetron should be flexible in the range of 8-32mg a day and selected as shown below.
Emetogenic chemotherapy and radiotherapy:
Ondansetron can be given either by or al ( tablets), i ntravenous or i ntramuscular a dministration. T he recommended intravenous (IV) or intramuscular (IM) dose of ondansetron is 8 mg administered as a slow injection in not less than 30 seconds immediately before treatment, followed by 8mg orally twelve hourly. Oral treatment is recommended to protect against delayed or prolonged emesis after the first 24 hours.
To protect against delayed or prolonged emesis after the first 24 hour s, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment.
Highly emetogenic chemotherapy e.g. high-dose cisplatin:
For patients receiving highly emetogenic chemotherapy, e .g. high-dose cisplatin, ondansetron can be given either by intravenous or intramuscular administration. Ondansetron has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:
Ondansetron may be administered as a single 8 mg IV or IM dose immediately before chemotherapy. Doses of greater than 8 mg and up to a maximum of 16 mg of ondansetron may only be given by IV infusion diluted in 50 to 100 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes. A single dose greater than 16 mg should not be given (see section 4.4).
For management of highly emetogenic chemotherapy, a dose of 8 mg of ondansetron may be administered by slow IV in not less than 30 seconds, or slow IM injection immediately before chemotherapy, followed by 2 further IV or IM doses of 8 mg 2 to 4 hours apart, or by a constant infusion of 1 mg/h for up to 24 hours.
A single dose of 16mg diluted in 50-100ml of saline or other compatible infusion fluid (see section 6.6) and infused over not less than 15 minutes immediately before chemotherapy.
The selection of dose regimen should be determined by the severity of the emetogenic challenge.
A single dose greater than 16 mg must not be given due to dose dependent increase of QT-prolongation risk (see sections 4.4, 4.8 and 5.1).
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.
Oral treatment is recommended to protect against delayed or prolonged emesis after the first 24 hours.
To protect against delayed or prolonged emesis after the first 24 hour s, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment.
Paediatric population:
CINV in children aged > 6 months and adolescents
The dose for CINV can be calculated based on body surface area (BSA) or weight - see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid (see section 6.6) and infused over not less than 15 minutes. Weight-based dosing results in higher total daily doses compared to BSA-based dosing (sections 4.4.and 5.1).
Ondansetron i njection s hould be di luted in 5% de xtrose or 0. 9% sodium c hloride or ot her c ompatible infusion fluid (see section 6.6) and infused intravenously over not less than 15 minutes.
There are no data from controlled clinical trials on the use of ondansetron in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy-induced nausea and vomiting in children.
Dosing by BSA:
Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m2. The intravenous dose must not exceed 8 mg.
Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1).
The total daily dose must not exceed adult dose of 32 mg.
Table 1: BSA-based dosing for Chemotherapy - Children aged >6 months and adolescents
|
BSA |
Day 1(a,b) |
Day 2 - 6(b) |
|
< 0.6 m2 |
5mg/m2 IV plus 2 mg syrup after 12 hours |
2 mg syrup every 12 hours |
|
> 0.6 m2 |
5mg/m2 IV plus 4 mg syrup after 12 hours |
4 mg syrup or tablet every 12 hours |
|
> 1.2 m2 |
5 mg/m2 IV or 8 mg IV plus 8 mg syrup or tablet after 12 hours |
8 mg syrup or tablet every 12 hours |
a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg
Dosing by bodyweight:
Weight-based dosing results in higher total daily doses compared to BSA-based dosing (see sections 4.4. and 5.1).
Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/kg. The intravenous dose must not exceed 8 mg.
Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32 mg.
Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2).
Table 2: Weight-based dosing for chemotherapy - Children aged >6 months and adolescents
|
Weight |
Day 1(a,b) |
Day 2 - 6(b) |
|
<10 kg |
Up to 3 dos es of 0. 15 m g/kg every 4 hours |
2 mg syrup every 12 hours |
|
> 10 kg |
Up to 3 dos es of 0. 15 m g/kg every 4 hours |
4 mg syrup or t ablet every 12 hours |
a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg
Elderly
Ondansetron is well tolerated by patients over 65 y ears and no alteration of dosage, dosing frequency or route of administration are required.
Renal Impairment
No alteration of daily dosage or frequency of dosing, or route of administration are required.
Hepatic Impairment
Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded.
Patients with poor sparteine/debrisoquine metabolism
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently, in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
Post-operative nausea and vomiting (PONV):
Adults: For the prevention of P ONV onda nsetron c an be a dministered or ally or by i ntravenous or intramuscular injection.
Ondansetron m ay be ad ministered as a si ngle d ose of 4 mg by IM or sl ow IV i njection administered at induction of anaesthesia. For treatment of established PONV a single dose of 4mg given by IM or slow IV injection is recommended.
Paediatric population
PONV in children aged> 1 month and adolescents: For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow IV injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.
For the treatment of P ONV af ter su rgery i n p aediatric p atients h aving su rgery p erformed u nder g eneral anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4mg.
There are no data on the use of ondansetron in the treatment of PONV in children below 2 years of age.
Elderly
There is limited experience in the use of ondansetron in the prevention and treatment of PONV in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Renal Impairment
No alteration of daily dosage or frequency of dosing, or route of administration are required.
Hepatic Impairment
Clearance of ondansetron is significantly reduced and serum half life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded.
Patients with poor sparteine/debrisoquine metabolism
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drugexposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
4.3 Contraindications
Concomitant use with apomorphine (see section 4.5)
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists. Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitivity reactions.
Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1). In addition, postmarketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.
Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.
There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised
As ondansetron is known to increase large bowel transit time, patients with signs of sub acute intestinal obstruction should be monitored following administration.
In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.
Paediatric population
Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.
CINV
When calculating the dose on an mg/kg basis and administering three doses at 4-hour intervals, the total daily dose will be higher than if one single dose of 5mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross-trial comparison indicates similar efficacy for both regimens (section 5.1).
Ondansetron is not indicated for prevention and treatment of postoperative nausea and vomiting in children after intra-abdominal surgery.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.
4.5 Interaction with other medicinal products and other forms of interaction
There is no e vidence that ondansetron either induces or inhibits the metabolism of most other medicinal products commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron i s ad ministered with al cohol, t emazepam, f urosemide, alfentanil, tramadol, m orphine, lignocaine, thiopental and or propofol.
Ondansetron i s m etabolised by m ultiple h epatic cytochrome P-450 e nzymes: C YP3A4, C YP2D6 a nd CYP1A2. Due to t he m ultiplicity of m etabolic en zymes cap able of m etabolising o ndansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no s ignificant change in overall ondansetron clearance or dose requirement.
Use of ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g. anthracyclines such as doxorubicin, daunorubicin or trastuzimab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias (see section 4.4).
There h ave b een p ost-marketing r eports de scribing pa tients w ith s erotonin s yndrome (including altered mental st atus, au tonomic instability and neuromuscular abnormalities) following t he concomitant us e of ondansetron and other serotonergic drugs (including SSRIs and SNRIs). (see section 4.4)
Apomorphine
Based on reports of profound hypotension and loss of consciousness when ondansetron was ad ministered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
Tramadol
Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Phenytoin, Carbamazepine and Rifampicin
In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.
4.6 Fertility, pregnancy and lactation Pregnancy
The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies d oes n ot i ndicate d irect o r i ndirect h armful ef fects wi th respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.
Breast-feeding
Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron should not breast-feed their babies.
Fertility
There is no information on the effects of ondansetron on human fertility.
4.7 Effects on ability to drive and use machines
Ondansetron has no or negligible influence on the ability to drive and use machines.
In psychomotor testing ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of ondansetron
4.8 Undesirable effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (^ 1/10), common (^ 1/100 and <1/10), uncommon (^ 1/1000 and <1/100), rare (^ 1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.The adverse event profiles in children and adolescents were comparable to that seen in adults
Immune system disorders
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disorders
Very common: Headache.
Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia)1
Rare: Dizziness during rapid IV administration, which in most cases is prevented or resolved by lengthening the infusion period.
Eye disorders
Rare: Transient visual disturbances (eg. blurred vision) predominantly during IV administration.
Very rare: Transient blindness predominantly during intravenous administration2.
Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Rare: QTc prolongation (including Torsade de Pointes)
Vascular disorders
Common: Sensation of warmth or flushing.
Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.
Gastrointestinal disorders
Common: Constipation.
Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests3.
General disorders and administration site conditions
Common: Local IV. injection site reactions.
1 Observed without definitive evidence of persistent clinical sequelae.
2 The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.
3 These events were observed commonly in patients receiving chemotherapy with cisplatin.
Paediatric population
The adverse event profiles in children and adolescents were comparable to that seen in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose Symptoms and signs
There is limited experience of ondansetron overdose. In the majority of cases, symptoms were similar to those already reported in patients receiving recommended doses (see section 4.8). Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block Ondansetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.
In all instances, the events resolved completely.
Treatment
There is no specific antidote for ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
The use of ipecacuanha to treat overdose with ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.
Paediatric population
Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Serotonin (5HT3) antagonists, ATC code: A04A A01
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
The role of ondansetron in opiate-induced emesis is not yet established.
Ondansetron does not alter plasma prolactin concentrations.
QT prolongation
The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction was 5.8 (7.8) msec. In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was greater than 60 msec..
No significant changes were seen in the measured electrocardiographic PR or QRS intervals.
Paediatric population
CINV
The efficacy of ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1 to 18 years (S3AB3006). On the days of chemotherapy, patients received either ondansetron 5 mg/m2 intravenous and ondansetron 4 mg orally after 8-12 hrs or ondansetron 0.45 mg/kg intravenous and placebo orally after 8-12 hrs. Post- chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2 intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups
A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in:
• 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2 intravenous together with 2-4 mg dexamethasone orally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg + 2 - 4 mg dexamethasone orally on the days of chemotherapy.
Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There was no difference in the overall incidence or nature of adverse events between the two treatment groups
The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an openlabel, noncomparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients.
Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for children aged < 12 yrs and 8 mg for children aged > 12 yrs (total no. of children n= 28). Complete control of emesis was achieved in 42% of patients.
PONV
The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670 children aged 1 to 24 months (post-conceptual age >44 weeks, weight > 3 kg). Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status < III. A single dose of ondansetron 0.1 mg/kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron ((28% vs. 11%, p <0.0001).
Four double-blind, placebo-controlled studies have been performed in 1469 male and female patients (2 to 12 years of age) undergoing general anaesthesia. Patients were randomised to either single intravenous doses of ondansetron (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarised in Table 3.
Table 3 Prevention and treatment of PONV in Paediatric Patients - Treatment response over 24 hours
|
Study |
Endpoint |
Ondansetron % |
Placebo % |
P value |
|
S3A380 |
CR |
68 |
39 |
< 0.001 |
|
S3GT09 |
CR |
61 |
35 |
<0.001 |
|
S3A381 |
CR |
53 |
17 |
< 0.001 |
|
S3GT11 |
no nausea |
64 |
51 |
0.004 |
|
S3GT11 |
no emesis |
60 |
47 |
0.004 |
CR = no emetic episodes, rescue or withdrawal
5.2 Pharmacokinetic properties
Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30ng/ml are attained approximately 1.5 hours after an 8mg dose. For doses above 8mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).
The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25ng/ml are attained within 10 minutes of injection.
Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Special patient populations
Children and adolescents (aged 1 month to 17 years)
In paediatric patients aged 1 to 4 months (n=19) undergoing elective surgery with general anaesthesia, weight normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.
In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (8-12 years old) were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 l at 12 years to 17 l at 3 years. When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.
Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children. Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.
Renal impairment
In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.
Elderly
Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration.
Hepatic impairment
Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.
Ondansetron in micromolar concentrations blocked cloned HERG potassium channels of the human heart. The clinical relevance of this finding is not clear.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid monohydrate Sodium citrate
Hydrochloric acid for pH adjustment Sodium chloride Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened product: 3 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 t o 8° C, unl ess di lution ha s t aken pl ace i n c ontrolled and va lidated a septic conditions.
6.4 Special precautions for storage
Do not store above 25°C.
Keep ampoule in the outer carton in order to protect from light
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I clear glass 2ml ampoules containing 2ml solution and type I clear glass 5ml ampoules containing 4ml solution. 1 or 5 ampoules are packed per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Ondansetron Solution for Injection should not be autoclaved.
Compatibility with intravenous fluids
Ondansetron Solution f or Injection s hould onl y be a dmixed w ith t hose i nfusion s olutions which are recommended:
Sodium Chloride Intravenous Infusion 0.9%w/v Glucose Intravenous Infusion 5%w/v Mannitol Intravenous Infusion 10%w/v Ringers Intravenous Infusion
Potassium Chloride 0.3%w/v and Sodium Chloride 0.9%w/v Intravenous Infusion Potassium Chloride 0.3%w/v and Glucose Intravenous Infusion 5%w/v
In keeping with good pharmaceutical practice dilutions of ondansetron solution for injection in intravenous fluids should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.
Compatibility studies have been undertaken i n pol yvinyl c hloride i nfusion ba gs a nd pol yvinyl c hloride administration set s. It is co nsidered that adequate stability would also be c onferred by the us e of polyethylene infusion bags or Type 1 glass bottles. Dilutions of ondansetron in sodium chloride 0.9%w/v or in glucose 5%w/v have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron Solution for Injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
Compatibility with other drugs
Ondansetron may be administered by intravenous infusion at 1mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Ondansetron giving set for ondansetron concentrations of 16 to 160 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml respectively);
Cisplatin: Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours.
5-Fluorouracil: Concentrations up to 0.8 mg/ml (e.g. 2.4g in 3 litres or 400mg in 500ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.
Carboplatin: Concentrations in the range 0.18 mg/ml to 9.9 mg/ml (e.g. 90 mg in 500 ml to 990 mg in 100 ml), administered over ten minutes to one hour.
Etoposide: Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250 mg in 1 litre), administered over thirty minutes to one hour.
Ceftazidime: Doses in the range 250 mg t o 2000 mg r econstituted w ith W ater f or I njections BP as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.
Cyclophosphamide: Doses in the range 100 mg to 1g, reconstituted with Water for Injections BP, 5 ml per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.
Doxorubicin: Doses in the range 1 0-100mg reconstituted with Water for Injections BP, 5 ml per 10 mg doxorubicin, as r ecommended by t he m anufacturer a nd gi ven as an intravenous bolus injection over approximately 5 minutes.
Dexamethasone: Dexamethasone so dium p hosphate 2 0mg m ay b e ad ministered as a sl ow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 16mg of ondansetron diluted in 50-100ml of a c ompatible infusion fluid ove r a pproximately 15 m inutes. C ompatibility be tween dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the s ame gi ving s et r esulting in c oncentrations in l ine of 32 m icrogram - 2.5mg/ml for dexamethasone sodium phosphate and 8 microgram - 1mg/ml for ondansetron.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG UK
8. MARKETING AUTHORISATION NUMBER(S)
PL 00289/1402 PA 237/62/1
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/06/2003 / 11/11/2009
10. DATE OF REVISION OF THE TEXT
18/10/2016
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