Setronon

Ondansetronas, 8mg/4ml, injekcinis tirpalas

Vartojimas: leisti į raumenis, į veną
Registratorius: PLIVA, SIA, Latvija
Receptinis: Receptinis

Sudedamosios medžiagos: Ondansetronas

SUMMARY OF PRODUCT CHARACTERISTICS

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).

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

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).

4.2.Posology and method of administration

Chemotherapy and radiotherapy:

Adults: The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. 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 oral (tablets), intravenous or intramuscular administration. For most patients receiving emetogenic chemotherapy or radiotherapy, Ondansetron 8mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment.

Highly emetogenic chemotherapy: 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:

A single dose of 8mg by slow intravenous or intramuscular injection immediately before chemotherapy.

A dose of 8mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8mg two to four hours apart, or by a constant infusion of 1mg/hour for up to 24 hours. A single dose of 32mg diluted in 50-100ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) 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.

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.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment.

Children (aged 2 years and over) and Adolescents (< 18 years): Experience in paediatric patients is limited. In children older than two years Ondansetron may be administered as a single intravenous dose of 5mg/m2 over 15 min immediately before chemotherapy, followed by 4mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment.

Elderly: Patients over 65 years require no alteration of dosage, dosing frequency or route of administration .

Patients with Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.

Patients with 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.

Post-operative nausea and vomiting (PONV):

Adults: For the prevention of PONV ondansetron can be administered orally or by intravenous or intramuscular injection.

Ondansetron may be administered as a single dose of 4mg given by intramuscular or slow intravenous injection at induction of anaesthesia. For treatment of established PONV a single dose of 4mg given by intramuscular or slow intravenous injection is recommended.

Children (aged 2 years and over): For prevention of PONV in paediatric patients having surgery performed under general anaesthesia (see section 4.4 Special warnings and precautions for use), ondansetron may be administered by slow intravenous injection at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia.

For treatment of established PONV in paediatric patients, ondansetron may be administered by slow intravenous injection at a dose of 0.1mg/kg up to a maximum of 4mg.

There is limited data on the use of ondansetron in the prevention and treatment of PONV in children under 2 years of age.

Elderly: There is limited experience in the use of ondansetron in the prevention and treatment of PONV in the elderly.

Patients with Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.

Patients with 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 active substance exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3.Contraindications

Hypersensitivity to ondansetron or to any of the excipients .

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.

As ondansetron is known to increase large bowel transit time, patients with signs of sub acute intestinal obstruction should be monitored following administration.

Ondansetron is not indicated for prevention and treatment of postoperative nausea and vomiting in children after intra-abdominal surgery.

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.

4.5.Interactions with other medicinal products and other forms of interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of most other medicinal products commonly co-administered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepan, frusemide and propofol.

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.Pregnancy and lactation

The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with 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.

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.

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.

4.8.Undesirable effects

Immune system disorders

Rare (>1/10,000, <1/1,000): immediate hypersensitivity reactions, sometimes severe including anaphylaxis. Anaphylaxis may be fatal.

Hypersensitivity reactions were also observed in patients, who were sensitive towards other selective 5-HT3-antagonists.

Nervous system disorders

Rare (>1/10,000, <1/1,000): There have been reports suggestive of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions without definitive evidence of persistent clinical sequelae and seizures have been rarely observed although no known pharmacological mechanism can account for ondansetron causing these effects.

Cardiac disorders

Rare (>1/10,000, <1/1,000): Chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia.

Gastrointestinal disorders

Common (>1/100, <1/10): Ondansetron is known to increase the large bowel transit time and may cause constipation in some patients. Patients with signs of subacute obstruction should be monitored.

Hepato-biliary disorders

Occasional asymptomatic increases in liver function tests were observed.

General disorders and administration site conditions

Common (>1/100, <1/10): headache, sensations of flushing or warmth, hiccups.

Rare (>1/10,000, <1/1,000): transient visual disturbances (e.g. blurred vision) and dizziness during rapid intravenous administration of ondansetron.

Occasionally, hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.

4.9.Overdose

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

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.

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.

In a study of 21 paediatric patients aged between 3 and 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 2mg (3-7 years old) or 4mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300mL/min at 12 years of age to 100mL/min at 3 years. Volume of distribution fell from about 75L at 12 years to 17L at 3 years. Use of weight-based dosing (0.1mg/kg up to 4mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.

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.

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration.

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

Preclinical 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

Sodium chloride

Water for injections.

6.2.Incompatibilities

Ondansetron Solution for Injection must not be mixed with other medicinal products except those mentioned in 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, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4.Special precautions for storage

Do not store above 25°C.

Keep container in the outer carton.

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.Instruction for use and handling (, and disposal)

Ondansetron Solution for Injection should not be autoclaved.

Compatibility with intravenous fluids:

Ondansetron Solution for Injection should only be admixed with those infusion solutions 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 in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use 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 to 2000 mg reconstituted with Water for Injections 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 10-100mg reconstituted with Water for Injections BP, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.

Dexamethasone: Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32mg of ondansetron diluted in 50-100ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram - 2.5mg/ml for dexamethasone sodium phosphate and 8 microgram - 1mg/ml for ondansetron.

7.Marketing Authorisation Holder

8.Marketing Authorisation Number

9.Date of First Authorisation/Renewal of THE Authorisation

10.Date of Revision of the Text