Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of Action
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the      6.3   Shelf Life control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT3 in the small intestine initiating a vomiting reflex by activating vagal afferents          The expiery date of the product is indicated on the packaging materials.
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   6.4   Special Precautions for Storage 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                      Store below 30°c. Store the vial in the box in order to protect from light.
probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central               After dilution: chemical and physical in-use stability has been demonstrated for 36 hours at 20C to 0
nervous system. The mechanisms of action in post-operative nausea and vomiting are not known                     8 C protected from light.
but there may be common pathways with cytotoxic induced nausea and vomiting.                                     From 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.
Ondansetron does not alter plasma prolactin concentrations.
6.5   Nature and content of container
The role of ondansetron in opiate-induced emesis is not yet established.
Type I glass ampoules.
QT Prolongation                                                                                                  5 ampoules are packed in a carton.
The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised, placebo               10 ampoules are packed in a carton.
and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women.                       25 ampoules are packed in a carton.
Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest                  Not all pack sizes may be marketed.
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             6.6   Special precautions for disposal and other handling (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                          Ondansetron Baxter 2mg/ml should not be autoclaved.
electrocardiographic PR or QRS intervals.                                                                        Compatibility with intravenous fluids; Ondansetron Baxter 2mg/ml should only be mixed with those infusion solutions which are Paediatric population                                                                                            recommended: 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                a)     Sodium chloride Intravenous Infusion BP 0.9 % w/v the days of chemotherapy, patients received either ondansetron 5 mg/m2 intravenous and                           b)     Glucose Intravenous Infusion BP 5% w/v ondansetron 4 mg orally after 8 to 12 hours or ondansetron 0.45 mg/kg intravenous and placebo                    c)     Mannitol Intravenous Infusion BP 10% w/v orally after 8 to 12 hours. Post-chemotherapy both groups received 4 mg ondansetron syrup twice                  d)     Ringers Intravenous Infusion daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2                       e)     Potassium Chloride 0.3%w/v and Sodium Chloride 0.9%w/v Intravenous Infusion BP intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally).                    f)     Potassium Chloride 0.3%w/v and Glucose 5%w/v Intravenous Infusion BP 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                 Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl groups.                                                                                                          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 A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged 1 to 17 years                 chloride 0.9%w/v or in glucose 5%w/v have been demonstrated to be stable in polypropylene demonstrated complete control of emesis on worst day of chemotherapy in:                                         syringes. It is considered that Ondansetron diluted with other compatible infusion fluids would be • 73% of patients when ondansetron was administered intravenously at a dose of 5 mg/m2                    stable in polypropylene syringes.
intravenous together with 2 to 4 mg dexamethasone orally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg and 2 to                   Compatibility with other drugs: 4 mg dexamethasone orally on the days of chemotherapy.                                                 Ondansetron Baxter 2mg/ml may be administered by intravenous infusion at 1mg/hour, e.g. from Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. There                      an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the was no difference in the overall incidence or nature of adverse events between the two treatment                 Ondansetron Baxter 2mg/ml giving set for ondansetron concentrations of 16 to 160 micrograms/mL groups.                                                                                                          (e.g. 8 mg/500 mL and 8 mg/50 mL respectively); The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, single-arm study (S3A40320). All children received three 0.15 mg/kg doses of                    Cisplatin: intravenous ondansetron, administered 30 minutes before the start of chemotherapy and then at 4                  Concentrations up to 0.48 mg/mL (e.g. 240 mg in 500 mL) administered over one to eight hours.
and 8 hours after the first dose. Complete control of emesis was achieved in 56% of patients.
5-Fluorouracil:
Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one                  Concentrations up to 0.8 mg/mL (e.g. 2.4g in 3 litres or 400 mg in 500 mL) administered at a rate of intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for                    at least 20 mL per hour (500 mL per 24 hours). Higher concentrations of 5- fluorouracil may cause children aged < 12 years and 8 mg for children aged ≥ 12 years (total no. of children n= 28).                    precipitation of ondansetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium Complete control of emesis was achieved in 42% of patients.                                                      chloride in addition to other excipients shown to be compatible.

PONV                                                                                                             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), The efficacy of a single dose of ondansetron in the prevention of post-operative nausea and                      administered over ten minutes to one hour.
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                       Etoposide: scheduled to undergo elective surgery under general anaesthesia and had an ASA status ≤ III. A                   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), single dose of ondansetron 0.1 mg/kg was administered within five minutes following induction of                 administered over thirty minutes to one hour.
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                         Ceftazidime: ondansetron (28% vs. 11%, p <0.0001).                                                                            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 Four double-blind, placebo-controlled studies have been performed in 1469 male and female                        intravenous bolus injection over approximately five minutes.
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             Cyclophosphamide: mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number               Doses in the range 100 mg to 1g, reconstituted with Water for Injections BP, 5 mL per 100 mg of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or                cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus following anaesthesia induction. Ondansetron was significantly more effective than placebo in                    injection over approximately five minutes.
preventing nausea and vomiting. The results of these studies are summarised in Table 3.
Doxorubicin:
Table 3 Prevention and treatment of PONV in Paediatric Patients – Treatment response over 24                     Doses in the range 10-100 mg reconstituted with Water for Injections BP, 5 mL per 10 mg hours                                                                                                            doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.
Study       Endpoint       Ondansetron %        Placebo %      p value Dexamethasone:
S3A380      CR             68                   39             ≤0.001 Dexamethasone sodium phosphate 20mg may be administered as a slow intravenous injection S3GT09      CR             61                   35             ≤0.001                                           over 2-5 minutes via the Y-site of an infusion set delivering 8 or 16mg of ondansetron diluted in 50- S3A381      CR             53                   17             ≤0.001                                           100 mL of a compatible infusion fluid over approximately 15 minutes. Compatibility between S3GT11      No nausea      64                   51             0.004                                            dexamethasone sodium phosphate and ondansetron has been demonstrated supporting S3GT11      No emesis      60                   47             0.004                                            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 CR = no emetic episodes, rescue or withdrawal                                                                    ondansetron.

Pharmacokinetic Properties