Danset
Ampoule
Qualitative & Quantitative Composition:
Each 1 ml of aqueous solution contains 2 mg
ondansetron as hydrochloride dihydrate.
Pharmaceutical Form:
Aclear, colourless, sterile solution for injection or infusion. nee
Clinical Particulars:
Indications:
DANSET injection is indicated for the it management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. DANSET is also indicated for the prevention and treatment of post
operative nausea and vomiting.
Dosage&Adminlstration:
DANSETis available for parenteral use.
Chemotherapy & Radiotherapy Induced Nausea & Vomiting (CINV and RINV):
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy I I
regimens used. The selection of dose regimen should ( be determined by the severity of the emetogenic
Populatlons:
-Adults
Emetogenic Chemotherapy & Radiotherapy
The recommended intravenous (IV) or intramuscular If (IM) dose of DANSET is 8 mg administered as a slow injection immediately before treatment.
Highly Emetogenlc Chemotherapy e.g. high-dose cisplatin
DANSET can be given by IV. IM
Administration. DANSET may be administered as a single 8 mg IV or IM dose immediately before chemotherapy. Doses of greater than 8 mg up to 16 mg , of DANSET may only be given by IV infusion diluted in 50 to 100 ml of saline or other compatible infusion fluid’
(see Instructions for Use and Handling) and infused over not less than 15 minutes. A single dose greater than 16 mg should not be given. (see Warnings and Precautions) For management of highly emetogenic chemotherapy. a dose of 8 mg of DANSET may be
administered by slow IV in not less than 30 seconds, or IM injection immediately before chemotherapy, followed by two 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. The efficacy of DANSET in highly emetogenic
chemotherapy may be enhanced by the addition of a single IV dose of dexamethasone sodium phosphate 20 mg, administered prior to chemotherapy.
-CINV in Children and Adolescents (aged 6 months I to 17 years)
The dose for CINV can be calculated based on body surface area (8SA) or weight. In paediatric clinical studies, DANSET was given by IV infusion diluted in 25 to 50 rnl of saline or other compatible infusion fluid (see Instructions for Use and Handling) and infused over not less than 15 minutes. Dosing by BSA DANSET should be administered immediately before chemotherapy as a single IV dose cf S mg/ m2. The IV dose musl nolexceed 8 mg. Table 1. BSA-based dosing for CINV (aged 6 months to 17 years)
BSA Day 1
< 0.6 m 5mg/m’IV
0.6 m’to.< 1.2 m’ 5mg/m’IV
> 1.2m2 5 mg/ m’ IV or 8 mg IV
Dosing by body weight
DANSET should be administered immediately before chemotherapy asa single IV dose of 0.15 mg/kg. The IV dose must not exceed 8 mg. On Day 1, two further IV doses may be given in 4-hourty intervals.
Table 2. Weight-based dosing for CINV (aged months to 17 years)
Body Weight Day 1 I
<10 kg Up to 3 doses of 0.15 mg/kg :
every 4 hours
> 10 kg Up to J doses of 0.15 mg/Kg
every 4 hours ‘
-Elderly
DANSET is well tolerated by patients over 65 years and no alterations of dosage, dosing frequency or route of administration are required.
-Renal Impairment
No alteration of daily dosage or frequency of dosinq, or route of administration are required. 31
-Hepatic Impairment
Clearance of ondansetron is significantly reduced and 0 serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In m such patients a total daily dose of 8 mg IV should not be,exceeded and therefore. :;9
-Patlents with Poor Sparteine I 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 orfrequencyof dosing are required.
Post-Operative Nausea & Vomiting (PONV)
-PONY In Adults
For prevention of post-operative nausea and vomiting,The recommended dose of OANSET injection is a single dose of 4 mg by IM or slow IV injection administered at the induction of anaesthesia. For treatment of established post-operative nausea and
vomiting, a single dose of 4 mg given by IM or slow IV injection is recommended.
-PONV in Children and Adolescents (aged 1 month to17years)
I For prevention and treatment of PONV in paediatric patients having surgery performed under general anaesthesia, DANSET may be administered by slow IV injection (not less than 30 seccnds) at a dose of 0.1 mgfkg uptoa maximumof4 mg either prior to, atorafler
induction of anaesthesia, or after surgery.
-Elderly There is limited experience in the use of OANSET in the prevention and treatment of post operative nausea and vomiting
in the elderly, however DANSET 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 in such patients a total daily dose of 8 mg IV should not be exceeded.
-Patients with Poor Sparteine/Debrisoquine Metabolism
59 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 frequencies of dosing are required .
Contraindications
Based on reports of profound hypotension and loss of in consciousness when ondansetron was administered out with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated. Hypersensitivity to any component of the preparation.
Warnings & Precautions:
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other the selective 5HT 3. Ondansetron prolongs the O’F interval in a dose dependent manner (see Clinical Pharmacclogy). In addition, post-marketing cases of Torsade de Pointes me have been reported in patients using ondansetron.
Avoid ondansetron in patients with congenital long aTlit o syndrome. Ondansetron should be administered with caution to
patients who have or may develop prolongation of Otc,Including patients with electrolyte abnormalities, Congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to OT prolongation or electrolyte abonrmaltities. Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration. As DANSET is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.
Interactions:
There is no evidence that DANSET either induces or in hibits the metabolism of other drugs commonly administered with it. Specific studies have shown that there are no pharmacokinetic interactions when
DANSET is administered with alcohol, temazepam, furosemide, tramadol or propofo!. Ondansetron is metabolised by multiple hepatic cytochrome P450 enzymes: CYP3A4, CYP2D6 and CYPIA2.
Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally cQD1pen~y other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Caution should be exercised when ondansetron is coadministered with drugs that prolong the OT interval and/or cause electrolyte abnormalities. (see Warnings and Precautions).
Apomorphine
Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
Tramadol
Data from small studies indicate that ondansetron may reduce the analgesic effectoftramadol.
Pregnancy & Lactation:
Pregnancy The safety of DANSET 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 DANSET in pregnancy is not recommended.
Lactation Tests have shown that ondansetron passes into the milk
of lactating animals. It is therefore recommended that mothers receiving DANSET should not breast-feed their babies.
Effects on Ability to Drive and Use Machines:
In psychomotor testing DANSET does not impair perfannance nor cause sedation. No detrimental effects on such activities are predicted from thepharmacology of DANSET.
Adverse Reactions:
Adverse events are listed below by system organ class and frequeocy. Frequencies are defined as: very common (>:1-/10); common (>1/100/to <1110); uncommon (>1/1000 to <11100); rare >1110,000 to <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
DANSET. 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) have been observed without definitive evidence of persistent clinical sequelae.
Rare: Dizziness during rapid IV administration.
*Eye disorders
Rare: Transient visual disturbances (e.g. blurred vision)
predominantly during IV administration.
Very rare: Transient blindness predominantly during IV administration. 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.
*Cardiac disorders
Uncommon: Arrhythmlas, chest pain with or without ST segment depression, bradycardia.
Rare: O’Ic prolongation (including Torsade de Pointes).
*Vasculardisorders
Common: Sensation of warmth orflushing.
Uncommon: Hypotension.
*Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.
*Gastrointestinal disorders
Common: Constipation.
Local burning sensation following insertion of suppositories.
*Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests, These events were observed commonly in Patients receiving chemotherapy with cisplatin. General disorders and administration site conditions
Common: Local IV injection site reactions.
Overdose symptoms and signs :
(see Adverse Reactions). Ondansetron prolongs ainterval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.
Treatment There is no specific antidote for DANSET, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate. The use of ipecacuanha to treat overdose with DANSET is not recommended as patients are unlikely
to respond due to the anti-emetic action of ondansetron itself.
Pharmacological Properties:
Pharmacodynamics
Mechanism of Action
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 5HT 3 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 tloor 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 5HT 3 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.
Pharmacodynamic Effects:
Ondansetron does not alter plasma prolactin concentrations.
QT Prolongation:
The effect of ondansetron on the OTc interval was evaluated in a double blind, randomized, 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 of32 mg, Ihe maximum mean (upper limit of 90% Cl) difference in QTcF from placebo after baseline- correction was 19.6 (21.5) msec.At the lower testedDose of 8 mg, the maximum mean (upper limitlof 90% Cl) difference in QTcF from placebo after b~seline- correction was 5.8 (7.8) msec. In this study, the~e were no QTcF measurements greater than 480 mseq and no QTcF prolongation was greater than 60 msec.
Pharmacokinetics:
The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Absorption: Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
Distribution: Ondansetron is not highly protein bound (70 10 76%). The disposition of ondansetron following IM or IV dosing in adults is similar with a steady state volume of distribution of about 140 L. Metabolism:Ondansetron is cleared from the systemic
circulation predominantly by hepatic metabolism through multiple enzymatic pathways. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron’s pharmacokinetics.
Elimination: Ondansetron is cleared from the systemic
circulation predominantly by hepatic metabolism. Less than 5% ofthe absorbed dose is excreted unchanged in the urine. The disposition of ondansetron following IM or IV dosing is similar with a terminal elimination half-life of about 3 hours.
Special Patient Populations:
-Children and Adolescents (aged 1 month to 17 years)
In paediatric patients aged 1 to 4 months (n~19) , undergoing surgery, 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 1 to 4 month patient population 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 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. 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 compensates for agerelated 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 IV administration of ondansetron. Based on this analYSis, Systemic exposure (AUC) of ondansetron fol/owing IV dosing in children and
adolescents was comparable to adults, with the exception of infants aged 1 to4 months. Volume of distribution 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 a 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.
-Elderly: Studies in healthy elderly volunteers show
slight age-related increases in both bioavailability and half-life of Ondansetron.
-Renal Impairment: In patients with moderate renal
impairment (creatinine clearance 15 to 60 mllmin). both systemic clearance and VOlume of distribution are reduced fOllowing IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination halflife (5.4 hours). Astudy in patients with severe renal impairment who required regular
haemOdialysis (studied between dialyses) showed ondansetron’s pharmacokinetics to be essentially unchanged fOllOWing IV administration.
-Hepatic Impairment: In patients with severe hepatic impairment, ondansetron’s systemic clearance is markedly reduced with prolonged elimination half-lives (15 to 32 hours) and an oral bioavailabilily approaching 100% due to reduced pre-systemic metabolism.
Pharmaceutica, Particulars:
list of Excipients: Citric acid, sodium citrate. sodium chloride, Water for Injections
Incompatibilities:
DANSET injection Should not be administered in the same syringe or infusion as any other medication (see Instructions for Use and Handling). DANsET injection should only be mixed with those infUSion solutions which are recommended (see Instructions for Use and Handling).
Shelf-Life:
The expiry date is indicated on the packaging.
Special Precautions for Storage:
Store below 30°C, Protect from light.
Nature & Contents of Container:
-Danset ampoule 4 mgl2 ml: supplied as 10r 3 glass ampoules each of 2 m! in a carton box + insert leaflet.
-Dansat ampoule 8 mgl4 ml: supplied as 10r 3 glass ampoules each of 4 rnl in a carton box +insert leaflet.
Instructions for Use/Handling
Injection (unpreserved) ampoules:
The solution for injection is unpreserved, should only be used once and injected or diluted immediately after opening. Any remaining solution should be discarded. Ondansetron injection ampoules should not be autoc1 aved. Compatibility studies have been carried out in polyvinyl chloride infusion bags and polyvinyl chloride
administration sets. Stability is conferred by the use of polyethylene infusion bags or Type 1 glass bottles. Dilutions of un preserved ondansetron injection in sodium chloride 0.9% w/v or in dextrose 5% w/v have been Demonstrated to be stable in polypropylene
syringes. Therefore, it is considered that unpreserved
ondansetron injection diluted with compatible infusion fluids recommended below would Also be stable in polypropylene synnges. In keeping with good pharmaceutical practice, IV solutions should be prepared at the time of infusion, under appropriate
aseptic conditions.
Compatibility with IV fluids:
Compatibility studies have shown that unpreserved ondansetron injection is stable for seven days at room temperature (below 25’C) under fluorescent lighting or in a refrigerator with the following IV infusion fluids: Sodium Chloride IV Infusion BP 0.9% w/v.
-Glucose IV Infusion BP 5% w/v.
-Mannitol IV Infusion BP 10% w/v.
-Ringers IV Infusion.
-Potassium Chloride 0.3% w/v and Sodium Chloride 0.9% w/v IV Infusion BP.
-Potassium Chloride 0.3% w/v and Glucose 5% w/v IV Infusion BP.
Compatibility with other drugs:
Ondansetron may be administered by IV infusion at 1 mg/h, from an infusion bag or syringe pump. The following drugs may be administered via the Y -site of the ondansetron giving set forondansetron concentrations of 16 to 160 micrograms Iml (e.g. 8
mg/500ml and 8 mg/50ml respectively
I Keep medicament out of reach of children I
Manufactured by:
ADWIA Co. S.A.E
10′” of Ramadan City- Egypt
