Osetron

Adults:

Osetron 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:

Osetron is indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in children aged > 6 months, and for the prevention and treatment of post-operative nausea and vomiting (PONV) in children aged > 1 month.

Osetron 4 mg / 2 ml Solution for Injection / Osetron 8 mg / 4 ml Solution for Injection:

For intravenous injection or after dilution for intravenous infusion.

4.2.1. Chemotherapy and radiotherapy induced nausea and vomiting

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 Osetron should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy

For patients receiving emetogenic chemotherapy or radiotherapy Osetron can be given either by oral or intravenous administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, Osetron 8 mg should be administered as a slow intravenous injection (in not less than 30 seconds) or as a short-time intravenous infusion over 15 minutes immediately before treatment, followed by 8 mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Osetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.

Highly emetogenic chemotherapy

For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, Osetron can be given either by oral, rectal or intravenous administration. Osetron has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:

- A single dose of 8 mg by slow intravenous injection (in not less than 30 seconds) immediately before chemotherapy.

- A dose of 8 mg by slow intravenous injection (in not less than 30 seconds) immediately before chemotherapy, followed by two further intravenous injections (in not less than 30 seconds) of 8 mg four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.

- A maximum initial intravenous dose of 16 mg diluted in 50-100 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes immediately before chemotherapy. The initial dose of Osetron may be followed by two additional 8 mg intravenous doses (in not less than 30 seconds) four hours apart.

A single dose greater than 16 mg must not be given due to dose dependent increase of QT-prolongation risk.

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

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

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

Paediatric population:

Chemotherapy-induced nausea and vomiting (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, Osetron was given by IV infusion diluted in 25 to 50 ml of saline or other compatible infusion fluid and infused over not less than 15 minutes

Osetron injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid and infused intravenously over not less than 15 minutes.

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

Dosing by BSA:

Osetron should be administered immediately before chemotherapy as a single intravenous dose of 5 mg/m2. The single intravenous dose must not exceed 8 mg.

Oral dosing can commence 12 hours later and may be continued for up to 5 days. See Table 1 below.

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 1: BSA-based dosing for Chemotherapy - Children aged >6 months and adolescents

a The intravenous dose must not exceed 8 mg.

b The total dose over 24 hours (given as divided doses) 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.

Osetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15 mg/Kg. The single intravenous dose must not exceed 8 mg.

Two further intravenous doses may be given in 4-hourly intervals.

Oral dosing can commence 12 hours later and may be continued for up to 5 days (see Table 2 below).

The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Table 2: Weight-based dosing for Chemotherapy - Children aged > 6 months and adolescents

a The intravenous dose must not exceed 8 mg.

b The total dose over 24 hours (given as divided doses) must not exceed adult dose of 32 mg.

Elderly:

In patients 65 to 74 years of age, the dose schedule for adults can be followed. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes.

In patients 75 years of age or older, the initial intravenous dose of Osetron should not exceed 8 mg. All intravenous doses should be diluted in 50-100 ml of saline or other compatible infusion fluid and infused over 15 minutes. The initial dose of 8 mg may be followed by two further intravenous doses of 8 mg, infused over 15 minutes and given no less than four hours apart.

Please refer also to 4.2.3 “Special Populations”.

4.2.2. Post-Operative Nausea and Vomiting (PONV)

Adults:

Prevention of PONV

For the prevention of PONV: Osetron can be administered orally or by intravenous injection.

Osetron may be administered as a single dose of 4 mg given by slow intravenous injection at induction of anaesthesia.

For oral administration:

16 mg one hour prior to anaesthesia.

Alternatively, 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.

Treatment of established PONV

For treatment of established PONV: A single dose of 4 mg given by slow intravenous 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 Osetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.

For the treatment of PONV after surgery in paediatric patients having surgery performed under general anaesthesia, a single dose of Osetron may be administered by slow intravenous injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg.

There are no data on the use of Osetron in the treatment of PONV in children below 2 years of age.

Elderly:

There is limited experience in the use of Osetron in the prevention and treatment of PONV in the elderly, however Osetron is well tolerated in patients over 65 years receiving chemotherapy.

Please refer also to 4.2.3 “Special Populations”.

4.2.3. Special Populations

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 Osetron 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 8 mg should not be exceeded and therefore parenteral or oral administration is recommended.

Patients with poor sparteine/Debrisoquine metabolism

The elimination half-life of Osetron 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.

Concomitant use with apomorphine.

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.

Rarely, transient ECG changes including QT interval prolongation have been reported in patients receiving Osetron. Osetron prolongs the QT interval in a dose-dependent manner. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using Osetron. Avoid Osetron in patients with congenital long QT syndrome. Osetron 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.

Caution should also be exercised in patients with cardiac rhythm or conduction disturbances and in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents.

Hypokalemia and hypomagnesemia should be corrected prior to Osetron 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 Osetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with Osetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised.

As Osetron 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 Osetron may mask occult bleeding. Therefore, such patients should be followed carefully after Osetron.

Paediatric Population:

Paediatric patients receiving Osetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.

CINV:

When calculating the dose on a mg/kg basis and administering three doses at 4-hour intervals, the total daily dose will be higher than if one single dose of 5 mg/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.

Excipient:

This medicinal product contains 3.6 mg sodium per ml of solution for injection. To be taken into consideration by patients on a controlled sodium diet.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Osetron has no influence on the ability to drive and use machines.

In psychomotor testing Osetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of Osetron.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and very rare (<1/10,000). 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 Osetron according to indication and formulation.

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 predominantly during rapid IV administration.

Eye Disorders

Rare: Transient visual disturbances (e.g. blurred vision) predominantly during IV administration.

Very rare: Transient blindness predominantly during intravenous administration⁽²⁾.

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 tests ⁽³⁾.

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 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.

Symptoms and Signs

There is limited experience of Osetron overdose, however, a limited number of patients received overdoses. In the majority of cases, symptoms were similar to those already reported in patients receiving recommended doses. 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.

Osetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose.

Treatment

There is no specific antidote for Osetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

The use of ipecacuanha to treat overdose with Osetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of Osetron itself.

Paediatric population

Paediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of Osetron (exceeded estimated ingestion of 4 mg/kg) in infants and children aged 12 months to 2 years.

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT₃) antagonists

ATC Code: A04AA01

Mechanism of Action

Osetron 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. Osetron 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 Osetron 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.

In a pharmaco-psychological study in volunteers Osetron has not shown a sedative effect.

Osetron does not alter plasma prolactin concentrations.

The role of Osetron in opiate-induced emesis is not yet established.

QT prolongation

The effect of Osetron on the QTc interval was evaluated in a double bind, randomised, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Osetron 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 Osetron 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 Osetron 5mg/m² intravenous and Osetron 4 mg orally after 8 to 12 hours or Osetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hours. Post-chemotherapy both groups received 4 mg Osetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49 % (5 mg/m² intravenous and Osetron 4 mg orally) and 41 % (0.45 mg/kg intravenous and placebo orally). Post-chemotherapy both groups received 4 mg Osetron 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 Osetron was administered intravenously at a dose of 5 mg/m² intravenous together with 2 to 4 mg dexamethasone orally

- 71% of patients when Osetron was administered as syrup at a dose of 8 mg together with 2 to 4 mg dexamethasone orally on the days of chemotherapy.

Post-chemotherapy both groups received 4 mg Osetron 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 Osetron in 75 children aged 6 to 48 months was investigated in an open-label, non-comparative, single-arm study (S3A40320). All children receive three 0.15 mg/kg doses of intravenous Osetron, administered 30 minutes before the start of chemotherapy and then at 4 and 8 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 Osetron followed by two oral Osetron doses of 4 mg for children aged < 12 years and 8 mg for children aged >12 years (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients.

PONV

The efficacy of a single dose of Osetron 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 > 3kg). Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status ≤ III. A single dose of Osetron 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 Osetron (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 Osetron (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. Osetron 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

CR = no emetic episodes, rescue or withdrawal

Following oral administration, Osetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in Osetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Mean bioavailability in healthy male subjects, following the oral administration of a single 8 mg tablet, is approximately 55 to 60%. 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 Osetron.

The disposition of Osetron following oral, intramuscular and intravenous dosing in adults 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 intramuscular and intravenous administration of Osetron.

A 4 mg intravenous infusion of Osetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of Osetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.

Following administration of Osetron suppository, plasma Osetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of Osetron. The absolute bioavailability of Osetron from the suppository is approximately 60% and is not affected by gender. The half-life of the elimination phase following suppository administration is determined by the rate of Osetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

Osetron is not highly protein bound (70-76%). Osetron 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 Osetron's pharmacokinetics. The pharmacokinetic properties of Osetron are unchanged on repeat dosing.

Special Patient Populations

Gender

Gender differences were shown in the disposition of Osetron, 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).

Paediatric population

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 patient population aged 1 to 4 months was reported to average 6.7 hours compared to 2.9 hours for the patients in the 5 to 24 months and 3 to 12 year age range. The differences in the pharmacokinetic parameters in the 1 to 4 months 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 Osetron.

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 Osetron 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 age-related changes and is effective in normalising systemic exposure in paediatric patients.

Population pharmacokinetic analysis was performed on 74 paediatric cancer patients aged 6 to 48 months and 41 surgery patients aged 1 to 24 months following intravenous administration of Osetron. Based on the population pharmacokinetic parameters for patients aged 1 month to 48 months, administration of the adult based dose (0.15 mg/kg intravenously every 4 hours for 3 doses) would result in a systemic exposure (AUC) comparable to that observed in paediatric surgery patients (aged 5 to 24 months), paediatric cancer patients (aged 3 to 12 years), at a similar doses. This exposure (AUC) is consistent with the exposure-efficacy relationship described previously in paediatric cancer subjects, which showed a 50% to 90% response rate with AUC values ranging from 170 to 250 ng.h/mL.

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 Osetron. Based on this analysis, systemic exposure (AUC) of Osetron 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.

Elderly

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of Osetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (> 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.

Based on more recent Osetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patients > 75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for IV dosing.

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 Osetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4 hours). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed Osetron's pharmacokinetics to be essentially unchanged following intravenous administration.

Hepatic Impairment

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, Osetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15 to 32 hours) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of Osetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Osetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.

Osetron in submicromolar concentrations blocked cloned HERG Potassium channels of the human heart. The clinical relevance of this finding is not clear.

Osetron injection should not be administered in the same syringe or infusion as any other medication.

Osetron injection should only be mixed with those infusion solutions that are recommended.

For single use only. Any unused solution should be discarded.

The solution should be visually inspected prior to use. Only clear and colourless solutions practically free from particles should be used.

Note: Osetron solution for injection should not be autoclaved.

6.6.1. Compatibility with solutions for infusion

Osetron solution for injection should only be admixed with those infusion solutions which are recommended:

Sodium Chloride 9 mg/ml (0.9%) solution for infusion

Glucose 50 mg/ml (5%) solution for infusion

Mannitol 100 mg/ml (10%) solution for infusion

Ringers solution for infusion

Potassium Chloride 3 mg/ml (0.3%) and Sodium Chloride 9 mg/ml (0.9%) solution for infusion

Potassium Chloride 3 mg/ml (0.3%) and Glucose 50 mg/ml (5%) solution for infusion

In keeping with good pharmaceutical practice, dilutions of Osetron injection in intravenous fluids should be prepared at the time of infusion. 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^oC, unless dilution has taken place in controlled and validated aseptic conditions.

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 I glass bottles. Dilutions of Osetron 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 Osetron injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.

6.6.2. Compatibility with other medicinal products

Dexamethasone-21-dihydrogenphosphate disodium:

Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 16 mg of Osetron diluted in 50-100 ml of a compatible infusion fluid (see 6.6.1 “Compatibility with solutions for infusion”) over approximately 15 minutes.

Osetron may be administered by intravenous infusion by 1 mg/hour. The following medicinal products may be administered only via a Y-site of an infusion set in concentrations of Osetron 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.

Carboplatin:

Concentrations not exceeding the range of 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.

5 -Fluorouracil:

Concentrations up to 0.8 mg/ml (e.g. 2.4 g in 3 litres or 400 mg in 500 ml) 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 Osetron. The 5-fluorouracil infusion may contain up to 0.045%w/v magnesium chloride in addition to other excipients shown to be compatible.

Etoposide:

Concentrations not exceeding the range of 0.144 mg/ml to 0.250 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 of 250 mg to 2000 mg reconstituted with water for injections as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2 g ceftazidime) and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide:

Doses in the range of 100 mg to 1 g, reconstituted with water for injections, 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 of 10 mg to 100 mg reconstituted with water for injections, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.