Ondansetron Tablets IP 4 mg

Each film coated tablet contains:

Ondansetron Hydrochloride IP

equivalent to Ondansetron 4 mg.

Excipients q.s.

Colour: Titanium Dioxide IP.

Tablet.

4 mg.

4.1.Therapeutic indication

Emigo®-4 Tablets is indicated for the treatment and management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.

Ondansetron is indicated for the prevention and treatment of post-operative nausea and vomiting (PONV). For treatment of established PONV, administration by injection is recommended.

4.2.Posology and method of administration

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 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 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy: Ondansetron can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration, using either Ondansetron 4 mg and 8 mg Tablets or other commercially-available ondansetron presentations.

For oral administration: 8 mg taken 1-2 hours before chemotherapy or radiation treatment, followed by 8 mg every 12 hours for a maximum of 5 days to protect against delayed or prolonged emesis.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron 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 (e.g., high-dose cisplatin): Ondansetron can be given either by rectal, intravenous or intramuscular administration, using other commercially-available ondansetron presentations.

A single dose of up to 24 mg ondansetron taken with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy, may be used.

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

The recommended dose for oral administration is 8 mg twice daily.

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. In paediatric clinical studies, ondansetron 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.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron injections 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 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 single 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 dose over twenty-four 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 daily dose over 24 hours (given as divided doses) must not exceed the adult dose of 32 mg.

Dosing by bodyweight

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron 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.

The total dose over twenty-four hours (given as divided doses) 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: 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 twenty-four hours (given as divided doses) must not exceed adult dose of 32 mg.

Elderly

Ondansetron is well tolerated by patients over 65 years and no alteration of oral dose 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 8 mg 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 is required.

Post-operative nausea and vomiting (PONV)

Adults

For the prevention of PONV: Ondansetron can be administered orally or by intravenous or intramuscular injection. For oral administration: 16 mg taken 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.

For the treatment of established PONV: Intravenous or intramuscular administration is recommended.

Paediatric population

PONV in children aged ≥ 1 month and adolescents

Oral formulation

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow IV injection (not less than 30 seconds) is recommended for this purpose.

Injection

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron 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 ondansetron 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 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 post-operative nausea and vomiting 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 8 mg 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 is required.

4.3.Contraindications

Concomitant use with apomorphine.

Hypersensitivity to the active substance 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. 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. In addition, post-marketing 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 hypomagnesaemia 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 subacute 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 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.

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

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol. Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. 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 compensated by 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 co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities. 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 trastuzumab), 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.

Serotonergic Drugs (e.g. SSRIs and SNRIs): 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 SSRIs and SNRIs). Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

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.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations, when administered during the first trimester of pregnancy. In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10,000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)). The available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Ondansetron should not be used during the first trimester of pregnancy.

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

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 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) 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 have been observed without definitive evidence of persistent clinical sequelae.

Rare: Dizziness predominantly during rapid IV administration, which in most cases is prevented or resolved by lengthening the infusion period.

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: 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#.

# These events were observed commonly in patients receiving chemotherapy with cisplatin.

Paediatric population

The adverse event profile in children and adolescents was 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 email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

Symptoms

There is limited experience of ondansetron overdose. 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.

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

Management

There is no specific antidote for ondansetron, therefore in 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 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.

5.1 Pharmacodynamic properties

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 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. Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opiate-induced emesis is not yet established

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.

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 + ondansetron 4 mg orally after 8-12 hours or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hours. 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 + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous + 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 open-label, non-comparative, 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 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 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.l 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

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 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg 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. 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 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 140 L. Equivalent systemic exposures is achieved after IM and IV administration of ondansetron. A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/mL. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/mL are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron 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 ondansetron. The absolute bioavailability of ondansetron 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 ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

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 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 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 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 (5.4 hours). 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

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. 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 ondansetron 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 intravenous dosing. Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the half-life of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

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 hours) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

No additional data of relevance.

The active ingredient in Emigo®-4 Tablets is ondansetron hydrochloride, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type.

1.Incompatibilities

Not applicable

2.Shelf-life

Refer on pack

3.Packaging information

10 Strips of 10 tablets each

4.Storage and handing instructions

Store below 30°C. Protected from light & moisture Keep out of reach of children.

QT Prolongation

Inform patients that Emigo®-4 Tablets may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Hypersensitivity Reactions

Inform patients that Emigo®-4 Tablets may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider.

Masking of Progressive Ileus and Gastric Distension

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that Emigo®-4 Tablets may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions

• Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and Emigo®-4 Tablets may cause a significant drop in blood pressure and loss of consciousness.
• Advise patients of the possibility of serotonin syndrome with concomitant use of Emigo®-4 Tablets and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Calcitriol, Omega-3 Acids, Mecobalamin, Folic Acid, Boron & Calcium Capsules

Each soft gelatin capsule contains:

Calcitriol IP 0.25 mcg

Omega-3 Acids BP containing:

Eicosapentaenoic Acid 180 mg

Docosahexaenoic Acid 120 mg

Mecobalamin IP 1500 mcg

Folic Acid IP 400 mcg

Boron 1.5 mg

(As Disodium Tetraborate BP)

Calcium Carbonate IP 500 mg

equivalent to Elemental Calcium 200 mg

Excipients q.s.

Approved colours used in the capsule shells.

Soft Gelatin Capsule

Calcitriol (0.25 mcg), Omega-3 Acids (EPA 180 mg, DHA120 mg), Mecobalamin (1500 mcg), Folic Acid (400 mcg), Boron (1.5 mg), Calcium (200 mg).

4.1 Therapeutic indication

For the treatment:

• hypocalcaemia and/or osteoporosis.
• vitamin and calcium deficiency states in adults
• post-menopausal osteoporosis

4.2 Posology and method of administration

Average adult dose is 1 capsule once daily. For treatment of post-menopausal osteoporosis: 1 capsule twice daily. Eucalmin® capsules are for oral administration only.

4.3 Contraindications

Eucalmin® capsules is contraindicated:

• in patients with known hypersensitivity to calcitriol (or drugs of the same class) and any of the component.
• in all diseases associated with hypercalcaemia for example from myeloma, bone metastases or other malignant bone disease, sarcoidosis; primary hyperparathyroidism and vitamin D overdosage.
• Severe renal failure.
• in patients with evidence of metastatic calcification
• if there is evidence of vitamin D toxicity.
• hypervitaminosis from any vitamin contained in this formulation,
• Relative contraindications are osteoporosis due to prolonged immobilisation, renal stones, severe hypercalciuria.
• If allergic to fish oil, as Eucalmin® capsules contains (Omega-3 acids).

4.4 Special warnings and precautions for use

There is a close correlation between treatment with calcitriol and the development of hypercalcaemia.

All other vitamin D compounds and their derivatives, including proprietary compounds or foodstuffs which may be “fortified” with vitamin D, should be withheld during treatment with Eucalmin® capsules.

An abrupt increase in calcium intake as a result of changes in diet (e.g. increased consumption of dairy products) or uncontrolled intake of calcium preparations may trigger hypercalcaemia. Patients and their families should be advised that strict adherence to the prescribed diet is mandatory and they should be instructed on how to recognise the symptoms of hypercalcaemia.

As soon as the serum calcium levels rise to 1 mg/100 ml (250 µ mol/l) above normal (9-11 mg/100 ml or 2250-2750 µ mol/l), or serum creatinine rises to >120 µ mol/l, treatment with Eucalmin® capsules should be stopped immediately until normocalcaemia ensues.

Immobilised patients, e.g. those who have undergone surgery, are particularly exposed to the risk of hypercalcaemia.

Calcitriol increases inorganic phosphate levels in serum. While this is desirable in patients with hypophosphataemia, caution is called for in patients with renal failure because of the danger of ectopic calcification. In such cases, the plasma phosphate level should be maintained at the normal level (2-5 mg/100 ml or 0.65-1.62 mmol/l) by the oral administration of appropriate phosphate-binding agents and low phosphate diet.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dl2.

Patients with vitamin D-resistant rickets (familial hypophosphataemia) who are being treated with Eucalmin® capsules must continue their oral phosphate therapy. However, possible stimulation of intestinal absorption of phosphate by Eucalmin® capsules should be taken into account since this effect may modify the need for phosphate supplementation.

Since calcitriol is the most effective vitamin D metabolite available, no other vitamin D preparation should be prescribed during treatment with Eucalmin® capsules, thereby ensuring that the development of hypervitaminosis D is avoided.

If the patient is switched from a long acting vitamin D preparation (e.g. ergocalciferol (vitamin D2) or colecalciferol) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value, thereby increasing the risk of hypercalcaemia.

Patients with normal renal function who are taking Eucalmin® capsules should avoid dehydration. Adequate fluid intake should be maintained.

In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.

4.5 Drugs interactions

Calcium and Calcitriol

• Dietary instructions, especially concerning calcium supplements, should be strictly observed, and uncontrolled intake of additional calcium-containing preparations avoided.
• Concomitant treatment with a thiazide diuretic increases the risk of hypercalcaemia. Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcaemia in such patients may precipitate cardiac arrhythmias (see section 4.4).
• A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it.
• Magnesium-containing drugs (e.g. antacids) may cause hypermagnesaemia and should therefore not be taken during therapy with Eucalmin® capsules by patients on chronic renal dialysis.
• Since Eucalmin® capsules also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration (normal values: 2-5 mg/100 ml, or 0.65-1.62 mmol/l).
• Patients with vitamin D-resistant rickets (familial hypophosphataemia) should continue their oral phosphate therapy. However, possible stimulation of intestinal phosphate absorption by calcitriol should be taken into account since this effect may modify the requirement for phosphate supplements.
• Bile acid sequestrants including cholestyramine and sevelamer can reduce intestinal absorption of fat-soluble vitamins and therefore may impair intestinal absorption of calcitriol.
• Certain antiretroviral agents: Decreased vitamin D levels have been associated with, e.g., efavirenz and zidovudine. Decreased formation of the active vitamin D metabolite has been associated with protease inhibitors.

Folic acid

• Anticonvulsants (phenytoin, fosphenytoin, phenobarbital, primidone): Folic acid supplementation can decrease the anticonvulsant serum concentration and increase seizure risk.
• Aspirin (high dose therapy): Can reduce folic acid levels by increasing urinary excretion
• Certain anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, valproate): Can cause folate, pyridoxine and vitamin D deficiencies
• Folate antagonists, e.g., methotrexate, sulfasalazine, pyrimethamine, triamterene, trimethoprim, and high doses of tea catechins: Block the conversion of folate to its active metabolites and reduce the effectiveness of supplementation
• Folate antimetabolites (methotrexate, raltitrexed): Folic acid supplementation can decrease the antimetabolite effects

Mecobalamin

Chloramphenicol: Can inhibit the haematological response to vitamin B12 therapy.

Omega-3 fatty acids

Omega-3 fatty acids can interact with several medications, which may affect their efficacy or increase the risk of side effects:

• Anticoagulants and Antiplatelet Drugs: Omega-3s can enhance the effects of blood-thinning medications like warfarin (Coumadin) and aspirin, increasing the risk of bleeding.
• Blood Pressure Medications: Omega-3 supplements might slightly lower blood pressure, which can enhance the effects of antihypertensive drugs, potentially leading to hypotension.
• Contraceptive Drugs: Some studies suggest that contraceptive drugs may reduce the effectiveness of omega-3 supplements.
• Orlistat: This weight-loss medication can reduce the absorption of omega-3 fatty acids.
• Vitamin E: Taking omega-3 supplements can reduce vitamin E levels in the body.

Boron

Boron is generally considered safe and does not have many known drug interactions. However, there are a few mild interactions to be aware of:

• Estrogens: Boron can interact with various forms of estrogen, including conjugated estrogens, estradiol, and synthetic Estrogens.
• Hormone Replacement Therapy: boron might affect the levels of hormones in body.

4.6 Use in special populations

Pregnancy

The safety of Eucalmin® capsules during pregnancy has not been established.

Supravalvular aortic stenosis has been produced in foetuses by near-fatal oral doses of vitamin D in pregnant rabbits. There is no evidence to suggest that vitamin D is teratogenic in humans even at very high doses. Eucalmin® capsules should be used during pregnancy only if the benefits outweigh the potential risk to the foetus.

Breast-feeding

It should be assumed that exogenous calcitriol passes into breast milk. In view of the potential for hypercalcaemia in the mother and for adverse reactions from Eucalmin® capsules in nursing infants, mothers may breastfeed while taking Eucalmin® capsules, provided that the serum calcium levels of the mother and infant are monitored.

4.7 Effects on ability to drive and use machines

On the basis of the pharmacodynamic profile of reported adverse events, this product is presumed to be safe or unlikely to adversely affect such activities.

4.8 Undesirable effects

The adverse reactions listed below reflect the experience from investigational studies of Eucalmin® capsules, and the post-marketing experience.

The most commonly reported adverse reaction was hypercalcaemia.

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: 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); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Since calcitriol exerts vitamin D activity, adverse effects may occur which are similar to those found when an excessive dose of vitamin D is taken, i.e. hypercalcaemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcaemia).

Occasional acute symptoms include decreased appetite, headache, nausea, vomiting, abdominal pain or abdominal pain upper and constipation.

Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalisation of elevated serum calcium within a few days of treatment withdrawal, i.e. much faster than in treatment with vitamin D3 preparations.

Chronic effects may include muscular weakness, weight decreased, sensory disturbances, pyrexia, thirst, polydipsia, polyuria, dehydration, apathy, growth retardation and urinary tract infections.

In concurrent hypercalcaemia and hyperphosphataemia of > 6 mg/100 ml or > 1.9 mmol/l, calcinosis may occur; this can be seen radiographically.

Hypersensitivity reactions including rash, erythema, pruritus and urticaria may occur in susceptible individuals.

Laboratory Abnormalities

In patients with normal renal function, chronic hypercalcaemia may be associated with a blood creatinine increase.

Post Marketing

The number of adverse effects reported from clinical use of Eucalmin® capsules in all indications is very low with each individual effect, including hypercalcaemia, occurring at a rate of 0.001 % or less.

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 email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Treatment of asymptomatic hypercalcaemia.

Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as for an overdose of vitamin D. Intake of high doses of calcium and phosphate together with Eucalmin® capsules may give rise to similar symptoms. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2 / dl2. A high calcium level in the dialysate may contribute to the development of hypercalcaemia.

Acute symptoms of vitamin D intoxication: anorexia, headache, vomiting, constipation.

Chronic symptoms: dystrophy (weakness, loss of weight), sensory disturbances, possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary tract infections. Hypercalcaemia ensues, with metastatic calcification of the renal cortex, myocardium, lungs and pancreas.

The following measures should be considered in treatment of accidental overdosage: immediate gastric lavage or induction of vomiting to prevent further absorption. Administration of liquid paraffin to promote faecal excretion. Repeated serum calcium determinations are advisable. If elevated calcium levels persist in the serum, phosphates and corticosteroids may be administered and measures instituted to bring about adequate diuresis.

Hypercalcaemia at higher levels (>3.2 mmol/L) may lead to renal insufficiency particularly if blood phosphate levels are normal or elevated due to impaired renal function.

Should hypercalcaemia occur following prolonged treatment, Eucalmin® capsules should be discontinued until plasma calcium levels have returned to normal. A low-calcium diet will speed this reversal. Eucalmin® capsules can then be restarted at a lower dose or given in the same dose but at less frequent intervals than previously.

In patients treated by intermittent haemodialysis, a low concentration of calcium in the dialysate may also be used. However, a high concentration of calcium in the dialysate may contribute to the development of hypercalcaemia.

5.1 Pharmacodynamic properties

Calcitriol

Calcitriol, the active form of vitamin D, works by binding to the vitamin D receptor (VDR) in various tissues such as the intestines, kidneys, and bones. This active form of vitamin D3, crucial for stimulating intestinal calcium transport and regulating bone mineralization.

-Calcitriol enhances the absorption of calcium and phosphate from the gastrointestinal tract. -It increases the reabsorption of calcium in the kidneys, reducing calcium loss through urine. -Calcitriol stimulates the release of calcium from bones into the bloodstream. -By binding to VDR, calcitriol acts as a transcription factor, regulating the expression of various genes involved in calcium and phosphate metabolism. This multi-faceted approach helps maintain adequate calcium levels in the blood, which is crucial for various bodily functions, including bone health and muscle function.

In osteoporosis, calcitriol enhances calcium absorption, increases circulating calcitriol levels, and reduces vertebral fracture frequency. Its effects onset and reversal are quicker than other vitamin D compounds, allowing for more precise dosage adjustments and easier management of potential overdosage.

Calcium Carbonate

Calcium is the most abundant mineral in the body. The major function of calcium is in the formation of the major inorganic bone component, hydroxyapatite. Approximately 60% of the weight of bone is due to the presence of calcium-rich mineral deposits. During menopause calcium absorption is decreased. If this calcium is not replaced by the dietary supply, plasma calcium is maintained by resorption of bone under the action of parathyroid hormone (PTH). If there is a continual low intake of calcium, or if intestinal absorption is impaired over a prolonged period, bone resorption will cause a severe decrease in bone mass and this dietary imbalance, together with a number of other factors, contributes to an increased risk of osteoporosis.

Various interventional studies which used a combined calcium and vitamin D, improves bone mineral density (BMD), reduces fracture risk, improves muscle strength there by reducing frequent falls.

Omega-3 Acids (Eicosapentaenoic Acid, Docosahexaenoic Acid)

Polyunsaturated fatty acids (PUFAs), specifically linoleic acid (n-6) and alpha-linolenic acid (n-3), are essential for human growth and function. Only plants and some fish can synthesize these fatty acids from shorter chain fats. While vegetable oils and dairy fats contain short- and medium-chain fatty acids, fish oils and certain plants are rich in n-3 fatty acids.

Omega-3 Acids (ω-3 PUFAs) are believed to support bone health through several mechanisms, including reducing inflammatory cytokines, modulating prostaglandin E2 (PGE2) production, enhancing calcium transport, and decreasing urinary calcium excretion. Research indicates that EPA and DHA can inhibit bone loss and resorption, increase calcium absorption, and improve bone mineral density (BMD).

Additionally, Omega-3 Acids may serve as competitive inhibitors in eicosanoid biosynthesis, leading to lower production of pro-inflammatory cytokines, particularly in conditions like rheumatoid arthritis. Studies show that n-3 PUFA supplements can have beneficial effects on joint diseases by suppressing pro-inflammatory factors like IL-1, IL-2, and TNF in cartilage tissue.

Mecobalamin and Folic acid

Elevated homocysteine levels and low vitamin B12 and folate status are linked to lower bone mass and higher fracture risk in both independent and frail elderly individuals. Vitamin B12 stimulates osteoblast proliferation and is crucial for their maturation. In contrast, high homocysteine can lead to skeletal abnormalities and decreased bone mineral density (BMD) by disrupting collagen cross-linking, which is essential for bone strength.

Research indicates a stronger relationship between serum folate levels and BMD compared to other osteoporosis risk factors. Low folate often reflects an inadequate diet, leading to deficiencies in nutrients necessary for bone mineralization. Folate is vital for various cellular processes, including DNA protection and reducing oxidative stress.

Combining folate and vitamin B12 supplementation is considered a safe and effective approach to lowering fracture risk in elderly patients.

Boron

Boron, a trace metalloid, is found in high levels in plant-based foods like dried fruits, nuts, and leafy greens. Daily boron needs likely range from 1 to 20 mg, influenced by factors like stress and the intake of other minerals. It plays a role in calcium and magnesium metabolism and is concentrated in bone, spleen, and thyroid, suggesting its importance in bone health and hormone regulation.

Low boron diets are linked to reduced testosterone levels, and supplements may enhance testosterone and estradiol levels, particularly in postmenopausal women. Boron is often marketed to athletes and bodybuilders for its potential benefits in increasing testosterone, muscle mass, and strength. Additionally, boron supplementation can reduce urinary losses of essential minerals like calcium, zinc, and magnesium, which may help combat bone demineralization in conditions like osteoporosis and osteoarthritis.

Boron is particularly significant when dietary vitamin D is insufficient, supporting optimal bone health and metabolic functions.

5.3 Pharmacokinetic properties

Calcitriol

Absorption: Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations following a single oral dose of 0.25-1µ g Calcitriol in healthy subjects were found within 2-6 hours. After a single oral dose of 0.5 mcg Calcitriol in healthy subjects, the average serum concentrations of calcitriol rose from a baseline value of 40.0 ± 4.4 pg/ml to 60.0 ± 4.4 pg/ml after two hours, and then fell to 53.0 ± 6.9 after four hours, to 50.0 ± 7.0 after eight hours, to 44 ± 4.6 after twelve hours and to 41.5 ± 5.1 pg/ml after 24 hours.

Distribution: During transport in the blood at physiological concentrations, calcitriol is mostly bound to a specific vitamin D binding protein (DBP), but also, to a lesser degree, to lipoproteins and albumin. At higher blood calcitriol concentrations, DBP appears to become saturated, and increased binding to lipoproteins and albumin occurs.

Biotransformation: Calcitriol is hydroxylated and oxidised in the kidney and in the liver by a specific cytochrome P450 enzyme: CYP24A1. Several metabolites with different degrees of vitamin D activity have been identified.

Elimination: The elimination half-life of calcitriol in plasma ranges between 5 to 8 hours. However, the pharmacological effect of a single dose of calcitriol lasts at least 4 days. The elimination and absorption kinetics of calcitriol remain linear in a very broad dose range and up to 165 µ g single oral dose. Calcitriol is excreted in the bile and may undergo an enterohepatic circulation.

Mecobalamin

Vitamin B12 is extensively bound to specific plasma proteins called transcobalamins; transcobalamin II appears to be involved in the rapid transport of the cobalamins to tissues.

Vitamin B12 diffuses across the placenta and also appears in breast milk. Vitamin B12 is stored in the liver, excreted in the bile, and undergoes extensive enterohepatic recycling. Part of a dose is excreted in the urine, most of it in the first 8 hours; urinary excretion, however, accounts for only a small fraction in the reduction of total body stores acquired by dietary means.

Folic Acid

Folic acid is converted to the metabolically active form 5-methyltetrahydrofolate in the plasma and liver. Folate is distributed into breast milk. The principal storage site of folate is the liver; it is also actively concentrated in the CSF. Folate undergoes enterohepatic circulation. Folate metabolites are eliminated in the urine and folate in excess of body requirements is excreted unchanged in the urine.

Boron

Absorption: Boron compounds, such as boric acid, are readily and completely absorbed when administered orally. Distribution: Once absorbed, boron is distributed throughout the body water via passive diffusion. It tends to accumulate in tissues like the liver, kidneys, and bones. Metabolism: Boron is not significantly metabolized in the body. It remains largely in its original form. Excretion: Boron is primarily excreted through the urine. The elimination half-life can vary, but it is generally rapid, with boron being cleared from the blood within hours

Omega-3 fatty acids

The pharmacokinetics of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), involve several key processes: Absorption: Omega-3 fatty acids are absorbed in the small intestine. They are typically ingested as triglycerides or ethyl esters, which are then hydrolyzed by pancreatic lipase to free fatty acids and monoglycerides.

Distribution: After absorption, omega-3 fatty acids are incorporated into chylomicrons and transported via the lymphatic system into the bloodstream. They are then distributed to various tissues, including the liver, heart, brain, and adipose tissue. Metabolism: In the liver, omega-3 fatty acids undergo beta-oxidation to produce energy or are re-esterified into triglycerides and phospholipids. They can also be converted into bioactive metabolites like eicosanoids, resolvins, and protectins, which have anti-inflammatory and cardioprotective effects.

Excretion: Omega-3 fatty acids and their metabolites are primarily excreted via the urine. Some are also excreted in the feces. Bioavailability: The bioavailability of omega-3 fatty acids can be influenced by factors such as the form of the supplement (triglyceride or ethyl ester), the presence of other dietary fats, and individual differences in digestion and absorption.

6.1 Animal Toxicology or Pharmacology

Subchronic toxicity studies in rats and dogs indicated that calcitriol at an oral dose of 20 ng/kg/day (twice the usual human dosage) for up to 6 months produced no or minimal adverse effects. A dose of 80 ng/kg/day (8 times the usual human dosage) for up to 6 months produced moderate adverse effects; changes seen appeared to be primarily the result of prolonged hypercalcaemia.

Reproductive toxicity studies in rats indicated that oral doses up to 300 ng/kg/day (30 times the usual human dose) did not adversely affect reproduction. In rabbits, multiple foetal abnormalities were observed in two litters at an oral maternally toxic dose of 300 ng/kg/day and one litter at 80 ng/kg/day, but not at 20 ng/kg/day (twice the usual human dose). Although there were no statistically significant differences between treated groups and controls in the numbers of litters or foetuses showing abnormalities, the possibility that these findings were due to calcitriol administration could not be discounted.

Calcitriol is a synthetic vitamin D analog which is active in the regulation of the absorption of calcium from the gastrointestinal tract and its utilization in the body. It has a calculated molecular weight of 416.65.

Chemically, calcitriol is 9, 10-seco(5Z,7E)-5,7,10(19) cholestatriene-1α, 3β, 25-triol and has the following structural formula:

Calcium Carbonate

Methylcobalamin appears as dark red crystals or crystalline powder. It is sparingly soluble in water, slightly soluble in ethanol and practically insoluble in acetonitrile.

Molecular Weight: 1344.38 g/mol.

Molecular Formula: C₆₃H₉₁C_oN₁₃O₁₄P.

Chemical Name: Methyl-5, 6-dimethylbenzimidazolylcobalamin

Folic acid

Folic acid is a yellow, yellow-brownish, or yellowish orange, odourless crystalline powder.

Very slightly soluble in water; insoluble in alcohol, in acetone, in chloroform, and in ether. Molecular Weight: 441.40 g/mol. Molecular Formula: C19H19N7O6. Chemical Name: (2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino} phenyl) formamido] pentanedioic acid.

Structural Formula:

Boron

Disodium tetraborate, commonly known as borax, is a boron compound with the chemical formula Na_₂B_₄O_₇·10H_₂O. It is a white, powdery substance that dissolves in water to form a basic solution.

Omega-3 fatty acids

Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs) with a double bond at the third carbon atom from the end of the carbon chain.

Omega-3 Fatty Acid is any fatty acid that contains an unsaturated bond originating from the 3rd carbon from the methyl end. Omega-3 fatty acids do not occur naturally with chain lengths shorter than 16 carbon units.

The three types of omega-3 fatty acids involved in human physiology are α-linolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (both commonly found in fish oil that originally come from microalgae that is further consumed by phytoplankton, a source of diet for fish).

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack

8.3 Packaging information

1 Blister strip of 10 capsules

8.4 Storage and handing instructions

Store protected from light and moisture at a temperature not exceeding 25°C. Keep out of reach of children.

• Capsule should be swallowed whole and not to be opened, chewed or crushed.
• The patient and his or her parents or spouse should be informed about compliance with dosage instructions, adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs. Patients should also be carefully informed about the symptoms of hypercalcemia.
• The effectiveness of Eucalmin® capsules therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg.

26th September 2024

Ondansetron Oral Solution IP 2 mg/5 ml

Each 5 ml contains:

Ondansetron Hydrochloride IP

Equivalent to Ondansetron 2mg

Excipients q.s.

In a flavoured syrupy base

Oral Solution.

2 mg/5 ml

FOR PAEDIATRIC USE.

4.1.Therapeutic indication

For chemotherapeutic induced nausea and vomiting.

4.2.Posology and method of administration

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 and infused over not less than 15 minutes.

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

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 single intravenous dose must not exceed 8 mg. Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 1). 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.

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. Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 2). 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 hrs (divided doses) must not exceed adult dose of 32 mg.

Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting

For both indications:

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 drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.

4.3.Contraindications

Concomitant use with apomorphine. Hypersensitivity to the active substance or to other selective 5-HT3 receptor antagonists (e.g. granisetron, dolasetron) 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. 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. In addition, post-marketing 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 hypomagnesaemia 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 subacute 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 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.

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

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, morphine, lignocaine, propofol, and thiopental.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. 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 compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.

Phenytoin, Carbamezapine 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. Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

Caution should be exercised when ondansetron is co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities. (See section 4.4). Use with 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 trastuzumab), 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 (section 4.4).

Serotonergic Drugs (e.g. SSRIs and SNRIs): 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 SSRIs and SNRIs).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations, when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10,000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)).

The available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

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

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 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) 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 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⁾

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.

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 email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

Symptoms and Signs

Little is known at present about overdosage with ondansetron. 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.

Ondansetron prolongs the QT interval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.

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.

Treatment

There is no specific antidote for ondansetron, 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 ondansetron is not recommended, as patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

5.1.Pharmacodynamic properties

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 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.

Ondansetron does not alter plasma prolactin concentrations.

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

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.

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 + ondansetron 4 mg orally after 8-12 hours or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hours. 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 + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous + 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 open-label, non-comparative, 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 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 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.l 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

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 30 mg/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg 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.

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.

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 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron. A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/mL. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/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

Gender

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).

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 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 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.

Elderly

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. 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 ondansetron 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 intravenous 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 ondansetron, 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 ondansetron's pharmacokinetics to be essentially unchanged following IV 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.

No additional data of relevance.

The active ingredient in EMIGO® Oral Soultion is ondansetron hydrochloride, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type.

8.1.Incompatibilities

Not applicable

8.2.Shelf-life

Refer on pack

8.3.Packaging information

30 ml

8.4.Storage and handing instructions

Store protected from light at a temperature not exceeding 30°C.

Keep out of reach of children.

SHAKE WELL BEFORE USE.

FOR PAEDIATRIC USE.

QT Prolongation

Inform patients that EMIGO® may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Hypersensitivity Reactions

Inform patients that EMIGO® may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider.

Masking of Progressive Ileus and Gastric Distension

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that EMIGO® may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions

• Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and EMIGO® may cause a significant drop in blood pressure and loss of consciousness.
• Advise patients of the possibility of serotonin syndrome with concomitant use of EMIGO® and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Each uncoated tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 2.5 mg

Losartan Potassium IP 50 mg

Excipients q.s.

Colour : Lake of Quinoline Yellow

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ ml in 2.73 ± 0.88 hrs (Tmax). Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC0-t value (t=48 hrs.) of tablet S (-) Amlodipine (2.5 mg) is 95.33 ± 14.45 ng.hr/ml. The AUC0-∞ value is recorded to be 140.91± 28.06 ng.hr/ml. The plasma elimination half-life of S (-) Amlodipine has been found to be 31.09 ± 12.65 hrs. Following oral administration, Losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of Losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. Both Losartan and its active metabolite are ≥ 99% bound to plasma proteins, primarily albumin. The volume of distribution of Losartan is 34 litres.

About 14% of an intravenously or orally-administered dose of Losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled Losartan Potassium, circulating plasma radioactivity primarily is attributed to Losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied. In addition to the active metabolite, inactive metabolites are formed Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of Losartan and its active metabolite is about 74 ml/min and 26 ml/min, respectively. When Losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral Losartan Potassium doses up to 200 mg. Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6 -9 hours, respectively. During once-daily dosing with 100 mg, neither Losartan nor its active metabolite accumulates significantly in plasma. 14 Both biliary and urinary excretion contribute to the elimination of Losartan and its metabolites. Following an oral dose of C-labelled losartan in man, about 35% / 43% of radioactivity is recovered in the urine and 58% / 50% in the faeces.

For the treatment of hypertension

Contraindications :

Hypersensitivity to any of the components of the formulation.

Owing to the absence of human data, the combination should not be administered to pregnant women.

Dosage and Administration :

One tablet to be taken orally, once daily.

Gingival hypertrophy and alopecia has been seen with S (-) Amlodipine. On the basis of the clinical data available, only minor side effects have been reported with the use of S (-) Amlodipine. On the basis of clinical data available, adverse events reported in less than 5% of the patients included anxiety (0.43%), anorexia (0.43%), irritation (0.43%), headache (2.13%) and facial flushing (2.13%). Caution should be exercised when administering S (-) Amlodipine to patients with impaired hepatic and renal function.

Common adverse events seen with Losartan are as follows : dizziness, muscle spasm, somnolence, headache, sleep disorders, palpitations, angina pectoris, symptomatic hypotension (especially in patients with intravascular volume depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics), orthostatic hypotension (including dose-related orthostatic effects), rash, abdominal pain, obstipation, vertigo, asthenia, fatigue, oedema, hyperkalemia

Clinical studies have shown that S (-) Amlodipine when combined with aspirin, nitrates, beta-blockers, statins, ACE inhibitors, H blockers, and Proton Pump Inhibitors 2 produced no drug interactions. No drug interaction has reported the use of Losartan.

Hepatic impairment and renal impairment

No controlled clinical study of S (-) Amlodipine has been performed in patients with hepatic impairment and renal impairment. Clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine. Losartan achieves significantly higher plasma concentrations in cirrhotic patients. Hence, caution should be taken while administering the combination to such patients.

Nursing Mothers

There is no data available on the use of S (-) Amlodipine in lactating women. Atenolol has been successfully used in pregnant patients. Hence, the combination should be administered only when the potential benefits outweighs the risk to the patient.

Children

Safety and effectiveness of this product in children has not been established.

Overdosage with racemic Amlodipine and Losartan may cause excessive peripheral vasodilation with marked hypotension possibly a reflex tachycardia and bradycardia. Hence, caution should be taken in case of an overdosage with Eslo Tan tablet. If massive overdose occurs, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements should be performed. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as Phenylephrine) should be considered with attention to circulating volume and urine output. If massive overdose occurs, gastric lavage should be employed. As this product is highly plasma protein bound, hemodialysis is not likely to be of benefit.

Store below 30°C. Protect from light & moisture.

Keep out of reach of children.

Refer on the pack

PVC/PVDC-Alu blister strip of 10 tablets

Ondansetron IP

Each uncoated orally disintegrating tablet contains:

Ondansetron IP 4 mg.

Excipients q.s.

Colour: Lake Erythrosine.

Orally disintegrating (Mouth Dissolving) tablet 4 mg.

4.1. Therapeutic indication

Adults:

Emigo®-MD Tablets is indicated in adults for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. Emigo®-MD Tablets is indicated for the prevention of post-operative nausea and vomiting (PONV).

Paediatric Population:

Emigo®-MD Tablets is indicated in children aged ≥6 months for the management of chemotherapy-induced nausea and vomiting (CINV).

No studies have been conducted on the use of orally administered ondansetron in the prevention and treatment of PONV in children aged ≥1 month, administration by IV injection is recommended for this purpose.

4.2. Posology and method of administration

Place the mouth dissolving tablet on top of the tongue, where it will disperse within seconds, then swallow.

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

Emetogenic chemotherapy and radiotherapy:

Ondansetron can be given either by rectal, oral (as a mouth dissolving tablet), intravenous, or intramuscular administration.

For oral administration: 8 mg taken 1 to 2 hours before chemotherapy or radiation treatment, followed by 8 mg every 12 hours for a maximum of 5 days to protect against delayed or prolonged emesis.

For highly emetogenic chemotherapy:

A single dose of up to 24 mg Ondansetron taken with 12 mg oral dexamethasone sodium phosphate, 1 to 2 hours before chemotherapy, may be used. To protect against delayed or prolonged emesis after the first 24 hours, treatment with Ondansetron may be continued for up to 5 days after a course of treatment. The recommended dose is 8 mg to be taken twice daily.

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 and infused over not less than 15 minutes. Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

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 single intravenous dose must not exceed 8 mg. Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 1).

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 8mg.

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

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15mg/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 (Table 2).

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

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

a. The intravenous dose must not exceed 8mg.

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

Elderly:

No alteration of oral dose or frequency of administration is required.

Post-operative nausea and vomiting (PONV)

Adults:

For the prevention of PONV: Ondansetron may be administered either orally (as an mouth dissolving tablet) or by intravenous or intramuscular injection. For oral administration: 16 mg taken one hour prior to anaesthesia. For the treatment of established PONV: Intravenous or intramuscular administration is recommended.

Paediatric population:

PONV in children aged ≥ 1 month and adolescents

Oral formulation:

No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting; slow IV injection (not less than 30 seconds) is recommended for this purpose.

Injection:

For prevention of PONV in paediatric patients having surgery performed under general 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 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 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.

For both indications

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 drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.

4.3. Contraindications

Concomitant use with apomorphine.

Hypersensitivity to the active substance 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. 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. In addition, post-marketing 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 hypomagnesaemia 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 subacute 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 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.

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

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental or propofol. Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. 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 compensated by 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 co-administered with drugs that prolong the QT interval and/or cause electrolyte abnormalities. 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 trastuzumab), 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.

Serotonergic Drugs (e.g. SSRIs and SNRIs): 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 SSRIs and SNRIs). Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.

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. Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of contraception.

Pregnancy

Based on human experience from epidemiological studies, ondansetron is suspected to cause orofacial malformations, when administered during the first trimester of pregnancy.

In one cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10,000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)). The available epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Ondansetron should not be used during the first trimester of pregnancy.

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

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 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) 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.

The following frequencies are estimated at the standard recommended doses of ondansetron. The adverse event profiles in children and adolescents were comparable to that seen in adults.

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.

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 email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9. Overdose

Symptoms

There is limited experience of ondansetron overdose. 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.

Ondansetron prolongs QT interval in a dose-dependent manner. ECG monitoring is recommended in cases of overdose. Cases consistent with serotonin syndrome have been reported in young children following oral overdose.

Management

There is no specific antidote for ondansetron, therefore in 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 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.

1.Pharmacodynamic properties

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 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.

Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opiate-induced emesis is not yet established

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.

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 + ondansetron 4 mg orally after 8-12 hours or ondansetron 0.45 mg/kg intravenous + placebo orally after 8-12 hours. 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 + ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous + 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 open-label, non-comparative, 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 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 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.l 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

CR = no emetic episodes, rescue or withdrawal

2.Pharmacokinetic properties

Absorption

Following oral administration of ondansetron, absorption is rapid with maximum peak plasma concentrations of about 30ng/mL being attained and achieved in approximately 1.5 hours after an 8mg dose.

Distribution

The syrup and tablet formulations are bioequivalent and have an absolute oral bioavailability of 60%.

Elimination

The disposition of ondansetron following oral, intravenous and intramuscular dosing is similar with a terminal elimination half-life of approximately 3 hours and a steady- state volume of distribution of about 140L. Ondansetron is not highly protein bound (70-76%) and 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 the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

Special Patient Populations

Gender 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). 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 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 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.

Elderly

Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. 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 ondansetron 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 intravenous dosing.

Renal impairment

In patients with renal impairment (creatinine clearance 15-60mL/min), systemic clearance and volume of distribution are reduced, 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 ondansetron's pharmacokinetics to be essentially unchanged.

Hepatic impairment

In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 hours) and an oral bioavailability approaching 100% because of reduced pre-systemic metabolism.

No additional data of relevance.

The active ingredient in EMIGO MD® tablets is ondansetron, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT3 receptor type.

1.Incompatibilities

Not applicable.

2.Shelf-life

Refer on pack

3.Packaging information

10 Blister strips of 10 tablets each

4.Storage and handing instructions

Store protected from light & moisture

at a temperature not exceeding 30°C.

Keep out of reach of children.

Directions for use:

Remove the tablet from blister pocket only before use & immediately place the tablet on top of the tongue where it will disintegrate in few seconds, then swallow with saliva.

Administration with liquid is not necessary.

QT Prolongation

Inform patients that EMIGO® may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Hypersensitivity Reactions

Inform patients that EMIGO® may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. Instruct patients to immediately report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems to their healthcare provider.

Masking of Progressive Ileus and Gastric Distension

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that EMIGO® may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions

• Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and EMIGO® may cause a significant drop in blood pressure and loss of consciousness.
• Advise patients of the possibility of serotonin syndrome with concomitant use of EMIGO® and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Eslo-1.25

Each uncoated tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 1.25 mg

Excipients q.s.

Colour : Yellow Oxide of Iron

Eslo-2.5

Each uncoated tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 2.5 mg

Excipients q.s.

Colour : Yellow Oxide of Iron

Eslo-5

Each uncoated tablet contains :

S (-) Amlodipine Besylate IP

equivalent to S (-) Amlodipine 5 mg

Excipients q.s.

Colour : Yellow Oxide of Iron

S (-) Amlodipine is the pharmacologically active isomer of Amlodipine.

S (-) Amlodipine is chemically designated as (S)-3-ethyl-5-methyl

2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,

5-pyridinedicarboxylate benzenesulphonate. Its empirical formula

is : C₂₀H₂₅ClN₂O₅ C₆H₆O₃S with a molecular weight of 567.1

Pharmacodynamics

Amlodipine is a racemate with an equal proportion of two enantiomers S and R. The S-enantiomer of Amlodipine is active and the R-enantiomer is inactive in terms of calcium channel blocking activity. S (-) Amlodipine has 1000 fold stronger calcium channel blocking activity than R-Amlodipine. S(-)Amlodipine is therefore responsible for all oftheCCB-mediated pharmacodynamic action ofAmlodipine including its anti-anginal activity. S (-) Amlodipine is a dihydropyridine a calcium channel blocker (CCB) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. S (-) Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, resulting in reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which S (-) Amlodipine relieves angina have not been fully delineated, but are thought to include the following :

• It dilates the peripheral small artery, decreasing peripheral resistance, causing the reduction of energy and oxygen requirement of cardiac muscle.
• It dilates the coronary artery and the small coronary arteries at normal and ischemic areas, increasing the oxygen supply of cardiac muscles of the coronary spasm patients.

Pharmacokinetics and Metabolism

Administration of S (-) Amlodipine 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.30 ± 1.071 ng/ ml in 2.73 ± 0.88 hrs. (Tmax). Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC value (t= 48 hrs.) 0-t of tablet S (-) Amlodipine (2.5 mg) is 95.33 ± 14.45 ng.hr/ml. The AUC0-∞ value is recorded to be 140.91± 28.06 ng.hr/ml. The plasma elimination half-life of S (-) Amlodipine has been found to be 31.09 ± 12.65 hrs.

• Essential hypertension
• Angina pectoris

Contraindications

Hypersensitivity to any of the components of the formulation.

Dosage and Administration :

The initial dose is 2.5 mg once a day for the treatment of hypertension and angina pectoris.On the basis of clinical response of patients, the dose may be increased to 5 mg once a day. Elderly individuals or patients with hepatic insufficiency may be started on 1.25 mg once daily. 1.25 mg dose may also be used when titrating up the dose from 2.5 mg to 3.75 mg as per the requirement of the patient.

Gingival hypertrophy and alopecia has been seen with S (-) Amlodipine. On the basis of the clinical data available, only minor side effects have been reported with the use of S (-) Amlodipine. On the basis of clinical data available, adverse events reported in less than 5% of the patients included anxiety (0.43%), anorexia (0.43%), irritation (0.43%), headache (2.13%) and facial flushing (2.13%). Caution should be exercised when administering S (-) Amlodipine to patients with impaired hepatic and renal function.

Clinical studies have shown that S (-) Amlodipine when combined with aspirin, nitrates, β-blockers, statins, ACE inhibitors, H receptor 2 blockers and proton pump inhibitors produced no drug interactions.

Precautions :

No controlled clinical study of S (-) Amlodipine has been performed in patients with hepatic impairment and renal impairment. Clinical studies in patients with normal liver function have shown that there is no elevation in the hepatic enzymes with the use of S (-) Amlodipine. However, caution should be taken while administering S (-) Amlodipine to such patients

Pregnant Women & Nursing Mothers

There is no data available on the use of S (-) Amlodipine in pregnant and lactating women, hence the drug should be administered only when the potential benefits outweigh the risk to the patient.

Children

Safety and efficacy of this product in children have not been established.

There are no reported cases of overdosage with the use of S (-) Amlodipine. Overdosage with racemic Amlodipine may cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Hence, caution should be taken in case of an overdosage with S (-) Amlodipine. If massive overdose occurs, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements should be performed. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (e.g. phenylephrine) should be considered with attention to circulating volume and urine output. If massive overdose occurs, gastric lavage should be employed. As this product is highly plasma protein bound, hemodialysis is not likely to be of benefit.

Store below 30°C. Protect from light & moisture

Keep out of reach of children

Presentation :

Eslo-1.25 : A composite blister strip of 2 x 15 tablets

Eslo-2.5 : A composite blister strip of 2 x 15 tablets.

Eslo-5 : A composite blister strip of 2 x 15 tablets.