Ondansetron Orifarm
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Ondansetron Orifarm 4 mg orodispersible tablet
Ondansetron Orifarm 8 mg orodispersible tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each orodispersible tablet contains 4 mg and 8 mg ondansetron, respectively.
Excipients with known effect: aspartame and sorbitol.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Orodispersible tablet
4 mg: White, flat, round, 7 mm bevel-edged tablet
8 mg: White, flat, round, 10 mm bevel-edged tablet
4. Clinical particulars
Therapeutic indications
Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting.
Posology and method of administration
Oral use.
For the different dosage regimens appropriate strengths and formulations are available.
Posology
Chemotherapy and radiotherapy induced nausea and vomiting
Adults
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron should be flexible and selected as shown below.
Emetogenic chemotherapy and radiotherapy
For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by oral or intravenous administration.
For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron should initially be administered intravenously immediately before treatment, followed by 8 mg orally every twelve hourly.
For oral administration:
Adults: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron associated with dexametasoneshould be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.
Highly emetogenic chemotherapy
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by oral, IV, IM or rectal administration.
For oral administration:
24 mg ondansetron orodispersible tablets taken together with oral dexamethasone sodium phosphate 12 mg, 1 to 2 hours before treatment.
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
Children (aged ≥ 6 month) and adolescents (< 18 years)
The dose for chemotherapy induced nausea and vomiting (CINV) can be calculated based on body surface area (BSA) or weight – see below.
Weight-based dosing results in higher total daily doses compared to BSA-based dosing (see section 4.4).
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 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 daily dose must not exceed adult dose of 32 mg.
Table 1: BSA-based dosing for Chemotherapy - Children aged ≥6 months and adolescents
|
BSA |
Day 1(a,b) |
Days 2-6(b) |
|
< 0.6 m² |
5 mg/m² i.v. plus 2 mg syrup after 12 hours |
2 mg syrup every 12 hours |
|
≥0.6 m² |
5 mg/m² i.v. plus 4 mg syrup or tablet after 12 hours |
4 mg syrup or tablet every 12 hours |
|
> 1.2 m2 |
5 mg/m2 IV or 8 mg IV plus 8 mg syrup or tablet after 12 hours |
8 mg syrup or tablet every 12 hours |
a. The intravenous dose must not exceed 8 mg.
b. The total daily dose must not exceed adult dose of 32 mg
Ondansetron orodispersible tablets cannot be used in children with a total body surface below 0.6 m2.
Dosing by bodyweight:
Weight-based dosing results in higher total daily doses compared to BSA-based dosing (see section 4.4 and 5.1: Clinical Studies).
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. The total daily dose must not exceed adult dose of 32 mg. Oral dosing can commence 12 hours later and may be continued for up to 5 days (Table 2).
Table 2: Weight-based dosing for Chemotherapy - Children aged ≥6 months and adolescents
|
Weight |
Day 1 (a,b) |
Days 2-6(b) |
|
≤10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
2 mg syrup every 12 hours |
|
> 10 kg |
Up to 3 doses of 0.15 mg/kg every 4 hours |
4 mg syrup or tablet every 12 hours |
a. The intravenous dose must not exceed 8 mg.
b. The total daily dose must not exceed adult dose of 32 mg.
Elderly
Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration is required.
Please refer also to ”Special populations”.
Post-operative nausea and vomiting:
Adults
Prevention of post-operative nausea and vomiting:
For the prevention of post-operative nausea and vomiting ondansetron can be administered orally or by intravenous injection.
For oral administration:
16 mg one hour prior to anaesthesia.
Alternatively, 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at
eight hourly intervals.
Treatment of established post-operative nausea and vomiting:
For the treatment of established post-operative nausea and vomiting intravenous administration is recommended.
Children (aged ≥ 1 month) and adolescents (< 18 years)
No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post-operative nausea and vomiting (PONV); slow IV injection (in not less than 30 seconds) is recommended for this purpose.
There are no data on the use of ondansetron in the treatment of PONV in children under 2 years of age.
Elderly
There is limited experience in the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Please refer also to ”Special populations”.
Special populations:
Patients with renal impairment:
No alteration of daily dosage or frequency of dosing, or route of administration are required.
Patients with hepatic impairment:
Clearance of 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 medicinal product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.
Method of administration
The tablet should be placed on the top of the tongue where it will rapidly disperse and should then be swallowed with or without water
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant use with apomorphine (see section 4.5).
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 (see section 5.1). 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 hypomagnesemia 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.
Since there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is coadministered with anaesthetics to patients with arrhythmias or cardiac conduction disorders or to patients who are being treated with antiarrhythmic agents or beta-blockers.
Ondansetron Orifarm contains aspartame, a source of phenylalanine. It may be harmful for patients with phenylketonuria.
Ondansetron Orifarm contains sorbitol. Patient with rare hereditary problems of fructose intolerance should not take this medicine.
Paediatric Population
Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents should be monitored closely for impaired hepatic function.
The medicinal product should not be used for children younger than two years, as for these patients the experience is limited.
CINV:
When calculating the dose on an mg/kg basis and administering three doses at 4-hourintervals, the total daily dose will be higher than if one single dose of 5mg/m2followed 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 (see section 5.1).
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 coadministered with it. Specific studies have shown that there are no interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lignocaine, 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.
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 trastuzimab), antibiotics (such as erythromycin or ketoconazole), antiarrhytmics (such as amiodarone) and betablockers (such as atenolol or timolol) may increase the risk of arrhythmias (see section 4.4).
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). (See section 4.4).
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
Pregnancy
The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.
Lactation
Tests have shown that ondansetron passes into the milk of lactating animals (See section 5.3). It is therefore recommended that mothers receiving ondansetron should not breastfeed their babies.
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 according to organ classes and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000) and very rare (<1/10,000).
Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.
|
Immune system disorders Rare |
Immediate hypersensitivity reactions sometimes severe, including anaphylaxis. |
|
Nervous system disorders Very common Uncommon Rare |
Headache. Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia).1 Dizziness during rapid IV administration. |
|
Eye disorders Rare Very rare |
Transient visual disturbances (eg. blurred vision) predominantly during rapid IV administration. Transient blindness predominantly during intravenous administration.2 |
|
Cardiac disorders Uncommon Rare |
Arrhythmias, chest pain with or without ST segment depression, bradycardia. QTc prolongation (including Torsade de pointes). |
|
Vascular disorders Common Uncommon |
Sensation of warmth or flushing. Hypotension. |
|
Respiratory, thoracic and mediastinal disorders Uncommon |
Hiccups. |
|
Gastrointestinal disorders Common |
Constipation. |
|
Hepatobiliary disorders Uncommon |
Asymptomatic increases in liver function tests3. |
|
Skin and subcutaneous tissue disorders Frequency not known |
Toxic epidermal necrolysis |
1 Observed without definitive evidence of persistent clinical sequelae.
2The 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.
3These events were observed commonly in patients receiving chemotherapy with cisplatin.
Paediatric population
The adverse event profiles in children and adolescents were comparable to that seen in adults.
Reporting 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 the national reporting system listed in Appendix V.
4.9 Overdose
Symptoms and signs
There is limited experience of ondansetron overdose. In the majority of cases, symptoms
were similar to those already reported in patients receiving recommended doses (see section 4.8). 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 dose-dependent manner. ECG monitoring is recommended in cases of overdose.
Treatment
There is no specific antidote for ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
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. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists.
ATC Code: A04AA01
Mechanism of action
Ondansetron is a potent, highly selective 5-HT3 receptor-antagonist.
Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT 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 5-HT3 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.
Clinical efficacy and safety
In a pharmaco-psychological study in volunteers ondansetron has not shown a sedative effect.
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, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose 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.
Clinical Studies
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 and ondansetron 4 mg orally after 8 to12 hours or ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hours. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst dayof chemotherapy was 49% (5 mg/m² intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and placebo orally). 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 to 4 mg dexamethasone orally
- 71% of patients when ondansetron was administered as syrup at a dose of 8 mg together with 2 to 4 mg dexamethasone orally on the days of chemotherapy
Post-chemotherapy both groups received 4 mg 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 4 and 8 hours after the first dose. Complete control of emesis was achieved in 56% of patients.
Another open-label, non-comparative, single-arm study (S3A239) investigated the efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral ondansetron doses of 4 mg for children aged < 12 yrs 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 (0.1 mg/kg for paediatric patients weighing 40 kg or less, 4 mg for paediatric patients weighing more than 40 kg; number of patients = 735)) or placebo (number of patients = 734). Study drug was administered over at least 30 seconds, immediately prior to or following anaesthesia induction. 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
|
Study |
Endpoint |
Ondansetron % |
Placebo % |
p value |
|
S3A380 |
CR |
68 |
39 |
≤ 0.001 |
|
S3GT09 |
CR |
61 |
35 |
≤ 0.001 |
|
S3A381 |
CR |
53 |
17 |
≤ 0.001 |
|
S3GT11 |
no nausea |
64 |
51 |
0.004 |
|
S3GT11 |
no emesis |
60 |
47 |
0.004 |
CR = no emetic episodes, rescue or withdrawal
5.2 Pharmacokinetic properties
Absorption
Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%). 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. 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).
Distribution
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.
Elimination
The protein binding of ondansetron is 70-76%. A direct effect of plasma concentration and anti-emetic effect has not been established. 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 has no effect on ondansetron’s pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Children and Adolescents (aged 1 month to 17 years)
In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight-normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the 1 to 4 month patient population was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for watersoluble 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 normalizing systemic exposure in paediatric patients.
In patients with moderate renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged.
Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron’s systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats; milk/plasma-ratio was 5.2:1
A study of cloned human cardiac ion channels has shown that ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The clinical relevance of this finding is uncertain.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol (E421)
Sorbitol (E420)
Crospovidone
Silica, colloidal hydrated
Microcrystalline cellulose
Crospovidone type B
Aspartame (E951)
Strawberry flavouring
Sodium stearyl fumarate
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
4 mg, orodispersible tablet:
Blister (Alu/Alu) : 6, 7, 10, 14, 28, 30 tablets.
Unit-dose blister (Alu/Alu): 6x1, 7 x1, 10 x1, 14 x1, 28 x1, 30 x1 tablets.
8 mg, orodispersible tablet:
Blister (Alu/Alu): 6, 7, 10, 14, 28, 30 tablets.
Unit-dose blister (Alu/Alu): 6x1, 7x1, 10x1, 14x1, 28x1, 30x1 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
2009-11-17/2014-11-17
10. DATE OF REVISION OF THE TEXT
2014-10-31