.

Name of the medicinal product

Rupatadine 1 mg/ml oral solution

2. Qualitative and quantitative composition

Each ml of oral solution contains:

1 mg of rupatadine (as fumarate)
Excipients:
Sucrose 300 mg/ml
Methyl Parahydroxybenzoate (E218) 1.00 mg/ml
For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral solution.
Clear yellow solution.

4. Clinical particulars

4.1 Therapeutic indications

Rupafin 1 mg/ml oral solution is indicated for the symptomatic treatment of:
-Allergic rhinitis (including persistent allergic rhinitis) in children aged 2 to 11 years (see section 5.1)
-Urticaria in children aged 2 to 11 years (see section 5.1).
4.2 Posology and method of administration

Children aged 2 to 11 years.

Dosage in children weighing equal or more than 25 kg:5 ml (5 mg of rupatadine) of oral solution once a day,
with or without food.
Dosage in children weighing equal or more than 10 kg up to less than 25 kg:2.5 ml (2.5 mg of rupatadine) of
oral solution once a day, with or without food.
The administration of the product to children aged under 2 years is not recommended due to the lack of data in
this population (see section 4.4).
In adults and adolescents (over 12 years of age),the administration of rupatadine 10 mg tablets is more
appropriate.
Patients with renal or hepatic insufficiency: As there is no clinical experience in patients with impaired kidney or
liver functions, the use of rupatadine is at present not recommended in these patients.
Instructions of use:
- To open the bottle press the cap and turn it anticlockwise.
- Take the syringe and put it in the perforated stopper and turn the bottle upside down.
- Fill the syringe with the prescribed dose.
- Administer directly from the dosing syringe.
- Wash the syringe after use.
4.3 Contraindications
Hypersensitivity to rupatadine or to any of the excipients.
4.4 Special warnings and precautions for use

Safety of rupatadine oral solution in children aged less than 2 years has not been established.
The combination of rupatadine with potent CYP3A4 inhibitors should be avoided and with moderate CYP3A4
inhibitors should be administered with caution (see section 4.5).
Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrates with a
narrow therapeutic index (e.g. cyclosporin, tacrolimus, sirolimus, everolimus, cisapride) could be required as
rupatadine may increase plasma concentrations of these drugs (see section 4.5).
The administration of rupatadine with grapefruit juice is not recommended (see section 4.5).
Cardiac safety of rupatadine 10 mg tablets was assessed in a Thorough QT/QTc study in adults. Rupatadine
up to 10 times therapeutic dose did not produce any effect on the ECG and hence raises no cardiac safety
concerns. However, rupatadine should be used with caution in patients with known prolongation of the QT
interval, patients with uncorrected hypokalemia, patients with ongoing proarrhythmic conditions, such as
clinically significant bradycardia, acute myocardial ischemia.
Increases of blood creatine phosphokinase, alanine aminotransferase and aspartate aminotransferase, as well
as abnormalities of liver function tests are uncommon adverse reaction reported with rupatadine 10 mg tablets
in adults.
This medicinal product contains sucrose, so it may be harmful to the teeth.Patients with rare hereditary
problems of fructose intolerance, glucose/galactose malabsorption or sucrase-isomaltase insufficiency should
not take this medicine.
This medicinal product contains methyl parahydroxybenzoate, may cause allergic reactions (possibly delayed).
4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed in children with rupatadine oral solution.
Interaction studies have only been performed in adults and adolescents (over 12 years of age) with rupatadine
10 mg tablets.
Effects of other drugs on rupatadine
Co-administration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole,
HIV protease inhibitors, clarithromycin, nefazodone) should be avoided and co-medication with moderate
CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem) should be used with caution.
The concomitant administration of rupatadine 20 mg and ketoconazole or erythromycin increases the systemic
exposure to rupatadine 10 times and 2-3 times respectively. These modifications were not associated with an
effect on the QT interval or with an increase of the adverse reactions in comparison with the drugs when
administered separately.
Interaction with grapefruit: The concomitant administration of grapefruit juice increased 3.5 times the systemic
exposure of rupatadine 10 mg tablet. This occurs because grapefruit has one or more compounds that inhibit
the CYP3A4 and can increase the plasmatic concentrations of drugs metabolised through this CYP3A4, like
rupatadine. In addition, it has been suggested that the grapefruit can affect intestinal drug transport systems as
the glycoprotein-P.Grapefruit juice should not be taken simultaneously.
Effects of rupatadine on other drugs
Caution should be taken when rupatadine is co-administered with other metabolised drugs with narrow
therapeutic windows since knowledge of the effect of rupatadine on other drugs is limited.
Interaction with alcohol: After administration of alcohol, a dose of rupatadine 10 mg tablet produced marginal
effects in some psychomotor performance tests although theywere not significantly different from those induced
by intake of alcohol only. A dose of 20 mg increased the impairment caused by the intake of alcohol.
Interaction with CNS depressants: As with other antihistamines, interactions with CNS depressants cannot be
excluded.
Interaction with statins: Asymptomatic CPK increases have been uncommonly reported in rupatadine clinical
trials. The risk of interactions with statins, some of which are also metabolised by the cytochrome P450
CYP3A4 isozyme, is unknown. For these reasons, rupatadine should be used with caution when it is
coadministered with statins.
4.6 Fertility, pregnancy and lactation

Pregnancy
Data on a limited number (2) of exposed pregnancies indicate no adverse effects of rupatadine on pregnancy
or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal
development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is
preferable to avoid the use of rupatadine during pregnancy.
Breastfeeding
Rupatadine is excreted in animal milk. It is unknown whether rupatadine is excreted into breast milk. A decision
must be made whether to discontinue breastfeeding or to discontinue/abstain from rupatadine therapy taking
into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
There are no clinical data on fertility. Studies in animals have shown a significant reduction of fertility at
exposure levels higher than those observed in humans at the maximum therapeutic dose (see section 5.3).
4.7 Effects on ability to drive and use machines

Rupatadine 10 mg had no influence on the ability to drive and use machines in a performed clinical trial.
Nevertheless, care should be taken before driving or using machinery until the patient's individual reaction to
rupatadine has been established.
4.8 Undesirable effects

Clinical trials with rupatadine oral solution in children aged 2-11 years included 626 patients. From these, 147
patients were treated with rupatadine 2.5 mg, 159 patients were treated with rupatadine 5 mg, 249 received
placebo and 71 received desloratadine.
The frequencies of adverse reactions are assigned as follows:
• Common (≥ 1/100 to < 1/10)
• Uncommon (≥ 1/1000 to < 1/100)
The frequencies of adverse reactions reported in patients treated with rupatadine oral solution during clinical
trials were as follows:

System Organ Class term Rupatadine Rupatadine Placebo

2.5 mg 5 mg
Frequency Preferred term (n=147) (n=159) (n=249)
Infections and infestations
Influenza 0 1(0.63%) 0
Nasopharyngitis 1 (0.68%) 0 0
Uncommon
Upper respiratory tract 1 (0.68%) 0 0
infection
Blood and lymphatic system disorders
Uncommon Eosinophilia 0 1(0.63%) 0
 Neutropenia 0 1(0.63%) 0
Nervous system disorders
Headache 2 (1.36%) 4 (2.52%) 4
Common (1.61%)
Somnolence 0 2 (1.26%) 0
Dizziness 0 1 (0.63%) 1
Uncommon
(0.40%)
Gastrointestinal disorders
Nausea 1 (0.63%) 2
Uncommon 0
(0.80%)
Skin and subcutaneous tissue disorders
Eczema 1 (0.63%) 1
0
Uncommon (0.40%)
Night sweats 0 1 (0.63%) 0
General disorders and administration site conditions
Uncommon Fatigue 0 1 (0.63%) 0
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
4.9 Overdose

No case of overdose has been reported in adults and children. In a clinical safety study in adults rupatadine at
daily dose of 100 mg during 6 days was well tolerated. The most common adverse reaction was somnolence. If
accidental ingestion of very high doses occurs symptomatic treatment together with the required supportive
measures should be given.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antihistamines for systemic use, ATC code: R06A X28.
Rupatadine is a second-generation antihistamine, long-acting histamine antagonist, with selective peripheral
H1-receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain
an antihistaminic activity and may partially contribute to the overall efficacy of the drug.
In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells
induced by immunological and non-immunological stimuli as well as the release of cytokines, particularly of the
TNFα in human mast cells and monocytes.The clinical relevance of the observed experimental data remains to
be confirmed.
Rupatadine oral solution had a similar pharmacokinetic profile in children between 6-11 years to that in adults
(> 12 years): a pharmacodynamic effect was also observed (suppression of the wheal area, antihistamine
effect) after 4 weeks of treatment. A randomised, double-blind and placebo-controlled confirmatory study in
children with persistent allergic rhinitis aged 6 to 11 years, showed that rupatadine oral solution had a better
profile in the reduction of nasal symptoms (rhinorrea and itchy nose mouth throat and/or ears) than placebo in
children with persistent allergic rhinitis after 4 and 6 weeks of treatment. Furthermore, a significant
improvement in quality of life was also observed throughout the study in comparison with placebo.
Chronic spontaneous urticaria was studied as a clinical model to assess the efficacy of antiH 1 compounds for all
urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and basically these
chronic patients can be more easily recruited into a clinical study. Urticaria is a mast cell-driven disease and
histamine and other mediators (PAF and cytokines) are the principal mediators to develop all urticarial lesions.
Since rupatadine has capacity to block the release of histamine and other inflammatory mediators, it is
expected to be effective treatment in providing symptomatic relief for other urticarial conditions, in addition to
chronic spontaneous urticaria, as recommended in clinical guidelines.
The efficacy of rupatadine oral solution in chronic spontaneous urticaria in children aged 2-11 years has been
demonstrated in a multicentre, randomized, active- and placebo-controlled study. Overall, 206 children were
included. Of them, 113 were between 2-5 years and 93 of them were between 6-11 years. Children were
treated with rupatadine (n=66), placebo (n=69) or desloratadine (n=71). Rupatadine dose administered was 2.5
mg in children weighting up to 25 kg and 5 mg in children weighting over 25 kg. Desloratadine dose
administered was 1.25 mg in children weighting up to 25 kg and 2.5 mg in children weighting over 25 kg. A
statistically significant improvement versus placebo was demonstrated in the mean change in weekly urticaria
activity score (UAS7; comprising hives and pruritus), the main endpoint, evaluated after 6 weeks of treatment
(rupatadine -11.77 vs. placebo -5.55; p <0.001).The mean percent reduction in the weekly number of hives at
study endpoint versus baseline was 56.7% with rupatadine, 49.4% with desloratadine and 22.7% with placebo.
The mean percent reduction in pruritus at study endpoint versus baseline was 56.8% with rupatadine, 46.7%
with desloratadine and 33.4% with placebo. Both active treatments (rupatadine and desloratadine) achieved
statistically significant greater improvements than placebo in the reduction in hives and pruritus, while there
were not statistically significant differences between the active treatments regarding these outcomes. The
percentage of patient responders of more than 50% in weekly urticaria activity score (UAS7 scale; urticaria and
pruritus) was observed in 61% of children treated with rupatadine compared with 36% of children treated with
placebo and 54% of children treated with desloratadine.
Clinical trials in volunteers (n= 375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria
did not show significant effect on the electrocardiogram when rupatadine tablets was administered at doses
ranging from 2 mg to 100 mg.
The European Medicines Agency has waived the obligation to submit the results of studies with Rupafin oral
solution in all subsets of the paediatric population in allergic rhinitis and chronic urticaria (see section 4.2).
5.2 Pharmacokinetic properties

Paediatric population
In the subgroup of children 2-5 and 6-11 years old, rupatadine was rapidly absorbed and the mean Cmax was of
1.9 and 2.5 ng/ml after repeated oral dose, respectively. In term of exposition, the mean total area under the
curve (AUC) value was 10.4 ng.h/ml in children 2-5 years and 10.7 ng·h/ml in children 6-11 years. All these
values are similar to those obtained in adults and adolescents.
The mean elimination half-life of rupatadine in children 2-5 years was 15.9 h and in children 6-11 years was
12.3 h, which are longer than that reported with tablets in adults and adolescents.
Effect of the intake of food
No interaction food study has been performed with rupatadine oral solution. The influence of food was
performed in adults and adolescents with rupatadine 10 mg tablets. Intake of food increased the systemic
exposure (AUC) to rupatadine by about 23%. The maximum plasma concentration (Cmax) was not affected by
food intake. These differences had no clinical significance.
Metabolism and elimination
In a study of excretion in adults, 34.6% of rupatadine administered was recovered in urine and 60.9% in faeces
collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by
oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means
that rupatadine is almost completely metabolised. Roughly, the active metabolites desloratadine and other
hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active
substances. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly
metabolised by the cytochrome P450 (CYP 3A4).
5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology,
repeated dose toxicity, genotoxicity, carcinogenic potential.
More than 100 times the clinically recommended dose in adults (10 mg) of rupatadine did neither extend the
QTc or QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs.
Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the
cardiac action potential in isolated dog Purkinje fibres at concentrations at least 2000 times greater than the
Cmax reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on
cloned human HERG channel, rupatadine inhibited that channel at a concentration 1685 times greater than the
Cmax obtained after the administration of 10 mg of rupatadine. Studies of tissue distribution in rats with
radiolabelled rupatadine showed that rupatadine does not accumulate in heart tissue.
In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/kg/day,
providing Cmax 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth
delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25
and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg.
The developmental No Adverse Effect Levels were determined at 5 mg/kg/day in rats and 100 mg/kg/day in
rabbits, yielding Cmax 45 and 116 times higher, respectively, than those measured in humans at the therapeutic
dose (10 mg/day).

6. Pharmaceutical particulars

6.1 List of excipients

Propylene glycol
Citric acid anhydrous
Disodium phosphate anhydrous
Saccharin sodium
Sucrose
Methylparahydroxybenzoate (E218)
Quinoline yellow (E104)
Banana flavour (Blend of flavouring substances, flavouring preparations and natural flavouring substances, and
propilenglicol)
Purified water
6.2 Incompatibilities

Not applicable
6.3 Shelf life

30 months.
The shelf life after first opening is the same as the expiry date placed on the box and the bottle.
6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container

120 ml amber polyethylene terephthalate (PET) bottle with low density polyethylene (LDPE) perforated stopper
closed with yellow high density polyethylene (HDPE) child-resistant closure in a cardboard box also containing
5 ml oral syringe (polypropylene, polyethylene) graduated at 0.25 ml.
6.6 Special precautions for disposal and other handling

No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

J. Uriach y Compañia, S.A.

Av. Camí Reial, 51-57
08184 Palau-solità i Plegamans (Spain)
Telephone: +34 93 864 96 92
Fax: +34 93 864 66 06

8. Marketing authorisation number(s)

PL11906/0009

9. Date of first authorisation/renewal of the authorisation

27/03/2012

10. Date of revision of the text

24/06/2018

Company contact details

Aspire Pharma Ltd

1. Name of the medicinal product

Rupatadine 10 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains:
10 mg of rupatadine (as fumarate)
Excipient with known effect: lactose 57.57 mg as lactose monohydrate
For the full list of excipients, see section 6.1.

3. Pharmaceutical form
Tablet.
Round, light salmon coloured tablets.

4. Clinical particulars
4.1 Therapeutic indications
Symptomatic treatment of allergic rhinitis and urticaria in adults and adolescents (over 12 years of age).
4.2 Posology and method of administration
Adults and adolescents (over 12 years of age)
The recommended dose is 10 mg (one tablet) once a day, with or without food.
Elderly
Rupatadine should be used with caution in elderly people (see section 4.4).
Paediatric patients
Rupatadine 10 mg Tablets is not recommended for use in children below age 12. In children aged 2 to 11
years, the administration of rupatadine 1 mg/ml oral solution is recommended.
Patients with renal or hepatic insufficiency
As there is no clinical experience in patients with impaired kidney or liver functions, the use of rupatadine 10
mg Tablets is at present not recommended in these patients.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
4.4 Special warnings and precautions for use
The administration of rupatadine with grapefruit juice is not recommended (see section 4.5).
The combination of rupatadine with potent CYP3A4 inhibitors should be avoided and with moderate CYP3A4
inhibitors should be administered with caution (see section 4.5).
Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrates with a
narrow therapeutic index (e.g. ciclosporin, tacrolimus, sirolimus, everolimus, cisapride) could be required as
rupatadine may increase plasma concentrations of these drugs (see section 4.5).
Cardiac safety of rupatadine was assessed in a Thorough QT/QTc study. Rupatadine up to 10 times
therapeutic dose did not produce any effect on the ECG and hence raises no cardiac safety concerns.
However, rupatadine should be used with caution in patients with known prolongation of the QT interval,
patients with uncorrected hypokalemia, patients with ongoing proarrhythmic conditions, such as clinically
significant bradycardia, acute myocardial ischemia.
Rupatadine 10 mg Tablets should be used with caution in elderly patients (65 years and older). Although no
overall differences in effectiveness or safety were observed in clinical trials, higher sensitivity of some older
individuals cannot be excluded due to the low number of elderly patients enrolled (see section 5.2).
Regarding use in children less than 12 years old and in patients with renal or hepatic impairment, see section
4.2.
Due to the presence of lactose monohydrate in rupatadine 10 mg tablets, patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not
take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults and adolescents (over 12 years of age) with rupatadine
10 mg tablets.
Effects of other drugs on rupatadine
Co-administration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole,
HIV protease inhibitors, clarithromycin, nefazodone) should be avoided and co-medication with moderate
CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem) should be used with caution.
The concomitant administration of rupatadine 20 mg and ketoconazole or erythromycin increases the systemic
exposure to rupatadine 10 times and 2-3 times respectively. These modifications were not associated with an
effect on the QT interval or with an increase of the adverse reactions in comparison with the drugs when
administered separately.
Interaction with grapefruit: The concomitant administration of grapefruit juice increased 3.5 times the systemic
exposure of rupatadine. Grapefruit juice should not be taken simultaneously.
Effects of rupatadine on other drugs
Caution should be taken when rupatadine is co-administered with other metabolised drugs with narrow
therapeutic windows since knowledge of the effect of rupatadine on other drugs is limited.
Interaction with alcohol: After administration of alcohol, a dose of 10 mg of rupatadine produced marginal
effects in some psychomotor performance tests although they were not significantly different from those
induced by intake of alcohol only. A dose of 20 mg increased the impairment caused by the intake of alcohol.
Interaction with CNS depressants: As with other antihistamines, interactions with CNS depressants cannot be
excluded
Interaction with statins: Asymptomatic CPK increases have been uncommonly reported in rupatadine clinical
trials. The risk of interactions with statins, some of which are also metabolised by the cytochrome P450
CYP3A4 isoenzyme, is unknown. For these reasons, rupatadine should be used with caution when it is
coadministered with statins.
4.6 Fertility, preganancy and lactation
Pregnancy
There are limited amount of data from the use of rupatadine in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or
postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of
rupatadine during pregnancy.
Breastfeeding
Rupatadine is excreted in animal milk. It is unknown whether rupatadine is excreted into breast milk. A decision
must be made whether to discontinue breastfeeding or to discontinue/abstain from rupatadine therapy taking
into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
There are no clinical data on fertility. Studies in animals have shown a significant reduction of fertility at
exposure levels higher than those observed in humans at the maximum therapeutic dose (see section 5.3).
4.7 Effects on ability to drive and use machines
Rupatadine 10 mg had no influence on the ability to drive and use machines. Nevertheless, care should be
taken before driving or using machinery until the patient's individual reaction on rupatadine has been
established.
4.8 Undesirable effects
Rupatadine 10 mg tablets has been administered to over 2025 adult and adolescents patients in clinical
studies, 120 of whom received rupatadine for at least 1 year.
The most common adverse reactions in controlled clinical studies were somnolence (9,5%), headache (6,9%)
and fatigue (3,2%)
The majority of the adverse reactions observed in clinical trials were mild to moderate in severity and they
usually did not require cessation of therapy.
The frequencies of adverse reactions are assigned as follows:
• Common (≥ 1/100 to < 1/10)
• Uncommon (≥ 1/1000 to < 1/100)
• Rare (≥1/10,000 to <1/1,000)
The frequencies of adverse reactions reported in patients treated with rupatadine 10 mg tablets during clinical
trials and spontaneous reporting were as follows:
• Infections and infestations
- Uncommon : Pharyngitis, Rhinitis
• Immune system disorders
- Rare: Hypersensitivity reactions (including anaphylactic reactions, angioedema and urticaria)*
• Metabolism and nutrition disorders
- Uncommon : Increased appetite
• Nervous system disorders:
- Common : Somnolence, Headache, Dizziness
- Uncommon : Disturbance in attention
• Cardiac disorders
- Rare: tachycardia and palpitations*
• Respiratory, thoracic, and mediastinal disorders
- Uncommon : Epistaxis, Nasal dryness, Cough, Dry throat, Oropharyngeal pain
• Gastrointestinal disorders
- Common : Dry mouth
- Uncommon : Nausea, Abdominal pain upper, Diarrhoea, Dyspepsia, Vomiting, Abdominal pain, Constipation
• Skin and subcutaneous tissue disorders
- Uncommon : Rash
• Musculoskeletal, connective tissues, and bone disorders
- Uncommon : Back pain, Arthralgia, Myalgia
• General Disorders and administration site condition
- Common : Fatigue, Asthenia
- Uncommon: Thirst, Malaise, Pyrexia, Irritability
• Investigations
- Uncommon : Blood creatine phosphokinase increased, Alanine aminotransferase increased, Aspartate
aminotransferase increased, Liver function test abnormal, Weight increased
* tachycardia and palpitations and hypersensitivity reactions (including anaphylactic reactions, angioedema and
urticarial) have been reported in post-marketing experience with rupatadine 10 mg tablets.
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 Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard or
search for MHRA Yellow Card in the Google Play or Apple App Store).
4.9 Overdose
No case of overdose has been reported. In a clinical safety study rupatadine at daily dose of 100 mg during 6
days was well tolerated. The most common adverse reaction was somnolence. If accidental ingestion of very
high doses occurs symptomatic treatment together with the required supportive measures should be given.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antihistamines for systemic use, ATC code: R06A X28.
Rupatadine is a second-generation antihistamine, long-acting histamine antagonist, with selective peripheral
H1-receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain
an antihistaminic activity and may partially contribute to the overall efficacy of the drug.
In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells
induced by immunological and non-immunological stimuli as well as the release of cytokines, particularly of the
TNFα in human mast cells and monocytes. The clinical relevance of the observed experimental data remains to
be confirmed.
Clinical trials in volunteers (n= 375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria
did not show significant effect on the electrocardiogram when rupatadine was administered at doses ranging
from 2 mg to 100 mg.
Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying
pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited
prospectively. Since histamine release is a causal factor in all urticarial diseases, rupatadine is expected to be
effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria,
as advised in clinical guidelines.
In a placebo-controlled trials in patients with Chronic Idiopathic Urticaria, rupatadine was effective reducing the
mean pruritus score from baseline over the 4 week treatment period (change vs baseline: rupatadine 57.5%,
placebo 44.9%) and decreasing the mean number of wheals (54.3% vs 39.7%).
5.2 Pharmacokinetic properties
Absorption and bioavailability
Rupatadine is rapidly absorbed after oral administration, with a tmax of approximately 0.75 hours after intake. The
mean Cmax was 2.6 ng/ml after a single oral dose of 10 mg and 4.6 ng/ml after a single oral dose of 20 mg.
Pharmacokinetics of rupatadine was linear for a dose between 10 and 20 mg after single and repeated doses.
After a dose of 10 mg once a day for 7 days, the mean Cmax was 3.8 ng/ml. The plasma concentration followed
a bi-exponential drop-off with a mean elimination half-life of 5.9 hours. The binding-rate of rupatadine to plasma
proteins was 98.5-99%.
As rupatadine has never been administered to humans by intravenous route, no data is available on its
absolute bioavailability.
Effect of the intake of food
Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The exposure to one of its
active metabolites and to the main inactive metabolite was practically the same (reduction of about 5% and 3%
respectively). The time taken to reach the maximum plasma concentration (tmax) of rupatadine was delayed by 1
hour. The maximum plasma concentration (Cmax) was not affected by food intake. These differences had no
clinical significance.
Metabolism and elimination
In a study of excretion in humans (40 mg of 14C-rupatadine), 34.6% of the radioactivity administered was
recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-
systemic metabolism when administered by oral route. The amounts of unaltered active substance found in
urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. Roughly, the
active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively,
of the total systemic exposure of the active substances. In vitro metabolism studies in human liver microsomes
indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP 3A4).
Specific patient groups
In a study on healthy volunteers to compare the results in young adults and elderly patients, the values for AUC
and Cmax for rupatadine were higher in the elderly than in young adults. This is probably due to a decrease of
the first-pass hepatic metabolism in the elderly. These differences were not observed in the metabolites
analysed. The mean elimination half-life of rupatadine in elderly and young volunteers was 8.7 hours and 5.9
hours respectively. As these results for rupatadine and for its metabolites were not clinically significant, it was
concluded that it is not necessary to make any adjustment when using a dose of 10 mg in the elderly.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of pharmacology, repeated
dose toxicity, genotoxicity, and carcinogenic potential.
More than 100 times the clinically recommended dose (10 mg) of rupatadine did neither extend the QTc or
QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs.
Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the
cardiac action potential in isolated dog Purkinje fibres at concentrations at least 2000 times greater than the
Cmax reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on
cloned human HERG channel, rupatadine inhibited that channel at a concentration 1685 times greater than the
Cmax obtained after the administration of 10 mg of rupatadine. Desloratadine, the metabolite with the greatest
activity, had no effect at a 10 micromolar concentration. Studies of tissue distribution in rats with radiolabelled
rupatadine showed that rupatadine does not accumulate in heart tissue.
In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/kg/day,
providing Cmax 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth
delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25
and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg.
The developmental No Adverse Effect Levels were determined at 5 mg/kg/day in rats and 100 mg/kg/day in
rabbits, yielding Cmax 45 and 116 times higher, respectively, than those measured in humans at the therapeutic
dose (10 mg/day).

6. Pharmaceutical particulars
6.1 List of excipients
Pregelatinised maize starch
Microcrystalline cellulose
Red iron oxide (E-172)
Yellow iron oxide (E-172)
Lactose monohydrate
Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Keep the blister in the outer carton in order to protect from light.
6.5 Nature and contents of container
PVC/PVDC/aluminium blister.
Packs of 3, 7, 10, 15, 20, 30, 50 and 100 tablets. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

J. Uriach y Compañía, S.A.
Av. Camí Reial, 51-57
08184 Palau-solità i Plegamans (Spain)

8. Marketing authorisation number(s)

PL 11906/0007

9. Date of first authorisation/renewal of the authorisation

24/10/2007

10. Date of revision of the text

05/12/2018

Company contact details

Aspire Pharma Ltd