Core0B Safety Profile

Active substance: Oxatomide Pharmaceutical form(s)/strength: Tablets (30mg), 0,25% oral suspension (2.5mg/mL) and 50mg gel P-RMS: PT/H/PSUR/0005/004 Date of FAR: 18.09.2012

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Oxatomide should be taken twice daily, after breakfast and after dinner.

Adults: 30 mg twice daily Children (older than 1 year): 0.5 mg/kg twice daily, i.e.

- For the oral suspension (preferable): 0.2 ml (0.5 mg) per kg of body weight, twice daily.

- For the tablets: 15 mg (1/2 tablet) twice daily, if body weight is between 15 and 35 kg, 30 mg (1 tablet) twice daily, when body weight is greater than 35 kg.

If one or more doses are missed, treatment should be continued. No special precaution is necessary regarding the manner of suspending the treatment, except in asthmatic disorders (see section 4.4).

In some countries, for children of bodyweight less than 15 kg, no adequate formulation may be available. Other pharmaceutical forms or strengths may be more appropriate for administration to this population.

4.3. Contraindications

Known hypersensitivity to the active substance or to any of the excipients. Patients with severe hepatic failure.

4.4. Warnings and special precautions for use

Oxatomide is not suited for prompt relief of allergic conditions such as asthma attacks. When Oxatomide is prescribed to asthma patients, the existing treatment regimen must not be interrupted abruptly, but its dosage gradually reduced. This is particularly important in patients under corticosteroid treatment.

Hepatitis, icterus, and hepatic function abnormality (moderate-to-marked elevations of liver enzyme tests), including very rare cases of fatal liver failure have been reported from post marketing experience. Patients should be carefully observed for adverse hepatic effects. If any abnormality is recognized, appropriate measures such as discontinuation of administration should be taken and Oxatomide should not be reintroduced.

Because of its hepatic elimination, care should be used in prescribing oxatomide in patients with known liver disease. If required, the treatment in such patients should preferably start with half the normal dose; the dosing interval may be maintained.

Dyskinesia and extrapyramidal symptoms have been reported in both adults and children. However, there were more reports of extrapyramidal disorders in children. It is likely that children may be more susceptible to the central nervous effects due to immaturity of the blood-brain barrier. Therefore, caution is recommended in children under six years and particularly those under 24 months of age.

In the geriatric population, age-related physiological changes (i.e., increased blood-brain barrier permeability and decreased liver metabolism) may affect the actions of H1-receptor antagonists.

Oxatomide, like other antihistamines, may interfere with allergy skin tests and treatment should, therefore, be interrupted for at least 3 days before skin testing.

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Oxatomide tablets contains lactose monohydrate. Patient with rare hereditary problems of galactose intolerance, lactase deficiency or malabsorption of glucose-galactose should not take this product.

Oxatomide oral suspension contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this product.

Oxatomide oral suspension contains parabens. This may cause allergic reactions (possibly delayed).

Oxatomide should be used with caution in the elderly, due to the increased risk of sedation.

Oxatomide intake is not recommended with alcoholic drinks or with medicines containing alcohol (see section 4.5).

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

Oxatomide is metabolized by cytochrome P450, specifically, the isoforms 3A4 and potentially 2D6 based on in vitro studies using human liver microsomes. Based on these in vitro studies, a potential interaction may exist between oxatomide and CYP 450 inhibitors such as itraconazole, ketoconazole, and cimetidine.

Patients are warned that Oxatomide may enhance the sedative effect of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, anxiolytics, and antipsychotics. The side-effects of anticholinergic drugs may be enhanced by the concomitant administration of Oxatomide. Concomitant use of MAO inhibitors and Oxatomide tablets is not advised.

4.6. Pregnancy and Lactation Kommentar [p1]: Assessor´s comment: If it is possible it will be more useful to have a sub-chapter for lactation In animals, neither a direct embryotoxic nor a direct peri- or postnatal toxic effect was noted. and a chapter for fertility (which is not There were no direct adverse effects on fertility either and secondary effects were only found included in the proposed CSP). at maternally toxic doses. Data from animal experiments point to a limited passage of Concerning the proposal to suspend breast feeding we do not support the proposed oxatomide through the placenta, but in pregnant women the safety of Oxatomide has not text, breastfeeding ... been established. When there is a need to administer Oxatomide during pregnancy, the potential hazards should be carefully weighed against the expected therapeutic benefits. There is insufficient information on the excretion of oxatomide in human milk. Breast-feeding should therefore be discontinued during treatment with Oxatomide

4.7. Effects on ability to drive and use machines

Patients who drive or operate machinery should be warned of the possibility of drowsiness and impaired mental alertness. Simultaneous intake of alcohol may potentiate these effects.

4.8. Undesirable effects

The safety of Oxatomide was evaluated in 772 adult subjects with perennial or seasonal allergies including rhinitis, conjunctivitis, asthma, acute and chronic urticaria, sinusitis, otitis, angioedema, and atopic dermatitis who participated in a 1-month randomized, multicenter trial. These subjects took at least 1 dose of Oxatomide and provided safety data. The most commonly reported ADRs were (with % incidence): Somnolence (28.7%), Weight Increased and/or Appetite Increased (3.0%), and Dry Mouth (2.1%).

3 / 7 Including the above-mentioned ADRs, Table 1 displays ADRs that have been reported with the use of Oxatomide from either clinical trial or postmarketing experiences. The displayed frequency categories use 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 <1/1000) Very rare (≤1/10,000)

Table 1: Adverse Drug Reactions Reported in Clinical Trial and Postmarketing Experiences System/ Adverse Drug Reactions Organ Frequency Category Class Uncommo Rare Not Very Commo Very rare Commo n n ≥ known ( 1/10,000 (≤1/10,000) n (≥1/100 (≥1/1,000 to

(≥1/10) to <1/10) to <1/100 <1/1,000) Blood and Thrombocytopenia, Lympha Leukopenia, tic Agranulocytosis, System Hemolytic anemia Disorde rs Immune Anaphylactic shock, System Anaphylactic reaction, Disorde Anaphylactoid reaction, rs Hypersensitivity Metabol ism and Nutritio Anorexia n Disorde rs Hallucination, Agitation, Excitability, Apathy, Psychia Confusional state, tric Insomnia, Irritability, Disorde Nervousness, rs Nightmare, Restlessness, Sleep disorder, Aggression Convulsions, Depressed level of consciousness, Sedation, Stupor, Nervous Lethargy, Paresthesia, System Somnole Extrapyramidal disorder, Disorde nce Coordination abnormal, rs Dyskinesia, Hypertonia, Hypotonia, Opisthotonus, Tremor, Ataxia,

4 / 7 System/ Adverse Drug Reactions Organ Frequency Category Class Uncommo Rare Not Very Commo Very rare Commo n n ≥ known ( 1/10,000 (≤1/10,000) n (≥1/100 (≥1/1,000 to

(≥1/10) to <1/10) to <1/100 <1/1,000) Dizziness, Headache, Dystonia, Disturbance in attention Eye Oculogyration, Vision Disorde blurred, Diplopia, rs Mydriasis, Gaze palsy Ear and Labyrint Tinnitus, Vertigo, h Hypoacusis Disorde rs Torsade de pointes, Ventricular fibrillation, Cardiac Ventricular arrhythmia, Disorde Ventricular extrasystoles, rs Arrhythmia, Tachycardia, Bradycardia, Palpitations Vascula r Shock, Hypotension, Disorde Flushing rs Respirat ory, Thoraci c and Bronchospasm, Mediasti Dyspnea, Nasal dryness nal Disorde rs Dry Reflux esophagitis, Gastroi mouth, Vomiting, Nausea, ntestina Gastroin Abdominal pain, l testinal Abdominal pain upper, Disorde disorder Dyspepsia, Diarrhea, rs Constipation Fatal liver failure, Hepatitis fulminant, Hepatitis cholestatic, Hepatob Hepatitis, Hepatocellular iliary damage, Hepatotoxicity, Disorde Jaundice cholestatic, rs Jaundice, Cholestasis, Hepatic function abnormal, Hepatic steatosis

5 / 7 System/ Adverse Drug Reactions Organ Frequency Category Class Uncommo Rare Not Very Commo Very rare Commo n n ≥ known ( 1/10,000 (≤1/10,000) n (≥1/100 (≥1/1,000 to

(≥1/10) to <1/10) to <1/100 <1/1,000) Toxic epidermal necrolysis, Stevens- Johnson syndrome, Skin Toxic skin eruption, and Erythema multiforme, Subcuta Erythema, Angioneurotic neous edema, Urticaria, Tissue Pruritus, Rash Disorde erythematous, rs Photosensitivity reaction, Drug eruption, Rash, Hyperhidrosis Muscul oskeleta l and Muscle rigidity, Muscle Connect weakness, Myalgia, ive Torticollis, Trismus Tissue Disorde rs Renal and Dysuria, Urinary Urinary retention Disorde rs Reprod uctive System Gynecomastia, and Galactorrhea Breast Disorde rs General Disorde Gait disturbance, rs and Fatigue, Malaise, Chest Adminis Asthenia discomfort, tration Hyperpyrexia, Pyrexia, Site Chills, Edema Conditi ons

6 / 7 System/ Adverse Drug Reactions Organ Frequency Category Class Uncommo Rare Not Very Commo Very rare Commo n n ≥ known ( 1/10,000 (≤1/10,000) n (≥1/100 (≥1/1,000 to

(≥1/10) to <1/10) to <1/100 <1/1,000) Electrocardiogram QT prolonged, Electrocardiogram abnormal, Liver function tests abnormal, Hepatic enzyme increased, Alanine aminotransferase Weight increased, Aspartate increase aminotransferase Investig d (and/or increased, Gamma ations Appetite glutamyl transferase increase increased, Blood bilirubin d) increased, Blood alkaline phosphatase increased, Blood creatine phosphokinase increased, Blood lactate dehydrogenase increased, Blood pressure decreased, Heart rate increased

Paediatric Patients The safety of Oxatomide was evaluated in 125 paediatric subjects (1 to 15 years) with perennial or seasonal allergies who participated in the same 1-month randomized, multicenter trial presented previously. These subjects took at least 1 dose of Oxatomide and provided safety data. Common ADRs (with % incidence) of Somnolence (13.6%) and Weight Increased and/or Appetite Increased (4.8%) were reported. The adverse events listed in Table 1 may also happen in the paediatric population.

4.9. Overdose

Symptoms The most commonly reported symptoms after overdosing are somnolence, stupor, and extrapyramidal symptoms such as dyskinesia, torticollis, oculogyria, dystonia, and hypertonia. Hyperexcitability and agitation are less common. Mydriasis and generalized muscle spasms have more rarely been reported. Very rare cases of coma, loss of consciousness, and QT prolongation have been reported following overdose.

Treatment There is no specific antidote available. Treatment consists of close observation of vital signs and supportive measures. An ECG should be performed to evaluate QT interval. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Extrapyramidal symptoms have been successfully treated with anticholinergic agents.

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