SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Dimenhydrinate [MAH] 6.2 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection contains 6.2 mg dimenhydrinate. 1 ampoule of 10 ml solution for injection contains 62 mg dimenhydrinate.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for injection

Clear, colourless solution with a pH of 6.5 – 7.5

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Dimenhydrinate [MAH] can be used for prophylaxis and symptomatic treatment of nausea and vomiting of different genesis, in particular kinetosis.

Note: Dimenhydrinate is not appropriate as a sole agent for treatment of chemotherapy induced nausea and vomiting.

4.2 Posology and method of administration

Posology

Usual dose for:

Adults and adolescents aged 14 years and over: 1 – 3 ampoules (corresponding to 62 – 186 mg dimenhydrinate) per day. The maximum daily dose of 400 mg should not be exceeded.

Children aged 6 to 14 years: 1 – 3 times daily 25 – 50 mg dimenhydrinate. The maximum daily dose of 150 mg should not be exceeded.

Children ≥ 6 kg bodyweight: 1 – 3 times daily 1.25 mg dimenhydrinate/kg body weight.

Method of administration For prophylaxis of motion sickness the first dose is given approx. ½ - 1 hour before start of journey. For the treatment of nausea and vomiting the doses are administered at regularly intervals throughout the day.

1 Dimenhydrinate [MAH] is administered very slowly by intravenous injection (10 ml in not less than 2 min). When applied via an injection port of an i.v. cannula the venous access should be flushed afterwards with Sodium chloride 9 mg/ml (0.9 %) solution for injection or Ringer’s solution.

For administration of an intravenous infusion, Dimenhydrinate [MAH] can be added to the following solutions for infusion: Glucose 5 % or 10 % Sodium chloride 9 mg/ml (0.9 %) solution for injection Ringer’s solution

Dimenhydrinate [MAH] is intended for short term use only. Therefore, a doctor should be consulted if symptoms persist. At the latest 2 weeks after start of treatment it should be checked whether treatment with Dimenhydrinate [MAH] is still necessary.

4.3 Contraindications

Dimenhydrinate [MAH] is contraindicated in patients with: - hypersensitivity to dimenhydrinate or other antihistamines, - acute asthma attack, - narrow-angle glaucoma, - pheochromocytoma, - porphyria, - prostatic hypertrophy with generation of residual urine, - seizures/convulsions (epilepsy, eclampsia).

4.4 Special warnings and precautions for use

Dimenhydrinate [MAH] should be used with caution in patients with: - impaired liver function, - hypokalaemia, hypomagnesaemia, - cardiac dysrhythmia/arrhythmia (e.g. tachycardia), - bradycardia, - congenital long QT syndrome or other clinical significant cardiac disorders (particularly coronary heart disease, conduction disturbance), - concomitant treatment with medicinal products that also cause prolongation of the QT interval (e.g. antiarrhythmic drugs class IA or III, antibiotics, malaria drugs, antihistamines, neuroleptics) or lead to hypokalaemia (see section 4.5), - chronic breathing difficulties and asthma, - pyloric stenosis.

4.5 Interaction with other medicinal products and other forms of interaction

If used concomitantly, the effects of dimenhydrinate and other CNS depressants (antipsychotic drugs, hypnotics, sedatives, analgesics, narcotics) may be enhanced.

The anticholinergic effect of dimenhydrinate (see section 4.8) may be potentiated in a non- predictable way if taken concomitantly with other agents with anticholinergic activity (e.g. atropine, biperiden, or tricyclic antidepressants).

When dimenhydrinate is given in conjunction with monoamine oxidase inhibitors enteroparesis that may be life-threatening, urinary retention or an increased intraocular pressure may develop. In addition, a drop in blood pressure may occur and central nervous system and breathing dysfunctions may be enhanced. Therefore, dimenhydrinate must not be used in conjunction with monoamine oxidase inhibitors.

2 The concomitant use of medicinal products that also prolong the QT interval (e.g. antiarrhythmic drugs class IA or III, antibiotics, malaria drugs, neuroleptics) or lead to hypokalaemia (e.g. certain diuretics) should be avoided (see section 4.4, 4.9 and 5.3).

The concomitant use of dimenhydrinate with antihypertensive medicinal products can lead to increased tiredness or to increased hypotensive effect.

Dimenhydrinate may cause false-negative results in allergy tests.

Caution should be used if dimenhydrinate is given during therapy with aminoglycoside antibiotics because it may mask ototoxic symptoms.

Alcohol consumption should be avoided during dimenhydrinate treatment because alcohol can change or increase the effects of dimenhydrinate in a non-predictable manner. The ability to drive and use machines is further impaired.

4.6 Fertility, pregnancy and lactation

Pregnancy There are inconsistent reports about the safe use of Dimenhydrinate [MAH] during pregnancy. A prospective study on pregnant women did not reveal any evidence for a relationship between dimenhydrinate treatment and malformations. Another study described an association between cardiovascular defects or inguinal hernia with dimenhydrinate exposition during pregnancy. A case-control study included 38,151 new-borns without congenital malformations and 22,843 with congenital malformations of whom a total of 2,640 children were exposed to dimenhydrinate. Dimenhydrinate showed no evidence of teratogenic potential. There are no indications that dimenhydrinate application leads to a higher abortion rate during the first trimester of pregnancy. Dimenhydrinate can stimulate preterm uterine contractions and increases the risk for premature labour. Animal studies with dimenhydrinate are insufficient with respect to reproductive toxicity (see section 5.3).

Dimenhydrinate [MAH] should only be used during pregnancy if a therapy without medication or a treatment with other, safe medicinal products were not effective. Dimenhydrinate [MAH] should not be used during the third trimester because it can trigger preterm uterine contractions.

Breastfeeding Dimenhydrinate is excreted into human breast milk. There are no data about the use of dimenhydrinate during breast feeding. Because undesirable effects on a nursing infant such as increased irritability cannot be excluded, either Dimenhydrinate [MAH] treatment should be discontinued or breast feeding should be discontinued.

Fertility No data are available (see section 5.3).

4.7 Effects on ability to drive and use machines

Drowsiness, disturbances of memory and a decreased ability to concentrate may negatively influence the ability to drive and use machines. This has to be considered especially after an insufficient sleeping period, when starting treatment, when changing medication or when concomitantly alcohol is used (see also section 4.5).

4.8 Undesirable effects

3 The frequency of undesirable effects listed in table 1 is classified according to 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

Especially at the beginning of the treatment undesirable effects such as somnolence, drowsiness, dizziness, and muscle weakness may occur depending on the individual susceptibility and dose. These side effects can last into the following day.

Table 1: Adverse reactions reported with dimenhydrinate

System organ class Frequency Blood and lymphatic Not known system disorders In exceptional cases blood cell damages can occur. Psychiatric disorders Common mood swings Not known drug dependence Nervous system Very Common disorders somnolence, drowsiness, dizziness Common restlessness, agitation, insomnia, anxiety, tremor Eye disorders Common visual disturbances, increased intraocular pressure Cardiac disorders Common tachycardia Gastrointestinal Common disorders nausea, pain in the stomach region, vomiting, obstipation, diarrhoea Hepato-biliary Not known disorders liver dysfunction (cholestatic icterus) Skin and subcutaneous Common tissue disorders dryness of mouth, nasal obstruction Not known allergic skin reactions and sensitivity to light (direct sun exposure should be avoided) Musculoskeletal and Very Common connective tissue muscle weakness disorders Renal and urinary Common disorders urinary dysfunctions

4 Sudden discontinuation after long-term daily treatment can temporarily cause insomnia. Therefore, treatment should be discontinued by gradually decreasing the dose in these cases.

As with other medicinal products with a hypnotic effect, development of drug dependence cannot be ruled out after long-term therapy. Therefore, the indication for a treatment longer than only short-term should be carefully checked.

Paediatric population

Particularly in children, there is the possibility of paradoxical reactions such as restlessness, excitation, insomnia, anxiety and shaking (tremor).

4.9 Overdose

Intoxications with dimenhydrinate, the active substance of Dimenhydrinate [MAH] can be life-threatening. Children are at special risk.

In case of overdose or intoxication with Dimenhydrinate [MAH] immediate medical attention is needed.

The signs of overdose with Dimenhydrinate [MAH] are mainly characterised by different stages of impaired consciousness, ranging from strong drowsiness to coma - depending on the applied dose. Apart from this, signs of the anticholinergic syndrome are observed: mydriasis, vision disturbances, tachycardia, hyperthermia, hot, reddened skin and dry mucosal membranes, constipation, CNS caused restlessness, anxiety, agitation, increased muscle reflexes, and hallucinations. Furthermore, tonic-clonic seizures and respiratory depression may occur that after high doses can lead to respiratory paralysis and cardiac arrest. In addition, cardiac dysrhythmias like prolonged QT intervals (whereas torsades de pointes cannot be ruled out) are possible.

In case of overdose vomiting should not be induced independently from the pharmaceutical form the patient received.

Further treatment should be based on the respective symptoms: in case of spasm diazepam can be given, fever-reducing treatment if necessary, artificial respiration in case of potential respiratory paralysis. Physostigmine salicylate is recommended as an antidote for anticholinergic symptoms (after performing a physostigmine test).

Due to high degree of plasma protein binding and a high distribution volume forced diuresis or haemodialysis are not effective in case of intoxications with dimenhydrinate as a sole agent.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, antihistamines

ATC code: A04AB02

Dimenhydrinate is the salt of diphenhydramine and 8-chlortheophylline. The pharmacological effects are caused by diphenhydramine.

Diphenhydramine is an ethanolamine derivate with H1 antihistaminic, anticholinergic and pronounced CNS sedating properties. In addition, dimenhydrinate has antiemetic and local anaesthetic effects.

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5.2 Pharmacokinetic properties

Dimenhydrinate has a good absorption after oral or rectal application. In blood it dissociates in diphenhydramine and 8-chlortheophylline.

Diphenhydramine has a pronounced first-pass metabolism in the liver (approx. 50 %).

Generally, the duration of effect is 3 – 6 hours.

Diphenhydramine is well distributed in the body, including the CNS. The redistribution from blood to tissue is fast. The relative volume of distribution is 3 to 4 l/kg. Dimenhydrinate binds strongly to plasma proteins, passes the placental barrier and is excreted into human breast milk.

Dimenhydrinate is metabolised in the liver and excreted mainly by the kidneys, mostly as metabolite and completely eliminated within 24 hours.

5.3 Preclinical safety data

Limited experience from animal studies with single and repeated dose application reveal no additional specific hazards to humans, beyond those already mentioned in other parts of the SmPC.

In electrophysiological in vitro tests with concentrations that exceeded the therapeutically effective dose by a factor of approximately 40, diphenhydramine blocked the rapid delayed rectifier K+ channel and extended the duration of the action potential. Therefore, diphenhydramine has the potential to induce torsade de pointes arrhythmias, if there are additional auxiliary factors. This is supported by single case reports of diphenhydramine.

Dimenhydrinate was tested in vitro for mutagenic effects. The tests did not show any relevant indications for mutagenic effects.

There are no data from long-term carcinogenicity studies with dimenhydrinate. Carcinogenicity studies with diphenhydramine did not provide any indication of a tumour- inducing potential in humans.

Reproductive toxicity Dimenhydrinate is only insufficiently investigated for reproductive toxicity. Animal studies on embryo- and foetal- toxicity of dimenhydrinate were negative, but the amount of data was insufficient. Animal studies have not been performed to assess the risk of impairment of fertility.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6 Incompatibilities can occur if Dimenhydrinate [MAH] solution for injection is mixed with medicinal products containing the following active substances: - Aminophylline - Heparin sodium - Hydrocortisone sodium succinate - Hydroxyzine hydrochloride - Phenobarbitone sodium - Phenytoin sodium - Prednisolone sodium phosphate - Promazine hydrochloride - Promethazine hydrochloride - Midazolam

6.3 Shelf life

unopened ampoule 2 years

shelf life after first opening For single use only.

shelf life after dilution Chemical and physical in-use stability has been demonstrated for 72 hours at 15 to 25 °C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the ampoules in the outer carton in order to protect from light.

6.5 Nature and contents of container

10 ml colourless glass ampoules (type I) in packs of 1, 3, 5, 6 or 10.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Dimenhydrinate [MAH] is compatible with the following solutions: - Glucose 5 % or 10 %, - Sodium chloride 9 mg/ml (0.9 %) solution for injection, - Ringer’s solution.

Dimenhydrinate [MAH] is preservative free and is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. The medicinal product should be inspected visually prior to use. The solution should only be used if it is clear, practically free from particles and if the container is undamaged.

7. MARKETING AUTHORISATION HOLDER

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[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

{DD/MM/YYYY} [To be completed nationally]

10. DATE OF REVISION OF THE TEXT

{MM/YYYY} [To be completed nationally]

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