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Produktinformationen för Lunea 12,5 mg filmdragerad tablett , MTnr 49276, gäller vid det tillfälle då läkemedlet godkändes. Informationen kommer inte att uppdateras eftersom läkemedlet inte marknadsförs i Sverige. Av samma anledning finns inte någon svensk produktinformation.

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[Doxylamine hydrogen succinate]12.5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5 mg of doxylamine hydrogen succinate.

Excipients with known effect:

Cochineal red A colour (E-124)………….0.02 mg

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Elongated, pink coloured tablets.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Short-term symptomatic treatment of occasional insomnia in adults over 18 years old.

4.2 Posology and method of administration

Posology

Adults (over the age of 18)

For oral use.

The recommended dose is 12.5 mg to 25 mg (1 to 2 tablets), administered 30 minutes before bedtime.

In the event of drowsiness during the day, it is advisable to reduce the dose from 25 mg to 12.5 mg or take the dose earlier to ensure that at least 8 hours elapse before waking.

The maximum daily dose should not exceed 25 mg (2 tablets).

The duration of treatment should be as short as possible. In general, the length of treatment can vary from a few days to one week.

This medication should not be administered for periods exceeding 7 days unless deemed advisable, in the best judgment of the physician.

Paediatric population

[Doxylamine hydrogen succinate]is not recommended for children and/or adolescents under 18 years of age. The efficacy and safety of doxylamine as a night time sleep aid in children and/or adolescents under 18 years of age has not been established.

Elderly

Adults over 65 years of age are more likely to suffer other conditions that may require reducing the drug dose (see section 4.4). The recommended starting dose is 12.5 mg (1 tablet), administered 30 minutes before bedtime. The dose may be increased to 25 mg (2 tablets) if the initial dose provides insufficient relief of insomnia. If undesirable effects occur, the dose should be 12.5 mg (1 tablet) a day. Effect of treatment should be continuously evaluated.

Renal and/or liver impairment

Data is lacking in patients with impaired renal and hepatic function. Patients with renal and/or liver disease may be at greater risk for adverse effects from doxylamine due to drug and metabolite accumulation. Doxylamine is contraindicated in patients with severe renal and liver impairment, as well as end-stage renal disease, and should be avoided in patients with moderate renal or hepatic impairment. Dose reduction to a maximum daily intake of 12.5 mg is recommended for patients with mild renal or hepatic impairment (see sections 4.3 and 4.4).

Method of administration

For oral use.

The tablets should be taken 30 minutes before going to bed with a sufficient amount of liquid (preferably water).

[Doxylamine hydrogen succinate] can be taken before or after meals, since there are no resulting differences in the bioavailability of the drug (see section 5.2).

[Doxylamine hydrogen succinate]should not be taken with alcoholic beverages (see section 4.5).

4.3 Contraindications

• Hypersensitivity to doxylamine succinate or to any of the excipients listed in section 6.1.

• Hypersensitivity to other antihistamines. The possibility of cross reactions with other antihistamines must be taken into account, so no H1 antihistamine must be used in patients who have developed hypersensitivity to any compound of the group.

• Asthma

• Chronic bronchitis

• Pulmonary emphysema

• Glaucoma

• Prostatic hypertrophy

• Stenosing peptic ulcer

• Pyloroduodenal obstruction

• Bladder neck obstruction

• Severe renal and liver impairment.

• Concomitant use of with monoamine oxidase inhibitors (MAOIs).

• Concomitant use of strong enzyme inhibitors of CYP450 isoenzymes. These include ISRS (fluoxetine, fluvoxamine, paroxetine), macrolide antibiotics (clarithromycin, erythromycin, telitromycin), anti-arrhythmics (amiodarone), protease-inhibitor antivirals (indinavir, ritonavir, telaprevir) and azole antimycotics (fluconazole, ketoconazole, itraconazole, voriconazole), terbinafin, kinidin, nefazodon, bupropion and gemfibrozil.

• [Doxylamine hydrogen succinate] is contraindicated during lactation (see section 4.6).

4.4 Special warnings and precautions for use

[Doxylamine hydrogen succinate] is not recommended for periods exceeding 7 days, unless deemed advisable, in the best judgment of the physician.

If daytime sleepiness occurs, it is advisable to reduce the dose (see section 4.2) or to anticipate the administration to ensure a period of at least 8 hours until awaking.

Hepatic / Renal impairment

Caution is recommended in patients with mild to moderate renal and hepatic impairment.

Seizures

Caution should be recommended in patients with epilepsy, since antihistamines can sometimes cause hyperexcitability, even at therapeutic doses, and could therefore lower the seizure threshold.

Cardiac disorders

Patients with heart failure should be treated carefully. Special carefulness is necessary when treating patients with arterial hypertension because antihistamines may increase the blood pressure.

Caution is also recommended in patients with prolongation of the QT-interval although this effect has not been observed with doxylamine, other antihistamines can prolong the mentioned interval.

Auditory function

Doxylamine may mask the ototoxic effects of some drugs (parenteral aminoglucosides, carboplatin, cisplatin, chloroquine and erythromycin, among others); hearing function should therefore be checked regularly.

Dehydration

H1 antihistamines can aggravate the symptoms of dehydration and heat stroke due to the decreased sweating caused by anticholinergic effects.

Concomitant treatment with other CNS-depressants

Alcohol intake should be avoided during treatment (see section 4.5).

Doxylamine may produce additive central nervous system (CNS) effect when taken concomitantly with alcohol, hypnotics, sedatives and other drugs producing CNS depression. Moreover, the anticholinergic effect of antihistamines may be potentiated if the drug is used with anticholinergic or tricyclic antidepressants (see section 4.5).

Elderly

Caution is required in patients over 65 years of age, due to their greater sensitivity to the appearance of adverse reactions to this medication. Effect of treatment should be continuously evaluated (see section 4.2).

The anticholinergic drug action of doxylamine succinate usually manifests with the occurrence of dry mouth, constipation, urinary retention and blurred vision, while it may also increase day-time sleepiness and vertigo. Increased risk for fall has also been described in elderly (section 4.8).

Antihistamines often have anticholinergic activity, to which elderly patients are particularly sensitive. Therapy with antihistamines should be administered cautiously, if at all, in patients with pre-existing conditions that are likely to be exacerbated by anticholinergic activity, such as urinary retention or obstruction; angle-closure glaucoma, untreated intraocular hypertension, or uncontrolled primary open-angle glaucoma; and gastrointestinal obstructive disorders.

Other conditions requiring caution

- Hypopotassaemia or other electrolytic alterations.

- Urinary retention.

Grapefruit juice

It is unknown whether grape fruit juice inhibits the metabolism of doxylamine. The patient is encouraged to avoid grapefruit when using doxylamine.

Effects of doxylamine on the pharmacokinetics of other medicinal products

There is limited knowledge about the potential of doxylamine to inhibit the metabolism of other drugs. Therefore, medicinal products with a narrow therapeutic index should not be usedtogether with doxylamine, due to the risk of increased exposure to these drugs (see section 4.5).

Tolerance

Repeated use of hypnotics / sedatives may result in loss of efficacy (tolerance), despite this effect has not been described for doxylamine.

Anterograde amnesia

Even in therapeutic doses hypnotics can generate anterograde amnesia, especially during the first few hours of intake, despite this effect has not been described for doxylamine. The risk rises with rising dosages but can be reduced by sufficiently long and uninterrupted sleep (7 – 8 hours).

Warnings on excipients

This drug contains cochineal red A colour (E-124), which may cause allergic reactions. It can cause asthma, particularly in patients allergic to acetylsalicylic acid.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Alcohol consumption should be avoided during treatment with doxylamine, since it can intensify the effect of the latter in an unpredictable way.

Epinephrine for the treatment of hypotension should not be used in patients taking doxylamine, since epinephrine in such cases can induce a greater drop in blood pressure. However, norepinephrine can be used to treat severe shock (see section 4.9).

Since several antihistamines are able to prolong the QT-interval (though this effect has not been observed in the case of doxylamine), the concomitant administration of other drugs that prolong the QT-interval (e.g., antiarrhythmic agents, certain antibiotics, certain antimalarial drugs, certain antihistamines, certain lipid-lowering drugs, and certain neuroleptics) is to be avoided.

The concomitant administration of cytochrome P450 inhibitors (e.g., azole derivatives or macrolides), or drugs that produce electrolytic alterations such as hypopotassaemia or hypomagnesaemia (e.g., certain diuretics) is to be avoided.

Antihistamines cause additive effects with both alcohol and with other central nervous system depressants (e.g., barbiturates, hypnotics, sedatives, anxiolytic drugs, opioid-type analgesics, antipsychotic agents, procarbazine).

Antihypertensive drugs with effects upon the central nervous system, such as guanabenz, clonidine or alpha-methyldopa, can intensify sedative action when administered with antihistamines.

The anticholinergic effects may be enhanced when administering doxylamine concomitantly with other anticholinergic drugs (antidepressants, drugs for treating Parkinson's disease, MAOIs, neuroleptics, atropinic antispasmodic drugs, disopyramide).

The concomitant use of doxylamine with the following products should be carefully evaluated: antihistamines applied to the skin (such as diphenhydramine cream, ointment, spray), antispasmodics (e.g., atropine, belladonna alkaloids) and scopolamine.

Pharmacokinetic interactions

Effects of other medicinal products on doxylamine pharmacokinetics:

The enzymes responsible for doxylamine metabolism are not known. Strong inhibitors of CYP450 isoenzymes should therefore not be used together with doxylamine, due to the potential risk increased doxylamine exposure and thereby higher risk for adverse effects and daytime sedation. These include, ISRS (fluoxetine, fluvoxamine, paroxetine), macrolide antibiotics (clarithromycin, erythromycin, telitromycin), anti-arrhythmics (amiodarone), protease-inhibitor antivirals (indinavir, ritonavir, telaprevir) and azole antimycotics (fluconazole, ketoconazole, itraconazole), bupropion and gemfibrozil (see section 4.3).

Effects of doxylamine on the pharmacokinetics of other medicinal products

There is limited knowledge about the potential of doxylamine to inhibit the metabolism of other drugs. Therefore, medicinal products with a narrow therapeutic index should not be used together with doxylamine, due to the risk of increased exposure to these drugs.

Drug-food interactions

A bioavailability study carried out in healthy volunteers revealed no differences in drug bioavailability when administered under fasting conditions or with food.

Interactions with diagnostic tests

Doxylamine may interfere with allergen skin tests. It is advisable to suspend this medication three days before undergoing such tests.

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological studies with a doxylamine containing medical product did not provide evidence for teratogenic effects in humans. Experience with the use of doxylamine during the second and third trimester is insufficient. Pharmacological effects on the foetus cannot be excluded. Non clinical data are insufficient with respect to reproductive toxicity (see section 5.3). It is preferable to avoid the use of [Doxylamine hydrogen succinate]during pregnancy.

Breastfeeding

Physico-chemical data suggest excretion of doxylamine succinate in human breast milk.. As newborn infants may be more sensitive to the effects of the antihistamines and to paradoxical irritability and excitation a risk to the suckling child cannot be excluded. Doxylamine is therefore contraindicated during lactation (see section 4.3).

Fertility

No data are available on the possible effects of doxylamine upon human fertility. Studies in animals have demonstrated no effects upon fertility even at doses far higher than those recommended in clinical practice (see section 5.3).

4.7 Effects on the ability to drive and use machines

[Doxylamine hydrogen succinate] has an important effect upon the ability to drive and use machines. Since [Doxylamine hydrogen succinate]induces sleep, it can lessen alertness and reaction capacity. It is therefore advisable to avoid driving or the use of machines while taking this medication, at least during the first days of treatment, until it is determined whether it affects the ability to drive and use machines, in accordance to the dose used and the time elapsed.

4.8 Undesirable effects

Summarised safety profile

The undesirable effects caused by doxylamine are generally mild and transient, and are more common during the first days of treatment.

The most frequent undesirable effects are somnolence and anticholinergic effects: dry mouth, constipation, blurred vision, urinary retention, increased bronchial secretions and dizziness.

List of adverse reactions:

The adverse reactions reported in the context of post-marketing experience with the medication are presented in decreasing order within each frequency interval:

Very common (≥1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥1/1000 to < 1/100)

Rare (≥1/10,000 to <1/1000)

Very rare (<1/10,000), including isolated reports

Very common:

Nervous system disorders:somnolence.

Common:

Gastrointestinal disorders:dry mouth, constipation.

Eye disorders: blurred vision.

Ear disorders: dizziness (vertigo).

Renal and urinary disorders: urinary retention.

Respiratory, thoracic and mediastinal disorders:increased bronchial secretion.

Uncommon:

General disorders and alterations at the site of administration: asthenia, peripheral oedema.

Gastrointestinal disorders: nausea, vomiting, diarrhoea.

Skin and subcutaneous tissue disorders:skin rash.

Hearing and labyrinth disorders:tinnitus.

Vascular disorders:orthostatic hypotension.

Eye disorders:diplopia.

Rare:

Psychiatric disorders: restlessness (especially in elderly people).

Nervous system disorders: tremor, seizures.

Blood and lymphatic system disorders:haemolytic anaemia, thrombocytopaenia, leukopaenia, agranulocytosis.

Other adverse reactions of unknown frequency, reported in post-marketing experience with the medication, are:

General disorders and alterations at the site of administration: malaise.

Other adverse reactions that have been described in published clinical studies of doxylamine:

Common:

Nervous system disorders: dizziness, headache.

Gastrointestinal disorders: upper abdominal pain.

General disorders and alterations at the site of administration: fatigue.

Psychiatric disorders: insomnia, restlessness.

Uncommon:

Gastrointestinal disorders: dyspepsia.

General disorders and alterations at the site of administration: relaxation sensation.

Psychiatric disorders: nightmares.

Respiratory, thoracic and mediastinal disorders: dyspnoea.

Description of selected adverse reactions

Other drug class adverse reactions generally described for some antihistamines (not specifically referred to doxyalmine) are:

Cardiac disorders: arrhythmia, palpitations.

Gastrointestinal disorders: duodenogastric reflux.

Hepatobiliary disorders: altered liver function (cholestatic jaundice).

Complementary tests: prolonged QT-interval on the electrocardiogram.

Metabolism and nutrition disorders: lessened or increased appetite.

Musculoskeletal and connective tissue disorders: muscle pain.

Nervous system disorders: altered coordination, extrapyramidal disorders, paresthesia, altered psychomotor activity.

Psychiatric disorders: depression.

Respiratory, thoracic and mediastinal disorders: diminished bronchial secretion.

Skin and subcutaneous tissue disorders: alopecia, allergic dermatitis, hyperhidrosis, photosensitivity reactions.

Vascular disorders: hypotension.

The frequency and severity of the adverse reactions can be reduced by individualised adjustment of the daily dose.

Persons over 65 years of age have a greater risk of experiencing adverse reactions, since they may suffer from other conditions or may be taking other medications at the same time.

If adverse reactions occur, these should be reported to the pharmacovigilance system and, if necessary, treatment should be discontinued.

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

Doxylamine overdose rarely proves life-threatening. Recovery is generally complete within 24-48 hours.

As a general rule, the possibility of multiple intoxication should be considered (i.e., involving the ingestion of several medications).

The symptoms of an overdose are drowsiness, central nervous system stimulation or depression, anticholinergic effects (mydriasis, fever, dry mouth, diminished intestinal tone), flushing, tachycardia, hypertension, nausea, vomiting, restlessness, altered gait, dizziness, irritability, sedation, arrhythmias, confusion and hallucinations. Patients may suffer delirium, psychosis, hypotension, seizures, respiratory depression, loss of consciousness, coma and death.

A severe complication can be rhabdomyolysis, resulting in renal failure. Consequently, systematic evaluation is warranted, based on the determination of creatine phosphokinase (CPK) activity. These serious adverse reactions have not been described at therapeutic dosing, i.e. the dose attributed to the occurrence of rhabdomyolysis and death are 13 mg/kg and 25 mg/kg, respectively, which is nearly 100 times the therapeutic range. The prognosis depends on the underlying drug toxicity, which may contribute to the reported mortality of about 5% observed in serious rhabdomyolysis. Most cases are, however, mild. If there are no other underlying complications, acute renal failure in rhabdomyolysis is reversible and has an excellent prognosis, although recovery may be delayed.

The lack of a specific antidote to antihistamine overdose means that treatment should be symptomatic and of a supportive nature, with possible inclusion of the following:

- Induction of vomiting.

- Gastric lavage (pumping).

- Vasopressors to treat the hypotension, such as norepinephrine or phenylephrine. However, epinephrine should not be used since it may reduce arterial pressure even further.

No studies have been performed on the use of haemodialysis, haemofiltration or peritoneal dialysis in the context of doxylamine overdose. However, these measures may be of limited benefit, due to the extensive distribution of the drug. Nevertheless, in the event multiple intoxication cannot be ruled out, haemodialysis and peritoneal dialysis might be advisable. Forced diuresis is effective only to a limited extent.

Early detection and treatment of rhabdomyolysis is necessary to minimise kidney damage. Treatment of rhabdomyolysis induced by doxylamine overdose is by aggressive hydration and urine alkalisation. Aggressive hydration with intravenous crystalloids such as 0.9% saline (NS) or lactated Ringer’s solution (LR) at a rate of 300–500 ml/h in an adult is essential. To date, it has been believed that there is no difference in effectiveness between NS and LR.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihistamines for systemic use, aminoalkyl ethers, doxylamine. ATC code: R06AA09.

Mechanism of action:

Doxylamine is an ethanolamine-derivative antihistamine with competitive, reversible and nonspecific antagonistic action upon the H1 histamine receptors.

Pharmacodynamic effects:

Doxylamine exerts potent hypnotic and sedative action as well as anti-emetic and anticholinergic activity. Doxylamine can cross the blood-brain barrier and acts upon the central H1 receptors, producing a sedative effect. It seems that this sedative effect may also occur due to antagonism of the muscarinic and serotonergic receptors.

Clinical efficacy and safety:

Doxylamine is effective in decreasing sleep onset latency and in increasing the depth of sleep and its duration.

The sleep inducing effect is reached within 30 minutes and it is maximum between 1-3 hours after administration corresponding to time for maximal plasma concentrations. The adverse events profile of doxylamine is due mainly to its pharmacology (combined anticholinergic/ histaminergic) and pharmacokinetics. Residual daytime sedation due to the half-life of doxylamine may follow when administered at bedtime. The degree of wakefulness and performance the following day has not been adequately investigated.

5.2 Pharmacokinetic properties

Absorption:

Doxylamine is very soluble, and in vitrostudies in Caco-2 cells suggest high permeability. The time to peak plasma concentration following oral administration is 2-3 hours (T_max).

A bioavailability study in healthy volunteers under fasting conditions and in the presence of food using [Doxylamine hydrogen succinate]25 mg film-coated tablets yielded the following pharmacokinetic results:

Parameter	With food		Fasting conditions
	Mean	CV (%)	Mean	CV (%)
Cmax (ng/ml)	120.99	15.0	118.21	19.2
Tmax * (hours)	2.50	41.7	2.00	27.7
AUCt (ng·h/ml)	1712.20	26.7	1746.97	31.6
AUC∞ (ng·h/ml)	1798.14	29.6	1830.05	33.6
AUCt/∞ (%)	95.84	3.2	95.91	2.2
Kel (hours-1)	0.0544	22.3	0.0553	24.4
T1/2el (hours)	13.49	28.1	13.11	19.5

* The median is presented for T_max, based on statistical analysis adopting a nonparametric approach.

Distribution:

Distribution of the drug is generally rapid. Binding to plasma proteins is low compared with other antihistamines (24% to human albumin). Doxylamine crosses the blood-brain barrier.

Biotransformation:

The biotransformation of doxylamine has not been exhaustively studied, and the enzymes involved have not been identified. The major metabolic pathways are N-demethylation, N-oxidation, hydroxylation, N-acetylation, N-desalkylation and ether cleavage. Doxylamine is a phenobarbital-type inducer of cytochrome P450 in mice, but it is still unclear if doxylamine can act as an enzyme inducer in human.

Elimination:

Doxylamine succinate has an elimination half-life of about 10-13 hours in healthy young adults, increasing to about 12-16 hours in the elderly. The drug is primarily excreted in the urine as unchanged doxylamine (approximately 60%), and as nordoxylamine and dinordoxylamine metabolites.

Data is lacking on the pharmacokinetics of doxylamine in patients with impaired renal and hepatic function. Increased drug exposure is however expected.

5.3 Preclinical safety data

Data from non-clinical studies revealed no special hazard for humans based on conventional studies of genotoxicity, chronic toxicity, reproductive and developmental toxicity.

Repeat dose toxicity studies have shown the oral administration of doxylamine to produce liver damage in rodents. Doxylamine is a potent inductor (phenobarbital type) of liver cytochrome P450 in mice, although no evidence has been found of this induction in humans. Repeat dose toxicity studies in dogs resulted in reduced weight gain and additionally mydriasis and tremor.

In the carcinogenicity studies (104 weeks), doxylamine induced liver tumours in mice and rats, and thyroid tumours in mice. The induction of CYP450 enzyme and thyroxine glucuronidation, with the subsequent decrease in serum thyroxine levels and increase in thyroid stimulating hormones, are the most probable mechanisms underlying the induction of these tumours in animals. This mechanism is not considered relevant for humans. In the studies described above systemic exposure data is lacking.

Studies in mice show that doxylamine crosses the placental barrier, and the drug is detected in the embryos at concentrations above the pregnant female plasma levels. No effects upon fertility in rats have been observed even at doses far higher than those recommended in clinical practice. Data on peri- and postnatal development is lacking.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core excipients:

Calcium hydrogen phosphate dihydrate (E-341)

Microcrystalline cellulose (E-460)

Sodium starch glycolate (type A) (potato starch)

Colloidal anhydrous silica (E-551)

Magnesium stearate (E-572)

Coating excipients:

Hypromellose (E-464)

Microcrystalline cellulose (E-460)

Macrogol 40 stearate Type I (E-431)

Propylene glycol (E-1520)

Titanium dioxide (E-171)

Cochineal red A colour (E-124)

Macrogol 400

Macrogol 6000

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

[Doxylamine hydrogen succinate]12.5 mg film-coated tablets are supplied in Aluminium blisters of 7 and 14 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation:

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]