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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Loprazolam 1mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Loprazolam Mesilate equivalent to 1mg Loprazolam.

Each tablet contains 41.855mg of lactose anhydrous.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Light yellow, biconvex, round, uncoated tablets with ‘L1’ debossed on one side and deep break line on other side.

The tablet can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Loprazolam is indicated for the short-term treatment of insomnia including difficulty in falling asleep and/or frequent nocturnal awakenings. Benzodiazepines should be used to treat insomnia only when it is severe, disabling or subjecting the individual to extreme distress. An underlying cause of insomnia should be sought before deciding upon the use of benzodiazepines for symptomatic relief.

4.2 Posology and method of administration

Adults: The recommended dose is 1mg at bedtime. This may be increased to 1.5mg or 2mg if necessary.

Elderly and debilitated patients: A starting dose of a half tablet may be appropriate. Dosage in the elderly should be limited to 1mg at bedtime.

Treatment should if possible be intermittent.

Dosage and duration of therapy should be individualized. The lowest dose to control symptoms should be used. Treatment should not normally be continued beyond 4 weeks.

Long term chronic use is not recommended.

Treatment should always be tapered off gradually.

Patients who have taken benzodiazepines for a long time may require a longer period during which doses are reduced.

Children: There is insufficient evidence to recommend the use of Loprazolam in children.

4.3 Contraindications

Hypersensitivity to the active substance, other benzodiazepines or to any of the excipients listed in section 6.1.

Acute pulmonary insufficiency.

Severe respiratory insufficiency.

Myasthenia gravis.

Phobic or obsessional states and sleep apnoea syndrome.

Monotherapy in depression or anxiety associated with depression and chronic psychosis and alcohol intake.

Severe hepatic insufficiency.

Pregnancy and lactation (see also 4.6 “Fertility, pregnancy and lactation”).

4.4 Special warnings and precautions for use

Psychiatric and paradoxical reactions

Benzodiazepines may cause reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects. Should this occur, treatment should be discontinued.

These reactions are more common in children and the elderly, and in patients with organic brain syndrome.

Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed and who exhibit aggressive behaviour towards self and others. Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders.

Duration of treatment

The duration of treatment should be as short as possible (see also 4.2. “Posology and method of administration”). Generally it varies from a few days to two weeks with a maximum period of four weeks, including the time required for gradual withdrawal of the medication.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain clearly how the dose will be gradually decreased.

Treatment must never be prolonged without re-assessment of the patient. Dependence

In general, the dependence potential of benzodiazepines is low but this increases when high doses are attained, especially when given over long periods and particularly in patients with a history of alcoholism or drug abuse. However, withdrawal symptoms occur even with normal therapeutic doses given for short periods of time. Withdrawal from benzodiazepines may be associated with physiological and psychological symptoms of withdrawal including depression, anxiety, tension, restlessness, confusion, irritability and headaches. Patients receiving benzodiazepines should be regularly monitored. Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. Therefore, the drug should always be discontinued gradually.

Rebound insomnia may also occur. It may be accompanied by other reactions such as changes in mood, anxiety, sleep disturbances and restlessness.

Tolerance

Some loss of efficacy with regard to the hypnotic effects may develop after repeated use for a few weeks.

Patients should be advised that since their tolerance for other CNS depressants will be diminished in the presence of Loprazolam, these substances should either be avoided or taken in reduced dosage.

Amnesia

Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after administration of the product and therefore to reduce the associated risk, patients should ensure that they will be able to have uninterrupted sleep for 7-8 hours (see section 4.8 “Undesirable effects”). Loprazolam should be used with caution in chronic pulmonary insufficiency, cerebrovascular disease and chronic renal or hepatic impairment.

Caution should be used in the treatment of patients with narrow-angle glaucoma.

This product contains lactose, 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

Loprazolam may be potentiated by alcohol or other drugs acting on the CNS or with Cisapride. Additive synergy has been observed with neuromuscular depressants (curare-like drugs and muscle relaxants).

Combination with CNS depressants e.g. antipsychotics, hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines, causes enhancement of the central depressive effects of Loprazolam.

Concomitant intake with alcohol is not recommended. The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machinery.

The risk of a withdrawal syndrome occurring is increased when Loprazolam is combined with other benzodiazepines prescribed as anxiolytics or hypnotics.

4.6 Fertility, Pregnancy and lactation

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression can be expected due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependency and may be at some risk for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, they should not be given to breast feeding mothers.

4.7 Effects on ability to drive and use machines

Attention should be drawn to the risk of drowsiness, sedation, amnesia, impaired concentration and muscular weakness, especially in drivers of vehicles and operators of machines, when taking the product (see also “Interactions”).

4.8 Undesirable effects

In general, Loprazolam is very well tolerated .

The following undesirable effects have been observed and reported during treatment with benzodiapines with the following frequencies: 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).

MedDRA System Organ Class	Frequency	Undesirable effects
Blood and lymphatic disorders	Very rare	Blood disorder
Psychiatric	Rare	Aggression, agitation, confusional
disorders	Very rare Not known	state, uncovering depression, suicidal ideation Libido disorder Psychological trauma
Nervous system	Common	Headache, somnolence,
disorders		hypotonia, dizziness, ataxia
	Not known	Anterograde amnesia
Eye disorders	Common	Blurred vision
	Very rare	Visual impairment
Vascular disorders	Very rare	Hypotension
Gastrointestinal disorders	Common	Nausea
	Very rare	Gastrointestinal disorders
Hepatobiliary disorders	Very rare	Jaundice
Skin and subcutaneous tissue disorders	Very rare	Rash
Renal and urinary disorders	Very rare	Urinary retention

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 at: www.mhra.gov.uk/yellowcard.

Overdose

As with other benzodiazepines, overdosage does not usually present a threat to life. Treatment is symptomatic and gastric lavage may be of use if performed shortly after ingestion. Use of a specific antidote such as flumazenil in association with symptomatic treatment in hospital should be considered.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Benzodiazepines, ATC code: N05CD11

Benzodiazepines have a widespread action as a result of their enhancing the release of gamma-amino butyric acid (GABA). They are effective as anti-convulsants, muscle relaxants, anti-anxiety agents, pre-medications and sedative hypnotics.

5.2    Pharmacokinetic properties

The pharmacokinetics of oral Loprazolam given in a single dose or in repeated doses on 7 consecutive nights were studied in a balanced cross-over trial in six healthy male subjects aged 22-37 years. The subjects were allocated randomly to the treatment phases which were separated by 2-week drug-free intervals. Loprazolam was administered as 1mg tablets.

On the night of administration of the single dose and the seventh repeated dose, venous blood samples were taken before and at intervals after treatment. Serum Loprazolam concentrations were measured using both a radioimmunoassay (RIA) and the more specific high pressure liquid chromatography and gas chromatography (HPLC/GC) technique. Maximum serum levels (Cmax) and the time taken to achieve them (Tmax) were measured, and the half-life (t_1/2) was calculated. The area under the serum concentration-time curve (AUC) was determined using the trapezoidal rule. The ratios of AUC and C_max after repeated doses to AUC and C_max after single doses were used to assess possible accumulation of Loprazolam._

5.3 Preclinical safety data

No additional data of relevance to the prescriber.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Anhydrous Microcrystalline Cellulose Magnesium Stearate

6.2    Incompatibilities

None

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 25^oC. Store in the original package in order to protect from light and moisture.

Nature and contents of container

Alu/PVC Blisters, packaged in cartons of 7, 10, 14, 15, 20, 28, 30 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

PRIMEGEN Limited Unit 15 Moorcroft,

Harlington Road,

Uxbridge,

UB8 3HD UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 43659/0014

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/03/2014

10 DATE OF REVISION OF THE TEXT

03/03/2015