LOPRAZOLAM 1 MG TABLETS - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Loprazolam 1mg Tablets

Dormonoct

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains loprazolam mesylate equivalent to 1mg loprazolam.

Excipients with known effect: Each tablet contains 85.155 mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Light yellow, biconvex, round tablets, 7mm in diameter marked with an ‚A‘ and ‚026‘ separated by a score line on one side. The other side is blank.

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: Dosage in the elderly should be limited to 1mg at bedtime.

Frail, debilitated or aged patients: A starting dose of a half tablet may be appropriate.

Dosage should not exceed 1mg.

Treatment should if possible be intermittent.

The lowest dose to control symptoms should be used. As with all hypnotics, long-term use of loprazolam is not recommended. Treatment should be as short as possible. Generally the duration of treatment varies from a few days to two weeks, with a maximum of four weeks, including tapering off process.

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.

Extension beyond the maximum treatment period should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with the duration of treatment.

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

4.3 Contraindications

Sensitivity to benzodiazepines, 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.

4.4 Special warnings and precautions for use

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.

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. Use of loprazolam may lead to the development of abuse and/or physical and psychological dependence. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of psychiatric disorders and/or alcohol or drug abuse. Therefore, loprazolam should be used with extreme caution in patients with current or a history of alcohol 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.

Rebound insomnia may also occur. It may be accompanied by other reactions such as changes in mood, anxiety, sleep disturbances and restlessness. The cause of insomnia should be identified wherever possible and the underlying factors treated before a hypnotic is prescribed.

Loprazolam should be used with caution in chronic pulmonary insufficiency, cerebrovascular disease and chronic renal or hepatic impairment.

Risks  from concomitant use of benzodiazepines and opioids

Concomitant use of benzodiazepines, including loprazolam, and opioids may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe loprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. (See Section 4.5)

Suicidal ideation/suicide attempt/suicide and depression

Some epidemiological studies suggest an increased incidence of suicidal ideation, suicide attempt and suicide in patients with or without depression, and treated with benzodiazepines and other hypnotics, including loprazolam. However, a causal relationship has not been established.

Fall

Due to its pharmacological properties, loprazolam can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries, especially in elderly (see section 4.8).

Excipients

Loprazolam contains lactose. Patients with rare hereditary problems of galactose intolerance, total 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.

Concommitant 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.

Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of sedation, respiratory depression, coma, and death, because of additive CNS depressant effect.

Limit dosage and duration of concomitant use of benzodiazepines and opioids. (See Section 4.4)

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from the use of loprazolam in pregnant women. Nevertheless, a large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of major malformations following exposure to benzodiazepines during the first trimester of pregnancy, although incidence of cleft lip and palate were reported in certain case-control studies.

The use of loprazolam is not recommended during pregnancy.

Benzodiazepines cross the placenta.

Women of childbearing potential should be informed to contact her physician regarding discontinuation of the product if they are pregnant or intend to become pregnant.

Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during the second and/or third trimester of pregnancy.

If loprazolam is administered during the late phase of pregnancy or during childbirth at high doses, effects on the neonate, such as respiratory distress, hypothermia, hypotonia, and feeding difficulties in the newborn are to be expected.

Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk of developing a withdrawal syndrome in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.

Breast-feeding

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”).

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

In general, Loprazolam is very well tolerated. However, the common side effects of benzodiazepines, including headaches, nausea, drowsiness, hypotonia, blurring of vision, dizziness and ataxia may occur on the following day, particularly in unusually sensitive patients or when dosage has been excessive.

Rare behavioural adverse effects of benzodiazepines include paradoxical aggressive outbursts, excitement, confusion and the uncovering of depression with suicidal tendencies. If these reactions should occur, use of the drug should be discontinued. Even more rare side effects reported with some benzodiazepines have been hypotension, gastro-intestinal and visual disturbances, skin rashes, urinary retention, changes in libido, blood dyscrasias and jaundice.

Frequency not known: speech disorders

Benzodiazepines may induce cognitive disorders (anterograde amnesia). In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Injury poisoning and procedural complications

Fall (see Section 4.4)

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 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

Benzodiazepines have a widespread action as a result of their enhancing the release of gamma-aminobutyric 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'/z) was calculated. The area under the serum concentration-time curve (AUC) was determined using the trapezoidal rule. The ratios of AUC and Cmax after repeated doses to AUC and Cmax after single doses were used to assess possible accumulation of Loprazolam.

n = 6 subjects, except for *n = 5, **n = 3.

5.3 Preclinical safety data

No additional data of relevance to the prescriber.

6.1 List of excipients

Povidone, Lactose, Colloidal silicon dioxide, Maize starch, Microcrystalline cellulose and Magnesium stearate.

6.2 Incompatibilities

None.

6.3 Shelf Life

24 months.

6.4 Special precautions for storage

Store below 25°C in a dry place. Protect from light.

6.5 Nature and contents of container

UPVC/aluminium foil blisters, packaged in cartons of 10, 28 or 30 tablets.