It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.

Roche Products (Ireland) Ltd

3004 Lake Drive, Citywest, Naas Road, Dublin 24,
Telephone: +353 1 469 0700
Fax: +353 1 469 0791
Medical Information e-mail: ireland.druginfo@roche.com

Summary of Product Characteristics last updated on medicines.ie: 28/07/2009

Rohypnol



1. NAME OF THE MEDICINAL PRODUCT

Rohypnol 1 mg film-coated tablets.


2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 mg tablet contains 1 mg of the active ingredient flunitrazepam.

For a full list of excipients see section 6.1.

Each tablet contains 117 mg of lactose. For warnings related to lactose, see section 4.4 Special warnings and precautions for use.


3. PHARMACEUTICAL FORM

Film-coated tablets (tablets).

Greyish-green oval shaped tablet with a break line on one side and 542 on the other side.

The tablet can be divided into equal halves.


4. CLINICAL PARTICULARS

4.1 Therapeutic indications

In the short-term management of disabling or severely distressful insomnia.


4.2 Posology and method of administration

Treatment should be as short as possible and should be started with the lowest recommended dose. The maximum dose should not be exceeded. Generally the duration of treatment varies from a few days to two weeks with a maximum of four weeks, including the tapering off process. Patients who have taken benzodiazepines for a prolonged time may require a longer period during which doses are reduced. Specialist help may be appropriate. Little is known regarding the efficacy or safety of benzodiazepines in long-term use.

In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status. Long-term chronic use is not recommended.

The product should be taken just before going to bed. Rohypnol tablets are for oral administration.

Adults

Usual dose 0.5 - 1mg; in exceptional circumstances the dose may be increased to 2mg.

Elderly or debilitated patients

Usual dose 0.5mg; in exceptional circumstances, the dose may be increased to 1mg. If organic brain changes are present, the dosage of Rohypnol should not exceed 0.5mg in these patients.

In patients with chronic pulmonary insufficiency (see section 4.4 Special warnings and precautions for use) and in patients with chronic renal or hepatic disease, dosage may need to be reduced.

Children

Rohypnol tablets are contraindicated for use in children.


4.3 Contraindications

1. Use in patients hypersensitive to flunitrazepam or any of the benzodiazepines, or to any of the excipients.

2. Use in children.

3. Use in patients with respiratory depression.

4. Use in patients with phobic or obsessional states or chronic psychoses.

5. Use in patients with myasthenia gravis.

6. Use in patients with sleep apnoea syndrome.

7. Use in patients with severe hepatic insufficiency.

8. Use in patients with acute pulmonary insufficiency.


4.4 Special warnings and precautions for use

Tolerance

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

Dependence

Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see section 4.8 Undesirable effects). The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.

Regular monitoring of such patients is essential; routine repeat prescriptions should be avoided and treatment should be withdrawn gradually. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of depression, nervousness, sweating, mood changes, diarrhoea, rebound insomnia, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact and hallucinations or epileptic seizures. In rare instances, withdrawal following excessive dosages may produce confusional states and psychotic manifestations.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment it is recommended that the dosage is decreased gradually.

Abuse of flunitrazepam has been reported.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2 Posology and method of administration) depending on the indication, but should not exceed four weeks for insomnia and eight to twelve weeks in case of anxiety, including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Amnesia

Benzodiazepines may induce anterograde amnesia. The condition usually occurs several hours after ingesting the product and therefore, to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7 to 8 hours (see also section 4.8 Undesirable effects).

Psychiatric and “paradoxical” reactions

Reactions like paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucination, psychoses, inappropriate behaviour, the uncovering of suicidal tendencies and other adverse behavioural effects are known to occur when using benzodiazepines. Extreme caution should therefore be used in prescribing benzodiazepines to patients with personality disorders. Should this occur, use of the drug should be discontinued. These reactions may be quite severe and are more likely to occur in the elderly.

Concomitant use of alcohol and/or CNS depressants

The concomitant use of Rohypnol with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Rohypnol, possibly including severe sedation and clinically relevant respiratory and/or cardiovascular depression (see also section 4.5 Interaction with other medicinal products and other forms of interaction).

Specific patient groups

Elderly should be given a reduced dose (see section 4.2 Posology and method of administration). Due to the myorelaxant effect of benzodiazepines, there is a risk of falls and consequently of hip fractures, particularly in the elderly when they get up at night.

A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression, (suicide may be precipitated in such patients).

Rohypnol should be used with extreme caution in patients with a history of alcohol or drug abuse.

In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Rohypnol 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

Enhancement of the central depressive effect may occur if Rohypnol is combined with centrally-acting drugs such as neuroleptics, tranquillisers, antidepressants, hypnotics, analgesics and anaesthetics, anti-epileptics and sedative anti-histamines. In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychic drug dependence. The elderly require special supervision.

Enhanced effects on sedation, respiration and haemodynamics may occur when Rohypnol is co-administered with any centrally acting depressants, including alcohol.

Alcohol should be avoided in patients receiving Rohypnol (see section 4.4 Special warnings and precautions for use).

See section 4.9 Overdose for warnings related to other central nervous system depressants, including alcohol.

When Rohypnol is used in conjunction with anti-epileptic drugs, side-effects and toxicity may be more evident, particularly with hydantoins or barbiturates or combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.

Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action, and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.


4.6 Pregnancy and lactation

There is no evidence as to drug safety in human pregnancy, nor is there evidence from animal work that it is free from hazard. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons. If Rohypnol is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become, or suspects she is, pregnant.

Administration of benzodiazepines in the last trimester of pregnancy or during labour has been reported to produce irregularities in the foetal heart rate, and hypotonia, poor sucking, hypothermia and moderate respiratory depression in the neonate.

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

Flunitrazepam has been detected in breast milk. The use of Rohypnol in mothers who are breast-feeding should be avoided.


4.7 Effects on ability to drive and use machines

Patients should be advised that, like all medicaments of this type, Rohypnol may modify patients' performance at skilled tasks (driving, operating machinery, etc.) Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Patients should further be advised that alcohol may intensify any impairment and should therefore be avoided during treatment (see section 4.5 Interaction with other medicinal products and other forms of interaction).


4.8 Undesirable effects

The elderly are particularly sensitive to the effects of centrally-depressant drugs.

The following adverse events have been reported, although their frequency is not known (cannot be estimated from the available data).

Blood and Lymphatic System Disorders: Blood dyscrasias.

Immune System Disorders: Hypersensitivity reactions, including rash, angioedema and hypotension, may occur.

Psychiatric Disorders: Confusional state, emotional disorder. These undesirable effects are reported most commonly and occur predominantly at the start of therapy, usually disappearing with prolonged administration. Libido disorders have been reported occasionally.

Depression : Pre-existing depression may be unmasked during benzodiazepine use.

Psychiatric and paradoxical reactions: Paradoxical reactions such as restlessness, agitation, irritability, aggression, delusion, anger, nightmares hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur with benzodiazepines or benzodiazepine-like agents. These reactions may be quite severe with this product and, are more likely to occur in the elderly.

Dependence: Chronic use (even at therapeutic doses) may lead to the development of physical dependence: abrupt discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4 Special warnings and precautions for use). Abuse has been reported.

Nervous System Disorders: Drowsiness during the day, headache, dizziness, vertigo, decreased alertness, ataxia. These undesirable effects are reported most commonly and occur predominantly at the start of therapy, usually disappearing with prolonged administration.

Anterograde amnesia may occur with therapeutic doses (see section 4.4 Special warnings and precautions for use), the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.

Cardiac Disorders: Cardiac failure including cardiac arrest.

Respiratory Disorders: Respiratory depression.

Eye Disorders: Diplopia. This undesirable effect is reported most commonly and occurs predominantly at the start of therapy, usually disappearing with prolonged administration.

Gastrointestinal Disorders: Nausea, vomiting.

Hepatobiliary Disorders: Jaundice.

Skin and Subcutaneous Tissue Disorders: Rash, urticaria.

Musculoskeletal and Connective Tissue Disorders: Muscle weakness. This phenomenon occurs predominantly at the start of therapy and usually disappears with prolonged administration.

Renal and Urinary Disorders: Urinary retention.

General Disorders and Administration Site Conditions: Fatigue. This phenomenon occurs predominantly at the start of therapy and usually disappears with prolonged administration.

Injury, Poisoning and Procedural Complications: An increased risk for falls and fractures has been reported in elderly benzodiazepine users (see section 4.4 Special warnings and precautions for use).


4.9 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Rohypnol is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment

Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

Further absorption should be prevented using an appropriate method, e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used, airway protection is imperative for drowsy patients. In case of mixed ingestion, gastric lavage may be considered, however not as a routine measure.

If CNS depression is severe consider the use of flumazenil (Anexate®), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil (Anexate®), for further information on the correct use of this drug.


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Benzodiazepine derivatives, ATC code: N05CD03.

Rohypnol is a full benzodiazepine agonist with a high affinity for the benzodiazepine central site. It has anxiolytic, anticonvulsant and sedative properties, and it causes slowing of psychomotor performance, amnesia, muscle relaxation and sleep induction.


5.2 Pharmacokinetic properties

Flunitrazepam is rapidly and almost completely absorbed after oral administration. The distribution half-life of flunitrazepam is about 3 hours; the elimination half-life is variable and may be between 16 ‑ 35 hours. The onset of effect is rapid and the duration of effect is dose-dependent. Flunitrazepam is almost completely metabolised. The main metabolites are the inactive 7‑aminoflunitrazepam and N-desmethyl-flunitrazepam which is less active than the parent compound. The steady state level of the active metabolite is below the minimum effective concentration. The volume of distribution is approximately 3.3 - 5.5 l/kg. Flunitrazepam is approximately 78% bound to plasma proteins.


5.3 Preclinical safety data

Carcinogenicity

Carcinogenicity studies of two years duration were conducted in mice and rats with doses of up to 25 and 50 mg/kg/d, respectively, administered orally. Histopathological examinations of the various tissues in both studies did not reveal any obvious signs of carcinogenicity of flunitrazepam.

Mutagenicity

Flunitrazepam has been investigated for mutagenic activity in a series of bacterial and mammalian genotoxicity tests. While mutagenic activity was observed in bacteria, the tests with mammalian cells in vitro and in vivo yielded no indication for a genotoxic activity. The effect in bacteria is not considered to be of relevance for human exposure conditions.

Impairment of fertility

Studies in rats at doses of up to 25 mg/kg revealed no adverse effects on fertility and early embryonic development.

Teratogenicity

Studies in rats (up to 25 mg/kg/day), rabbits (up to 5 mg/kg/day) and mice (up to 100 mg/kg/day) revealed no teratogenic action of flunitrazepam even at hypnotic doses.


6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

Lactose Anhydrous

Microcrystalline Cellulose

Magnesium Stearate

Hypromellose

Ethylcellulose

Povidone K90

Sodium Starch Glycolate (Type A)

Indigotine (E132)

Triacetin

Titanium Dioxide (E171)

Talc

Yellow Iron Oxide (E172)


6.2 Incompatibilities

Not applicable.


6.3 Shelf life

5 years.


6.4 Special precautions for storage

Store in original container. Do not store above 25°C.


6.5 Nature and contents of container

Blisters formed from PVC/PVDC film and aluminium foil, in packs of 30.


6.6 Special precautions for disposal and other handling

No special requirements.


7. MARKETING AUTHORISATION HOLDER

Roche Products Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom


8. MARKETING AUTHORISATION NUMBER(S)

PA 50/8/1


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 June 1982

Date of last renewal: 11 June 2007


10. DATE OF REVISION OF THE TEXT

25 June 2009

Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24, Ireland.

Rohypnol and Anexate are registered trade marks



It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.