1. Name Of The Medicinal Product
Stesolid® rectal tubes 10 mg.
2. Qualitative And Quantitative Composition
Diazepam 4 mg/ml.
3. Pharmaceutical Form
Enema.
4. Clinical Particulars
4.1 Therapeutic Indications
Diazepam has anticonvulsant, sedative, and muscle relaxant properties. It is used in the treatment of severe anxiety and tension states, as a sedative and premedication, in the control of muscle spasm, and in the management of alcohol withdrawal symptoms.
Stesolid rectal tubes 10 mg may be used in acute severe anxiety and agitation, epileptic and febrile convulsions, tetanus, as a sedative in minor surgical and dental procedures, or in other circumstances in which a rapid effect is required but where intravenous injection is impracticable or undesirable.
Stesolid rectal tubes 10 mg may be of particular value for the immediate treatment of convulsions in infants and children.
4.2 Posology And Method Of Administration
Sensitivity to diazepam varies with age.
Children above 1 year of age:
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0.5 mg/kg body weight
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Adults:
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0.5 mg/kg body weight
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Elderly patients:
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0.25 mg/kg body weight
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A maximum dose of 30 mg diazepam is recommended, unless adequate medical supervision and monitoring are available.
4.3 Contraindications
• Known hypersensitivity to diazepam, benzodiazepines or any of the excipients
• Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur)
• Acute pulmonary insufficiency; respiratory depression, acute or chronic severe respiratory insufficiency (ventilatory failure may be exacerbated)
• Myasthenia gravis (condition may be exacerbated)
• Sleep apnoea (condition may be exacerbated)
• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged)
• Acute porphyria
• Diazepam should not be used as monotherapy in patients with depression or those with anxiety and depression as suicide may be precipitated in such patients.
• Planning a pregnancy (see section 4.6).
• Pregnancy (unless there are compelling reasons – see section 4.6).
4.4 Special Warnings And Precautions For Use
Tolerance
Some loss of efficacy to the hypnotic effects of diazepam may develop after repeated use for a few weeks.
Dependence
Use of benzodiazepines may lead to development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of 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, hallucinations or epileptic seizures.
As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol dependants.
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.
Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the medicinal product should be discontinued.
They are more likely to occur in children and the elderly.
Amnesia
Diazepam may induce anterograde amnesia. The condition occurs most often several hours after administering the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. Anterograde amnesia may occur using therapeutic doses, the risk increases with higher doses.
Specific patient groups
Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Elderly should be given a reduced dose (see posology). 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).
In common with other benzodiazepines, the use of diazepam may be associated with amnesia and should not be used in cases of loss or bereavement as psychological adjustment may be inhibited.
Stesolid rectal tubes 5 mg should not be used in phobic or obsessional states, as there is insufficient evidence of efficacy and safety in such conditions.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Stesolid should not be used concomitantly with disulfiram due to its ethanol content. A reaction may occur as long as two weeks after cessation of disulfram
Stesolid contains 15 mg/ml benzyl alcohol. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.
Stesolid rectal tubes, contains benzoic acid (E210) and sodium benzoate (E211) and it may be mildly irritating to the skin and mucous membranes.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Not recommended
Alcohol
Diazepam should not be used together with alcohol (enhanced sedative effects: impaired ability to drive/ operate machinery).
Sodium oxybate
Avoid concomitant use (enhanced effects of sodium oxybate).
HIV-protease inhibitors
Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine.
Take into account
Centrally acting drugs
Enhancement of the central depressive effect may occur if diazepam is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.
Anti-epileptic drugs
Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported.
Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment.
Side effects may be more evident with hydantoins or barbiturates.
Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).
Narcotic analgesics
Enhancement of the euphoria may lead to increased psychological dependence.
Other drugs enhancing the sedative effect of diazepam
Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants - baclofen and tizanidine.
Compounds that affect hepatic enzymes (particularly cytochrome P450):
• Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines.
Itraconazloe, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiapines. The effects of benzodiapines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.
• Inducers (eg rifampicin) may increase clearance of benzodiazepines
Antihypertensives, vasodilators& diuretics:
Enhanced hypotensive effect with ACEinhibitors, alpha-blockers, angiotensin–II receptor antagonists, calcium channel. blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.
Dopaminergics
Possible antagonism of the effect of levodopa.
Zidivudine
Increased zidovudine clearance by diazepam.
Oestrogen-containing contraceptives
Possible inhibition of hepatic metabolism of diazepam.
Theophylline
Increases metabolism of diazepam which possibly reduces the effect.
Caffeine
Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.
Grapefruit juice
Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). This interaction may of little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.
4.6 Pregnancy And Lactation
In animal studies administration of benzodiazepines during gestation has lead to cleft palate, CNS malformation and permanent functional disturbances in the offspring.
There is no evidence as to the safety of diazepam in human pregnancy. It should not be used, especially during the first and last trimesters, unless the benefit is considered to outweigh the potential risk.
In labour, high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hyperthermia in the neonate, and irregularities in the foetal heart.
If benzodiazepines are 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 neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.
Infants born to mothers who took benzodiazepines chronically during the later states of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
Since benzodiazepines are found in breast milk, benzodiazepines should not be given to breast feeding mothers.
4.7 Effects On Ability To Drive And Use Machines
Sedation, amnesia, impaired muscular function may adversely effect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions). Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose.
4.8 Undesirable Effects
During the first week of administration or when high doses are used they may have a sedative effect and cause some degree of drowsiness. In such cases there is an advantage in administering half the total daily intake at night, the remainder being given in divided doses during the day.
The elderly and debilitated are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of diazepam should not exceed one-half that recommended for other adults.
Skin and appendages disorders
Allergic reactions (skin rash or itching) occur rarely.
Central and peripheral nervous disorders
Drowsiness, sedation, unsteadiness, ataxia is common (these effects are dose-related and may persist into the following day even after a single dose), light-headedness, headache, vertigo, dystonic effects occur rarely. Impaired motor ability, dizziness, muscle weakness, tremor, slurred speech.
Vision disorders
Visual disturbances occur rarely.
Psychiatric disorders
Libido fluctuations occur rarely. Anterograde amnesia (amnesia may be associated with inappropriate behaviour), concentration difficulties, abnormal psychological reactions, behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, delusions, rages, nightmares, hallucinations, psychoses, inappropriate behaviour, numbed emotions, the uncovering of depression with suicidal tendencies and dependence (see section 4.4). Abuse of benzodiazepines has been reported.
Gastro-intestinal system disorders
Gastrointestinal upsets occur rarely. Increased salivary secretion.
Liver and billiary system disorders
Jaundice occurs rarely.
Endocrine disorders
Gynaecomastia.
Cardio disorders
Hypotension occurs rarely.
Respiratory system disorders
Respiratory depression, apnoea.
Blood disorders
Blood dyscrasias occur rarely.
Urinary system disorders
Urinary retention occurs rarely.
Body as a whole-general disorders
Fatigue, anaphylaxis.
Withdrawal effects
Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see 4.4 Special Warnings and Special Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.
Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.
4.9 Overdose
Features
The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.
Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.
Management
Maintain a clear airway and adequate ventilation.
Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.
Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.
Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.
If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.
Supportive measures are indicated depending on the patient's clinical state.
Benzodiazepines are not significantly removed from the body by dialysis.
Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.
Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients postcardiac arrest is also contraindicated.
It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.
Occasionally a respirator may be required but generally few problems are encountered, although behavioral changes are likely in children.
If excitation occurs, barbiturates should not be used.
Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Diazepam has anticonvulsant, sedative, and muscle relaxant properties.
5.2 Pharmacokinetic Properties
Absorption: Diazepam is quickly absorbed from the rectal mucosa. The maximum serum concentration is reached within 17 minutes. Absorption is 100% compared with that of intravenous injection of diazepam.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzoic acid
Ethanol
Propylene glycol
Sodium benzoate
Benzyl alcohol
Purified water.
6.2 Incompatibilities
None known.
6.3 Shelf Life
30 months at 25°C.
6.4 Special Precautions For Storage
The storage temperature must not exceed 25°C.
6.5 Nature And Contents Of Container
Carton containing sealed low density polyethylene tubes, single packed in aluminium laminated bags.
Package size: 5 x 2.5 ml
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
Administrative Data
7. Marketing Authorisation Holder
Actavis Group PTC ehf.
Reykjavikurvegi 76-78
220 Hafnarfjordur
Iceland
8. Marketing Authorisation Number(S)
PL -30306/0041
9. Date Of First Authorisation/Renewal Of The Authorisation
26/06/2006
10. Date Of Revision Of The Text
22/06/2011
