Brotizolam
Short acting benzodiazepine for sleep disorders
Brotizolam is a thienodiazepine and belongs to the group of short acting benzodiazepines. Boehringer Ingelheim launched the substance in the 1980s under the trade name Lendormin. In Germany, brotizolam is available only on prescription, in 0.25 mg tablets. The substance falls under the Narcotics Act if prescribed above the defined thresholds, but is typically prescribed on a private prescription or, for as needed use, on a narcotics prescription.
Brotizolam is characterised by a rapid onset and a relatively short duration of action, which makes it particularly useful for sleep onset difficulties. At the same time, all the typical risks of the benzodiazepine class are present: dependence developing within a few weeks, tolerance, withdrawal on abrupt discontinuation, cognitive side effects and fall risk in older patients. The current S3 Guideline on Insomnia recommends non pharmacological treatments such as cognitive behavioural therapy as first line and restricts benzodiazepines to short crisis interventions.
Mechanism of Action
Brotizolam binds allosterically to the benzodiazepine binding site of the GABA A receptor. Binding enhances the inhibitory effect of the neurotransmitter γ aminobutyric acid (GABA) at the GABA A receptor; the chloride channel opens more frequently and neuronal hyperpolarisation increases. The consequences are sedative, hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects.
The hypnotic effect sets in within 15 to 30 minutes of intake. The half life is 3 to 6 hours and the clinical duration of action 6 to 8 hours. This clearly distinguishes brotizolam from long acting benzodiazepines such as diazepam (half life of active metabolites up to 100 hours), with a noticeably smaller next morning hangover effect. Residual fatigue and cognitive impairment the following day cannot be ruled out, especially in older patients and when combined with alcohol or other centrally depressant substances.
Metabolism is predominantly hepatic via CYP3A4, with renal elimination of metabolites. CYP3A4 inhibitors such as ketoconazole, clarithromycin and grapefruit juice raise plasma levels and thereby the effect and side effects, so such co medication is problematic.
Indications
- Short term treatment of sleep onset disorders in the context of a sleep disorder with relevant distress
- Initiation of restful sleep in acute stress situations (jet lag, shift work, short term crises)
- Sleep disorders in chronic disease as an adjunctive short term measure, always combined with cognitive behavioural strategies
Brotizolam is not indicated for long term therapy or for the treatment of underlying psychiatric disorders such as depression or anxiety. For anxiety disorders, other benzodiazepines or antidepressants are available; for chronic sleep disorders, cognitive behavioural therapy, sleep hygiene education and melatonergic substances are the preferred options.
Dosage and Administration
Adults: 0.25 mg orally immediately before going to bed. If effect is insufficient, the dose may be increased to 0.5 mg; further escalation is uncommon. Older patients over 65: 0.125 mg (half a tablet) as starting dose, cautious titration, with attention to the increased risk of falls and delirium.
Intake should only take place when at least 7 to 8 hours of uninterrupted sleep are possible, to avoid next morning residual fatigue. Food shortly before or during intake slightly reduces absorption and the hypnotic effect may be delayed.
Duration of therapy: as short as possible, ideally less than 2 weeks, at most 4 weeks including the taper phase. With longer use the dependence risk rises markedly. Once started, therapy should not be stopped abruptly but tapered gradually over 1 to 2 weeks.
Renal impairment: no adjustment in mild impairment; lower dose in moderate to severe impairment. Hepatic impairment: contraindicated in moderate to severe impairment because of slower metabolism and enhanced sedation.
Side Effects
Common: next morning fatigue, drowsiness, dizziness, headache, muscle weakness, ataxia, blurred vision, reduced responsiveness, impaired concentration.
Uncommon: paradoxical reactions (restlessness, aggression, nightmares, hallucinations) particularly in older patients and children, anterograde amnesia (memory gaps for events after intake), depression, libido changes, rebound insomnia after discontinuation.
Rare to very rare: paradoxical disinhibition, complex sleep behaviour (sleepwalking, sleep eating, driving while asleep), respiratory depression at high doses or in combination with other centrally depressant substances, allergic reactions, elevation of liver transaminases.
Dependence: after several weeks of intake there is a risk of physical and psychological dependence. Withdrawal can be accompanied by insomnia, anxiety, tremor, sweating, tachycardia and, in severe cases, seizures or delirium. Gradual tapering over 1 to 2 weeks is standard; with longer use, dose reduction may need to extend over several weeks.
Interactions
- Centrally depressant substances (alcohol, opioids, neuroleptics, other benzodiazepines, first generation antihistamines, barbiturates): strongly enhanced sedation and respiratory depression; combined intake particularly with opioids is a relevant risk factor for death
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir): markedly elevated plasma levels; avoid combination if possible or halve the dose
- CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort): reduced plasma levels and efficacy
- Grapefruit juice: raises plasma levels; avoid during therapy
- Muscle relaxants: additive muscle relaxing effect, fall risk
Special Notes
Contraindications: known hypersensitivity, myasthenia gravis, severe respiratory insufficiency, sleep apnoea syndrome, severe hepatic impairment, narrow angle glaucoma, intoxication with alcohol or other centrally depressant substances, known addiction disorder (relative), children and adolescents under 18 years.
Priscus list: brotizolam is on the Priscus list of potentially inappropriate medications for older patients. The risk of falls, cognitive impairment and delirium is elevated in this group. In older patients with sleep disorders, non pharmacological measures and melatonergic substances should be considered first.
Pregnancy: avoid if possible in the first trimester; benzodiazepines have been associated with a slightly increased risk of cleft lip and palate. In the third trimester there is a risk of floppy infant syndrome in the newborn with muscular hypotonia, sedation, feeding difficulties and respiratory depression. Breastfeeding: passes into breast milk; sedation of the infant is possible and breastfeeding during therapy is not recommended.
Driving ability: the day after intake, driving is markedly impaired, particularly in combination with alcohol or at higher doses. Plan at least 8 hours of sleep after intake; when unsure about one's own driving ability, do not drive. In case of doubt consult the physician.
Monitoring: clinical review with every prescription, addiction history in at risk patients. In recurrence or chronic sleep disorder, offer cognitive behavioural therapy for insomnia (CBT I) as evidence based first line therapy.
You might also be interested in
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Frequently Asked Questions
How quickly does brotizolam cause dependence?
Physical and psychological dependence can develop within only a few weeks of daily intake. For this reason therapy is strictly limited to a few weeks. In at risk patients (known addiction disorder, chronic pain with opioids) particular caution is warranted. The decision to prescribe is made individually.
Why not just take it for longer?
Longer use leads to tolerance; the sleep inducing effect fades and higher doses become necessary. At the same time, discontinuation becomes more difficult and rebound insomnia worsens the original sleep disorder. The S3 Guideline therefore recommends cognitive behavioural therapy as a long term effective and low side effect method.
Can I drive the morning after taking it?
Only with sufficient distance from intake (at least 8 hours of sleep) and when no residual fatigue remains. In older patients, at higher doses or in combination with alcohol, driving ability is often impaired for longer. In case of doubt do not drive and consult the physician.
Are there alternatives to brotizolam?
Cognitive behavioural therapy for insomnia (CBT I) is the evidence based first line for chronic sleep disorders. For acute or short term sleep disorders, melatonin, melatonergic antidepressants such as agomelatine, low potency neuroleptics such as prothipendyl or first generation antihistamines such as diphenhydramine can be alternative options, each with its own benefit risk profile.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline on Non Restorative Sleep and Sleep Disorders
- Gelbe Liste, Brotizolam active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace consultation with a licensed physician or pharmacist. Medicines should only be taken on medical prescription or via a pharmacy. All information is based on product information and recognised scientific sources published at the time of creation; the manufacturer's current summary of product characteristics is always authoritative. Sanoliste assumes no liability for the completeness, timeliness or accuracy of the information presented. In a medical emergency, call the emergency number 112 (Europe).