BENZODIAZEPINES

---

• SIDE EFFECTS

• All benzodiazepines
• Drowsiness
• Loss of coordination
• Memory impairment
• Trouble speaking (dysarthria)
• Fatigue/tiredness
• Confusion
• Altered libido - increased or decreased
• Appetite changes - increased or decreased
• Low blood pressure (hypotension)
• Dizziness


• Clonazepam
• Increased salivation

---

• CONTRAINDICATIONS / PRECAUTIONS

• All benzodiazepines
• Pregnancy - benzodiazepines may cause fetal harm and should be avoided in pregnancy. A nested case-control study published in 2019 found an association between benzodiazepine exposure in early pregnancy and spontaneous abortion. [PMID 31090881]
• Acute narrow angle glaucoma - acute narrow angle glaucoma is listed as a contraindication in most benzodiazepine package inserts. In the medical literature, there is very little information regarding this interaction. It's unclear if benzodiazepines have any effect on narrow-angle glaucoma. [8]
• Drug addiction and abuse - benzodiazepines are both psychologically and physically addictive medications. Use caution in susceptible patients.
• Withdrawal reactions - abrupt withdrawal may cause symptoms that include heightened perception, impaired concentration, alteration in sense of smell, paresthesias, muscle cramps, diarrhea, headache, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, and decreased appetite. See withdrawal prevention below for recommendations on stopping benzodiazepines.
• Seizure - abrupt withdrawal or dose reductions may lead to seizures. Patients on higher doses and longer courses of therapy are at greater risk. Doses should be tapered slowly when appropriate.
• Decreased alertness - benzodiazepines depress CNS activity and may impair the ability to operate motor vehicles and other dangerous machinery
• Respiratory depression - benzodiazepines may suppress respiratory drive. Use with caution in patients with respiratory disease.
• Allergic reactions - in rare cases, benzodiazepines have been associated with anaphylactoid reactions including angioedema
• Neonatal withdrawal - infants born to mothers who are taking benzodiazepines may be at risk for withdrawal symptoms. Flaccidity and respiratory depression may occur immediately after birth.
• Amnesia - cases of amnesia and not remembering complex behaviors such as driving have been reported with benzodiazepine use
• Depression - benzodiazepines may worsen depression including depression that is associated with panic disorder. Use caution when prescribing to susceptible patients and consider limiting quantity and monitoring for suicidal ideation.
• Mania - episodes of mania and hypomania have been reported with benzodiazepine use.
• Amnesia - cases of amnesia and not remembering complex behaviors such as driving have been reported with benzodiazepine use
• Nursing - most benzodiazepines are excreted in breastmilk and may cause lethargy and weight loss in exposed infants. Lorazepam, oxazepam, and temazepam appear to be safe in breastfeeding. [5,6,7]
• Kidney disease - elimination may be reduced. Use caution.
• Liver disease - elimination may be reduced. Use caution.

• Alprazolam
• Asian patients - maximal concentrations and half-life are 15 - 25% higher in Asian patients
• Cigarette smoking - alprazolam concentrations may be reduced by as much as 50% in smokers compared to nonsmokers
• Uricosuric effect - alprazolam has a weak uricosuric effect

• Clobazam
• Serious skin reactions - serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults in the postmarketing setting. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. Clobazam should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
• Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.

---

• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

• All benzodiazepines
• Opiate medications - combined use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death. Use caution when combining.
• Central Nervous System (CNS) Depressants - benzodiazepines may potentiate the effects of other CNS depressants (e.g. opiates, alcohol, anticonvulsants, antihistamines, etc.). Risk for adverse events may be increased. Use caution when combining.

• Alprazolam (Xanax®, Xanax XR®)
• CYP3A4 strong inhibitors - DO NOT COMBINE. Alprazolam is a CYP3A4 sensitive substrate and should not be given with CYP3A4 strong inhibitors (e.g. ketoconazole, itraconazole) except ritonavir (see below).
• Ritonavir - alprazolam should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam together, or when ritonavir is added to a patient treated with alprazolam. Increase alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. It is not necessary to reduce alprazolam dosage in patients who have been taking ritonavir for more than 10 to 14 days, because long-term ritonavir usage induces CYP3A4 and this offsets its CYP3A4 inhibition.
• CYP3A4 weak and moderate inhibitors - alprazolam is a CYP3A4 sensitive substrate. CYP3A4 weak and moderate inhibitors may raise alprazolam levels and increase the risk of adverse events. Avoid concomitant use or consider dose reductions when combining.
• CYP3A4 inducers - alprazolam is a CYP3A4 sensitive substrate. CYP3A4 inducers may decrease alprazolam exposure and reduce its effectiveness.
• Digoxin - alprazolam may increase blood levels of digoxin. Monitor digoxin levels closely when combining.
• Desipramine and imipramine - alprazolam may increase blood levels of desipramine and imipramine


• Chlordiazepoxide (Librium®)
• Disulfiram (Antabuse®) - disulfiram decreases the clearance of chlordiazepoxide. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [9]

• Clobazam (Onfi®)
• Cannabidiol - cannabidiol is a CYP3A4 and CYP2C19 substrate and a CYP2C19 inhibitor. Co-administration with clobazam may increase clobazam exposure. Consider reducing the dosage of clobazam and/or cannabidiol when combining.
• CYP2C19 strong and moderate inhibitors - clobazam is a CYP2C19 sensitive substrate, and exposure may be increased up to 5-fold when taken with CYP2C19 strong and moderate inhibitors. Consider dose adjustments when combining.
• CYP2D6 substrates - clobazam is a CYP2D6 inhibitor, and it may increase exposure to CYP2D6 substrates. Consider dose adjustments when necessary.
• Oral contraceptives - clobazam is a weak CYP3A4 inducer and it may decrease exposure to oral contraceptives. Use of additional non-hormonal contraception is recommended when using clobazam.


• Clonazepam (Klonopin®)
• CYP3A4 inducers and inhibitors - clonazepam appears to be a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.


• Diazepam (Valium®)
• CYP3A4 inducers and inhibitors - diazepam is a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
• CYP2C19 inducers and inhibitors - diazepam is a CYP2C19 sensitive substrate. Use caution with CYP2C19 inducers and inhibitors.
• Disulfiram (Antabuse®) - disulfiram decreases the clearance of diazepam. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [9,11]

• Lorazepam (Ativan®, Loreev XR®)
• UDP-glucuronosyltransferase (UGT) Inhibitors - UGT inhibitors decrease lorazepam clearance. Reduce lorazepam dose when combining.
• Valproate - valproate is a UGT inhibitor, and it decreases lorazepam clearance. Lorazepam dose should be reduced by 50% when taken with valproate.
• Probenecid - probenecid is a UGT inhibitor, and it decreases lorazepam clearance. Lorazepam dose should be reduced by 50% when taken with probenecid.


• Temazepam (Restoril®)
• Disulfiram (Antabuse®) - disulfiram may decrease the clearance of temazepam. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [12]


• Triazolam (Halcion®)
• CYP3A4 strong inhibitors - DO NOT COMBINE. Triazolam is a CYP3A4 sensitive substrate, and CYP3A4 strong inhibitors greatly increase triazolam exposure.
• CYP3A4 moderate and weak inhibitors - triazolam is a CYP3A4 sensitive substrate. CYP3A4 moderate and weak inhibitors increase exposure to triazolam and may increase the risk of adverse events. Use caution and consider dose reductions when combining.
• CYP3A4 strong inducers - triazolam is a CYP3A4 sensitive substrate. CYP3A4 strong inducers may decrease triazolam exposure and reduce its effectiveness. Use caution when combining.
• Cimetidine - coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%
• Isoniazid - coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%.
• Ranitidine - coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam.
• Oral contraceptives - coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%

---

• BENZODIAZEPINE WITHDRAWAL

• Withdrawal symptoms
• Withdrawal symptoms typically develop within 2 - 3 days with shorter-acting agents and within 5 - 10 days with longer-acting agents
• Withdrawal symptoms can be psychiatric, autonomic, and neurologic
• Psychiatric symptoms
• Anxiety
• Insomnia
• Depression
• Irritability
• Psychosis/delirium
• Autonomic symptoms
• Tremor
• Sweating
• Nausea and vomiting
• Shortness of breath
• Increased heart rate
• Elevated blood pressure
• Muscle tension
• Neurologic symptoms
• Seizures
• Cognitive impairment
• Memory impairment
• Sound sensitivity
• Photophobia
• Hypersomnia
• Muscle tension/spasms
• Motor tics

• Withdrawal prevention
• In order to prevent withdrawal symptoms, benzodiazepines should be tapered over a period of 4 - 8 weeks
• Patients who are taking multiple benzodiazepines should be switched to one, preferably diazepam because it has a long half-life
• Regimens for tapering include the following:
• Reduce the dose by 50% every week OR
• Reduce the daily dose by 10 - 25% every 2 weeks [14]

• Withdrawal treatment
• Patients taking very high doses (e.g. ≥ 100 mg of diazepam or equivalent a day) should have inpatient withdrawal treatment
• Treatment of withdrawal symptoms may include the following:
• Insomnia - trazodone, mirtazapine, melatonin, antihistamines
• Depression and mood disorders - SSRIs, mood stabilizer (e.g. carbamazepine), antipsychotics
• Anxiety - beta blockers, SSRIs, gabapentin, hydroxyzine, buspirone [14]

---

• PRICE ($) INFO

---

• BIBLIOGRAPHY

• 1 - Package insert for drug unless otherwise specified
• 2 - PMID 22876380 - NICE clinical GL on alcohol withdrawal
• 3 - PMID 6733001 - Flurazepam study
• 4 - PMID 18175099 - lorazepam article
• 5 - Toxnet website
• 6 - Toxnet website
• 7 - Toxnet website
• 8 - PMID 11975064 - glaucoma
• 9 - PMID 6106489 - Disulfiram and oxazepam, lorazepam, librium, and diazepam
• 10 - PMID 2338112 - Disulfiram and alprazolam
• 11 - PMID 29739 - Disulfiram and librium, diazepam, and oxazepam
• 12 - PMID 7934566 - Disulfiram and temazepam
• 13 - PMID 19125841 - Febrile seizure GL
• 14 - PMID 28328330 - Treatment of Benzodiazepine Dependence, NEJM (2017)