Alprazolam (Xanax®)
Dosage forms
Tablet
- 0.25 mg
- 0.5 mg
- 1 mg
- 2 mg
Orally disintegrating tablet
- 0.25 mg
- 0.5 mg
- 1 mg
- 2 mg
Solution
- 1 mg/ml
- Comes in 30 ml bottles
Dosing
Anxiety disorders and transient anxiety
- Starting: 0.25 - 0.5 mg three times a day as needed. Increase dose every 3 - 4 days as needed.
- Maximum: 4 mg/day
- Elderly: starting dose is 0.25 mg two to three times daily as needed. Increase dose gradually.
- Liver disease: starting dose is 0.25 mg two to three times daily as needed. Increase dose gradually.
- When discontinuing after chronic therapy, decrease daily dose by no more than 0.5 mg a day every 3 days
Pharmacokinetics
- Peak plasma concentration: 1 - 2 hours
- Half-life: 11.2 hours (range: 6.3 – 26.9 hours)
- Average half-life is prolonged in elderly (16.3 hours), liver disease (19.7 hours), and obesity (21.8 hours)
Other
- Alprazolam is a CYP3A4 sensitive substrate. See alprazolam drug interactions for more.
- Disulfiram (Antabuse®) does not appear to affect the metabolism of alprazolam [10]
- See alprazolam-specific precautions below
Generic / Price
- Generic (30 tablets) - $
- Generic (30 disintegrating tablets) - $-$$
- Generic (30 ml solution) - $$
Alprazolam (Xanax XR®)
Dosage forms
Tablet, extended-release
- 0.5 mg
- 1 mg
- 2 mg
- 3 mg
Dosing
Panic disorder
- Starting: 0.5 - 1 mg once daily. Increase dose every 3 - 4 days in increments of no more than 1 mg/day.
- Maintenance: 3 - 6 mg once daily
- Maximum: 10 mg once daily
- Elderly: starting dose is 0.5 mg once daily. Increase dose gradually as needed.
- Hepatic impairment: starting dose is 0.5 mg once daily. Increase dose gradually as needed.
- When tapering off, decrease dose by no more than 0.5 mg/day every 3 days
Switching from Xanax to Xanax XR
- Total daily Xanax dose may be given as once daily Xanax XR tablet
Pharmacokinetics
- Xanax XR has the same pharmacokinetics as immediate-release Xanax except that it is absorbed more slowly. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing.
- High-fat meals increase the absorption of Xanax XR
- Peak plasma concentration: 1 - 2 hours
- Half-life: 11.2 hours (range: 6.3 – 26.9 hours)
- Average half-life is prolonged in elderly (16.3 hours), liver disease (19.7 hours), and obesity (21.8 hours)
Other
- Do not cut, chew, crush, or break tablets
- Alprazolam is a CYP3A4 sensitive substrate. See alprazolam drug interactions for more.
- See alprazolam-specific precautions below
Generic / Price
- YES/$Chlordiazepoxide (Librium®)
Dosage forms
Capsule
- 5 mg
- 10 mg
- 25 mg
Dosing
Anxiety
- Mild-to-moderate: 5 - 10 mg three to four times a day as needed
- Severe: 20 - 25 mg three to four times a day as needed
- Elderly: 5 mg two to four times a day as needed
Alcohol withdrawal
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life: 24 - 48 hours
Other
- Disulfiram decreases the clearance of chlordiazepoxide. Consider using another benzodiazepine (e.g. alprazolam, oxazepam, lorazepam) in patients who are receiving disulfiram. [9]
Generic / Price
- YES/$Chlordiazepoxide + clidinium (Librax®)
Dosage forms
Capsule
- Chlordiazepoxide : clidinium
- 5 mg : 2.5 mg
Dosing
Anxiety-related gastrointestinal disorders
- 1 - 2 capsules three to four times a day as needed
- Take before meals and at bedtime
Other
- Clidinium is an anticholinergic agent
- Librax® does not have FDA-approved indications
Generic / Price
- YES/$Chlordiazepoxide + amitriptyline (Limbitrol®)
Dosage forms
Tablet
- Chlordiazepoxide : amitriptyline
- 5 mg : 12.5 mg
- 10 mg : 25 mg
Dosing
Depression associated with anxiety
- 3 or 4 tablets daily given in divided doses
- Reduce dose to minimum effective dose
- Do not exceed 6 tablets a day
Other
- Amitriptyline is a tricyclic antidepressant
Generic / Price
- YES/$ (30 tablets)Clobazam | Onfi® | Sympazan®
Dosage forms
Tablet (Onfi®)
- 10 mg
- 20 mg
Suspension (Onfi®)
- 2.5 mg/ml
- Comes in 120 ml bottle
Oral film (Sympazan®)
- 5 mg
- 10 mg
- 20 mg
- Film comes in a pouch
- Comes in packages of 60 pouches
Dosing
Seizures associated with Lennox-Gastaut syndrome (≥ 2 years old)
- Dosing is based on weight (see table below)
- Doses > 5 mg/day should be given in divided doses twice daily. A 5 mg daily dose can be administered once daily.
- Do not proceed with dose escalation more rapidly than weekly, because it takes 5 - 9 days to reach steady-state
- Taper drug gradually by decreasing the daily dose 5 - 10 mg/day at weekly intervals
- May take without regard to food
- Tablets may be halved and crushed
- Oral film (Sympazan) is applied on top of the tongue where it adheres and dissolves
≤ 66 pounds (30 kg) | > 66 pounds (30 kg) | |
---|---|---|
Starting dose | 5 mg | 10 mg |
Starting Day 7 | 10 mg | 20 mg |
Starting Day 14 | 20 mg | 40 mg |
Elderly
- Starting dose is 5 mg, and titration should occur at half the recommended dose
CYP2C19 Poor Metabolizers
- Exposure to active metabolite is increased
- Starting dose is 5 mg, and titration should occur at half the recommended dose
Liver disease
- Child-Pugh A/B: starting dose is 5 mg, and titration should occur at half the recommended dose
- Child-Pugh C: has not been studied. No recommendation given.
Kidney disease
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: has not been studied. No recommendation given.
Pharmacokinetics
- Peak plasma concentration: 0.5 - 5 hours
- Half-life:
- Clobazam: 36 - 42 hours
- Active metabolite: 71 - 82 hours
Other
- Clobazam is a sensitive CYP2C19 substrate. See clobazam drug interactions below.
- See clobazam-specific precautions below
Generic / Price
- Tablet (#60) - YES/$
- Suspension (120 ml) - YES/$$
- Oral film (#60) - NO/$$$$
Clonazepam (Klonopin®)
Dosage forms
Tablet
- 0.5 mg
- 1 mg
- 2 mg
Orally disintegrating tablet
- 0.125 mg
- 0.25 mg
- 0.5 mg
- 1 mg
- 2 mg
Dosing - Adults
Panic disorder
- Starting: 0.25 mg twice a day
- Maintenance: 0.5 mg twice a day
- Maximum: 2 mg twice a day
- Increase in increments of 0.125 - 0.25 mg/dose at intervals of 3 days
- Total daily dose may be given once daily at bedtime to minimize side effects
- When discontinuing, decrease by 0.125 mg/dose every 3 days
Seizure disorder
- Starting: 0.5 mg three times a day
- Maximum: 20 mg/day
- Increase in increments of 0.5 - 1 mg/day every 3 days
Dosing - Children
Seizure disorder (up to 10 years old or 30 kg)
- Starting: 0.01 - 0.03 mg/kg/day given in 2 or 3 divided doses
- Maintenance: 0.1 - 0.2 mg/kg/day given in 3 divided doses
- Maximum: 0.2 mg/kg/day
- Increase daily dosage by no more than 0.25 - 0.5 mg every third day
Pharmacokinetics
- Peak plasma concentration: 1 - 4 hours
- Half-life: 30 - 40 hours
Other
- Clonazepam is likely a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
Generic / Price
- YES/$Clorazepate (Tranxene®)
Dosage forms
Tablet
- 3.75 mg
- 7.5 mg
- 15 mg
Dosing
Anxiety (adults)
- Starting: 30 mg/day
- Maintenance: 15 - 60 mg/day
- Maximum: 60 mg/day
- May be given 2 - 3 divided doses
- In elderly or debilitated patients, consider initial daily dose of 7.5 to 15 mg
- May take without regard to food
Acute alcohol withdrawal (adults)
- First 24 hours: 30 mg initially; followed by 30 to 60 mg in divided doses
- Second 24 hours: 45 to 90 mg in divided doses
- Third 24 hours: 22.5 to 45 mg in divided doses
- Day 4: 15 to 30 mg in divided doses
- Day 5 and on: 7.5 - 15 mg/day until ready to discontinue
- Maximum: 90 mg/day
- May take without regard to food
Adjunct to Antiepileptic drugs (≥ 12 years)
- Starting: 7.5 mg three times a day
- Maximum: 90 mg/day
- Dosage should be increased by no more than 7.5 mg every week
- May take without regard to food
Adjunct to Antiepileptic drugs (9 - 11 years)
- Starting: 7.5 mg two times a day
- Maximum: 60 mg/day
- Dosage should be increased by no more than 7.5 mg every week
- May take without regard to food
Pharmacokinetics
- Peak plasma concentration: ?
- Half-life: 40 - 50 hours
Generic / Price
- YES/$Diazepam (Valium®)
Dosage forms
Tablet
- 2 mg
- 5 mg
- 10 mg
Solution
- 1 mg/ml
Concentrate (Intensol)
- 5 mg/ml
Dosing - Adults
Anxiety disorder
- 2 - 10 mg two to four times a day as needed
Alcohol withdrawal
Muscle spasm
- 2 - 10 mg three to four times a day as needed
Seizure disorders (adjunctive treatment)
- 2 - 10 mg two to four times a day as needed
Elderly patients
- Starting: 2 - 2.5 mg one to two times a day as needed
Dosing - Children
Children ≥ 6 months old
- Dosing: 1 - 2.5 mg three to four times a day as needed. Increase gradually as needed and tolerated.
Pharmacokinetics
- Peak plasma concentration: 1 - 1.5 hours
- Half-life:
- Diazepam - up to 48 hours
- Active metabolite - up to 100 hours
- Half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age
Other
- Food slows absorption
- Diazepam is a CYP3A4 and CYP2C19 sensitive substrate. Use caution with CYP3A4 and CYP2C19 inhibitors and inducers.
- Disulfiram decreases the clearance of diazepam. Consider using another benzodiazepine (e.g. alprazolam, oxazepam, lorazepam) in patients who are receiving disulfiram. [9,11]
Generic / Price
- Generic (30 tablets) - $
- Generic (1 mg/ml, 180 ml) - $
- Generic (5 mg/ml, 30 ml) - $
Diazepam (Diastat® AcuDial)
Dosage forms
Rectal gel
- Comes in 2.5 mg, 10 mg, and 20 mg delivery system
- 10 mg delivery system may be dialed to 5, 7.5, and 10 mg doses
- 20 mg delivery system may be dialed to 12.5, 15, 17.5, and 20 mg doses
- Comes in pack with 2 delivery systems
Dosing
Acute seizure (≥ 2 years old)
- 2 - 5 years: 0.5 mg/kg
- 6 - 11 years: 0.3 mg/kg
- ≥ 12 years: 0.2 mg/kg
- Dose should be rounded up to next available dose
- A second dose may be given 4 - 12 hours after the first dose
- It takes ∼ 3 minutes for therapeutic concentrations to reach the brain with the rectal route [13]
Pharmacokinetics
- Peak plasma concentration: 1.5 hours
- Half-life:
- Diazepam - 46 hours
- Active metabolite - 71 hours
- It takes ∼ 3 minutes for therapeutic concentrations to reach the brain with the rectal route [13]
Other
- Comes in a single dose rectal delivery system
- Applicator can be dialed to appropriate dose
- See patient instructions for proper delivery technique
Generic / Price
- YES/$$$-$$$$ (2 delivery systems)Diazepam (Valtoco® nasal spray)
Dosage forms
Nasal spray device
- 5 mg
- 10 mg
- 15 mg
- 20 mg
- Comes in carton with 2 devices
Dosing
Frequent seizure activity (≥ 6 years)
- Dosing for Valtoco is based on age and weight and is presented in the table below
- A second dose, when required, may be administered after at least 4 hours after the initial dose
- Do not use more than 2 doses to treat a single episode
- It is recommended that Valtoco be used to treat no more than one episode every five days and no more than five episodes per month
Dose Based on Age and Weight | Administration | |||
---|---|---|---|---|
6 to 11 years (0.3 mg/kg) |
≥ 12 years (0.2 mg/kg) |
Dose (mg) | Number of Devices | Number of Sprays |
10 to 18 kg | 14 to 27 kg | 5 | One 5 mg device | One spray in one nostril |
19 to 37 kg | 28 to 50 kg | 10 | One 10 mg device | One spray in one nostril |
38 to 55 kg | 51 to 75 kg | 15 | Two 7.5 mg devices | One spray in each nostril |
56 to 74 kg | ≥ 76 kg | 20 | Two 10 mg devices | One spray in each nostril |
Pharmacokinetics
- Peak plasma concentration: 1.5 hours
- Half-life (10 mg dose): 49.2 hours
Generic / Price
- NO/$$$$Flurazepam (Dalmane®)
Dosage forms
Capsule
- 15 mg
- 30 mg
Dosing
Insomnia
- 30 mg one time before bedtime as needed
- 15 mg may be sufficient in elderly and debilitated patients
Pharmacokinetics
- Peak plasma concentration: 30 - 60 minutes
- Half-life:
- Flurazepam: 2.3 hours
- Active metabolite: 47 - 100 hours [3]
Generic / Price
- YES/$Lorazepam | Ativan® | Loreev XR®
Dosage forms
Tablet
- 0.5 mg
- 1 mg
- 2 mg
Solution
- 2 mg/ml
- Comes in 30 ml bottle
Capsule, extended-release (Loreev XR®)
- 1 mg
- 2 mg
- 3 mg
Dosing - Tablet / Solution
Anxiety
- Starting: 2 - 3 mg/day given in two to three divided doses
- Maintenance: 2 - 6 mg/day given in two to three divided doses
- Elderly: 1 - 2 mg/day given in two to three divided doses
Alcohol withdrawal
Insomnia
- 2 - 4 mg given once at bedtime
Dosing - Loreev XR®
Anxiety
- Initiate Loreev XR in patients who are being treated with lorazepam tablets, administered three times daily in evenly divided doses
- Discontinue lorazepam tablets and administer the first dose of Loreev XR in the morning the day after the final dose of lorazepam tablets
- The recommended once daily dosage of Loreev XR is equal to the total daily dose of lorazepam tablets. For example, the recommended dosage for patients who have been receiving lorazepam tablets at a dosage of 1 mg three times daily is Loreev XR 3 mg once daily in the morning.
- Take once daily in the morning with or without food. Swallow capsules whole or open the capsule and sprinkle the entire contents over a tablespoon of applesauce, followed by drinking water. Consume all the sprinkles without chewing within 2 hours; do not store for future use.
- If dose adjustments are required, discontinue Loreev XR and switch to lorazepam tablets. Once a new dose is established, Loreev XR may be restarted at the new daily dosage.
- When discontinuing, Loreev XR should be tapered to reduce the risk of withdrawal reactions
- When combining with UGT inhibitors (e.g. valproate, probenecid), switch to lorazepam tablets so that the lorazepam dose may be reduced. UGT inhibitors increase lorazepam exposure.
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life (lorazepam): 12 hours
- Half-life (Loreev XR): 20 hours
- Lorazepam is metabolized by glucuronide conjugation
- Liver and kidney disease only have a minor effect on lorazepam pharmacokinetics [4]
Other
- See drug interactions below
- Lorazepam is safe in breastfeeding [5]
- Disulfiram (Antabuse®) does not appear to affect the metabolism of lorazepam [9]
Generic / Price
- Lorazepam tablet and solution: YES/$
- Loreev XR: NO/$$$$
Oxazepam (Serax®)
Dosage forms
Capsule
- 10 mg
- 15 mg
- 30 mg
Dosing
Mild-to-moderate anxiety
- 10 - 15 mg three to four times a day as needed
Severe anxiety
- 15 - 30 mg three to four times a day as needed
Alcohol withdrawal
- 15 - 30 mg three to four times a day as needed
Elderly
- Starting: 10 mg three times a day as needed
- Maintenance: 15 mg three to four times a day as needed
Pharmacokinetics
- Peak plasma concentration: 3 hours
- Half-life: 8.2 hours
- Oxazepam is metabolized by glucuronide conjugation
Other
- Oxazepam is safe in breastfeeding [6]
- Oxazepam is the short-acting metabolite of diazepam [6]
- Disulfiram (Antabuse®) does not appear to affect the metabolism of oxazepam [9]
Generic / Price
- YES/$Quazepam (Doral®)
Dosage forms
Tablet
- 15 mg
Dosing
Insomnia
- Starting: 7.5 mg once at bedtime
- Maintenance: 7.5 - 15 mg once at bedtime
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life:
- Quazepam: 39 hours
- Active metabolite: 73 hours
Other
- Tablet is scored so that it can be halved
Generic / Price
- NO/$$$$Temazepam (Restoril®)
Dosage forms
Capsule
- 7.5 mg
- 15 mg
- 22.5 mg
- 30 mg
Dosing
Insomnia
- Starting: 15 mg one time at bedtime
- Maintenance: 7.5 - 30 mg one time at bedtime
- Elderly: 7.5 mg one time at bedtime
Pharmacokinetics
- Peak plasma concentration: 1.5 hours
- Half-life (biphasic):
- Short: 0.4 - 0.6 hours
- Terminal: 8.8 hours
Other
- Temazepam is a metabolite of diazepam [7]
- Temazepam appears to be safe in breastfeeding [7]
Generic / Price
- YES/$Triazolam (Halcion®)
Dosage forms
Tablet
- 0.125 mg
- 0.25 mg
Dosing
Insomnia
- Starting: 0.25 mg once daily before bedtime
- Maintenance: 0.125 - 0.5 mg once daily before bedtime
- Max: 0.5 mg once daily before bedtime
- Elderly: start with 0.125 mg once daily. Do not exceed 0.25 mg once daily.
- A dosage of 0.125 mg once daily may be sufficient for some patients (e.g. patients with low body weight, elderly)
Pharmacokinetics
- Peak plasma concentration: within 2 hours
- Half-life: range of 1.5 - 5.5 hours
Other
- Triazolam is a CYP3A4 sensitive substrate. Do not use with strong CYP3A4 inhibitors. Use caution with moderate and weak inhibitors.
Generic / Price
- YES/$- 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 (e.g. alprazolam, oxazepam, lorazepam) in patients who are receiving disulfiram. [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 (e.g. alprazolam, oxazepam, lorazepam) in patients who are receiving disulfiram. [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
Pricing legend
- $ = 0 - $50
- $$ = $51 - $100
- $$$ = $101 - $150
- $$$$ = > $150
- Pricing based on 30 tablets unless otherwise specified
- Pricing based on information from GoodRX.com®
- Pricing may vary by region and availability
- 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)