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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
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]
- 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
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.
- 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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Clearance is decreased. Use a starting dose of 0.5 mg once daily and titrate gradually.
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.
- Disulfiram (Antabuse®) does not appear to affect the metabolism of alprazolam [10]
- 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
Generic / Price
- YES/$Chlordiazepoxide (Librium®)
Dosage forms
Capsule
- 5 mg
- 10 mg
- 25 mg
Dosing
Anxiety
- Mild-to-moderate: 5 - 10 mg three to four times a day as needed
- Severe: 20 - 25 mg three to four times a day as needed
- Elderly: 5 mg two to four times a day as needed
Alcohol withdrawal
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution.
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life: 24 - 48 hours
Other
- Disulfiram decreases the clearance of chlordiazepoxide. Consider using another benzodiazepine (e.g. alprazolam, oxazepam, lorazepam) in patients who are receiving disulfiram. [9]
Generic / Price
- YES/$Chlordiazepoxide + clidinium (Librax®)
Dosage forms
Capsule
- Chlordiazepoxide : clidinium
- 5 mg : 2.5 mg
Dosing
Anxiety-related gastrointestinal disorders
- Dosing: the usual maintenance dose is 1 - 2 capsules three to four times a day as needed, taken before meals and at bedtime
- Elderly: the initial dose should not exceed 2 capsules per day. Titrate gradually.
- When discontinuing, the dose should be tapered to prevent withdrawal
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution.
Other
- Clidinium is an anticholinergic agent
- Librax® does not have an FDA-approved indication
Generic / Price
- YES/$Chlordiazepoxide + amitriptyline (Limbitrol®)
Dosage forms
Tablet
- Chlordiazepoxide : amitriptyline
- 5 mg : 12.5 mg
- 10 mg : 25 mg
Dosing
Depression associated with anxiety
- 10/25 mg strength tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily.
- 5/12.5 mg in an initial dosage of 3 or 4 tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses
- When discontinuing, the dose should be tapered to prevent withdrawal
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution.
Other
- Amitriptyline is a tricyclic antidepressant
Generic / Price
- YES/$ (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.
- 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.
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
Panic disorder (adults)
- Starting: 0.25 mg twice daily
- Maintenance: 1 mg/day
- Maximum: 4 mg/day
- Increase in increments of 0.125 - 0.25 mg/dose at intervals of 3 days
- The 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 (adults)
- Starting: 0.5 mg three times a day
- Maximum: 20 mg/day
- Increase in increments of 0.5 - 1 mg/day every 3 days
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
Kidney disease
- Clonazepam metabolites are renally excreted and may accumulate in kidney disease. Use caution.
Liver disease
- Clonazepam undergoes hepatic metabolism, and liver disease may increase exposure. Use caution.
Pharmacokinetics
- Peak plasma concentration: 1 - 4 hours
- Half-life: 30 - 40 hours
Other
- Start with lower doses and titrate slowly in elderly patients
- Clonazepam may increase salivation. Use caution in patients at risk for aspiration (e.g. dementia, cognitive impairment).
- Clonazepam is likely a CYP3A4 sensitive substrate. Use caution with CYP3A4 inducers and inhibitors.
Generic / Price
- Tablet (#30) - YES/$
- Orally disintegrating tablet (#30) - 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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution.
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 (adults)
- 2 - 10 mg two to four times a day as needed
Alcohol withdrawal
Muscle spasm (adults)
- 2 - 10 mg three to four times a day as needed
Seizure disorders (adjunctive treatment in adults)
- 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
Children ≥ 6 months old
- Dosing: 1 - 2.5 mg three to four times a day as needed. Increase gradually as needed and tolerated.
Kidney disease
- Diazepam metabolites are substantially excreted by the kidneys. Use caution.
Liver disease
- In patients with cirrhosis, clearance is decreased, and the average half-life is increased 2- to 5-fold. May worsen hepatic encephalopathy. Exercise caution and do not use in severe liver disease.
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]
Kidney disease
- Diazepam metabolites are substantially excreted by the kidneys. Use caution.
Liver disease
- In patients with cirrhosis, clearance is decreased and average half-life is increased 2- to 5-fold. May worsen hepatic encephalopathy. Use caution in patients with liver disease.
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
Generic / Price
- YES/$$-$$$ (2 delivery systems)Diazepam (Valtoco® nasal spray)
Dosage forms
Nasal spray device
- 5 mg
- 10 mg
- 15 mg
- 20 mg
- Comes in carton with 2 devices
Dosing
Frequent seizure activity (≥ 6 years)
- Dosing for Valtoco is based on age and weight and is presented in the table below
- A second dose, when required, may be administered after at least 4 hours after the initial dose
- Do not use more than 2 doses to treat a single episode
- It is recommended that Valtoco be used to treat no more than one episode every five days and no more than five episodes per month
Dose Based on Age and Weight | Administration | |||
---|---|---|---|---|
6 to 11 years (0.3 mg/kg) |
≥ 12 years (0.2 mg/kg) |
Dose (mg) | Number of Devices | Number of Sprays |
10 to 18 kg | 14 to 27 kg | 5 | One 5 mg device | One spray in one nostril |
19 to 37 kg | 28 to 50 kg | 10 | One 10 mg device | One spray in one nostril |
38 to 55 kg | 51 to 75 kg | 15 | Two 7.5 mg devices | One spray in each nostril |
56 to 74 kg | ≥ 76 kg | 20 | Two 10 mg devices | One spray in each nostril |
Kidney disease
- Diazepam metabolites are substantially excreted by the kidneys. Use caution.
Liver disease
- In patients with cirrhosis, clearance is decreased and average half-life is increased 2- to 5-fold. May worsen hepatic encephalopathy. Use caution in patients with liver disease.
Pharmacokinetics
- Peak plasma concentration: 1.5 hours
- Half-life (10 mg dose): 49.2 hours
Other
Generic / Price
- NO/$$$$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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution.
Pharmacokinetics
- Peak plasma concentration: 30 - 60 minutes
- Half-life:
- Flurazepam: 2.3 hours
- Active metabolite: 47 - 100 hours [3]
Generic / Price
- YES/$Lorazepam (Ativan®)
Dosage forms
Tablet
- 0.5 mg
- 1 mg
- 2 mg
Solution
- 2 mg/ml
- Comes in 30 ml bottle
Dosing
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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life: 12 hours
- Lorazepam is metabolized by glucuronide conjugation
Other
- See lorazepam drug interactions below
- Lorazepam is safe in breastfeeding [5]
- Disulfiram (Antabuse®) does not appear to affect the metabolism of lorazepam [9]
Generic / Price
- Tablet (#30): YES/$
- Solution (30 ml): YES/$
Lorazepam (Loreev XR®)
Dosage forms
Capsule, extended-release
- 1 mg
- 2 mg
- 3 mg
Dosing
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.
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
Pharmacokinetics
- Peak plasma concentration: 14 hours
- Half-life: 20 hours
- Lorazepam is metabolized by glucuronide conjugation
Other
- See lorazepam drug interactions below
- Lorazepam is safe in breastfeeding [5]
- Disulfiram (Antabuse®) does not appear to affect the metabolism of lorazepam [9]
Generic / Price
- NO/$$$$Oxazepam (Serax®)
Dosage forms
Capsule
- 10 mg
- 15 mg
- 30 mg
Dosing
Mild-to-moderate anxiety
- 10 - 15 mg three to four times a day as needed
Severe anxiety
- 15 - 30 mg three to four times a day as needed
Alcohol withdrawal
- 15 - 30 mg three to four times a day as needed
Elderly
- Starting: 10 mg three times a day as needed
- Maintenance: 15 mg three to four times a day as needed
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
Pharmacokinetics
- Peak plasma concentration: 3 hours
- Half-life: 8.2 hours
- Oxazepam is metabolized by glucuronide conjugation
Other
- Oxazepam is safe in breastfeeding [6]
- Oxazepam is the short-acting metabolite of diazepam [6]
- Disulfiram (Antabuse®) does not appear to affect the metabolism of oxazepam [9]
Generic / Price
- YES/$Quazepam (Doral®)
Dosage forms
Tablet
- 15 mg
Dosing
Insomnia
- Starting: 7.5 mg once at bedtime
- Maintenance: 7.5 - 15 mg once at bedtime
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Quazepam is extensively metabolized in the liver. It has not been studied in liver disease. Use caution. May worsen hepatic encephalopathy.
Pharmacokinetics
- Peak plasma concentration: 2 hours
- Half-life:
- Quazepam: 39 hours
- Active metabolite: 73 hours
Other
- Tablet is scored so that it can be halved
Generic / Price
- NO/$$$$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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
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]
- Disulfiram (Antabuse®) may decrease the clearance of temazepam. Consider using another benzodiazepine that has not been shown to interact with disulfiram (alprazolam, oxazepam, lorazepam). [12]
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)
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Use caution. May worsen hepatic encephalopathy.
Pharmacokinetics
- Peak plasma concentration: within 2 hours
- Half-life: range of 1.5 - 5.5 hours
Other
- Triazolam is a CYP3A4 sensitive substrate. It should not be taken with strong CYP3A4 inhibitors, and caution, including possible dose reductions, should be used with weak and moderate inhibitors. Strong CYP3A4 inducers may decrease its exposure and effectiveness.
Generic / Price
- YES/$- MECHANISM OF ACTION
- Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Benzodiazepines bind GABA(A) receptors in the brain, enhancing GABA-mediated synaptic inhibition.
- 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
- CONTRAINDICATIONS / PRECAUTIONS
- All benzodiazepines
- Pregnancy - published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association between benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. Taking benzodiazepines late in pregnancy may cause neonatal sedation and withdrawal (see below).
- Neonatal sedation and withdrawal - infants born to mothers taking benzodiazepines late in pregnancy may be at risk for sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties). Monitor exposed infants closely after birth.
- 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]
- 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. 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 for recommendations on discontinuing 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 in susceptible patients.
- 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 caution in patients with respiratory disease.
- Allergic reactions - in rare cases, benzodiazepines have been associated with anaphylactoid reactions including angioedema
- 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.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All benzodiazepines
- Opioid medications - combined use of benzodiazepines and opioids 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.) and increase the risk for adverse events. 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, and CYP3A4 weak and moderate inhibitors may increase alprazolam exposure. Avoid concomitant use or consider dose reductions when combining.
- CYP3A4 inducers - alprazolam is a CYP3A4 sensitive substrate, and CYP3A4 inducers may decrease its exposure.
- Digoxin - alprazolam may increase blood levels of digoxin. Monitor digoxin levels closely when combining.
- Desipramine - alprazolam may increase desipramine exposure
- Imipramine - alprazolam may increase imipramine exposure
- 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.
- 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.
- BENZODIAZEPINE WITHDRAWAL
- Withdrawal symptoms
- Benzodiazepine withdrawal symptoms (see below) typically develop within 2 - 3 days of stopping a short-acting agent and 5 - 10 days with a long-acting agent
- 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
- Benzodiazepines may be tapered by reducing the dose by 50% every week or by reducing 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)