Benzodiazepines (not including sedative/hypnotics*)
[Developed, October 1993; Revised, December 1996; November 1997; November 1998;
December 1999; December 2000; December 2001; April 2003; January 2009]
MEDICAID DRUG USE REVIEW CRITERIA FOR OUTPATIENT USE
(*Sedative/hypnotic benzodiazepines are included in Sedative/Hypnotics criteria.)
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied
retrospectively; prospective application is indicated with [*].
1.*
Dosage
Adults
Non-sedative/hypnotic benzodiazepines are FDA-approved for use in the outpatient setting to
manage anxiety (alprazolam, chlordiazepoxide, clorazepate, oral diazepam, lorazepam,
oxazepam), panic disorder (alprazolam, clonazepam), acute musculoskeletal (MS) conditions
including spasticity (oral diazepam), and seizures (clonazepam, clorazepate, oral and rectal
diazepam).
The adult maximum recommended doses for non-sedative/hypnotic benzodiazepines are
summarized in Table 1.
Table 1
Adult Benzodiazepine Maximum Recommended Daily Doses
DRUG NAME
alprazolam (Xanax®, generics)
chlordiazepoxide (Librium®,
generics)
clonazepam (Klonopin®,
generics)
clorazepate (Tranxene®,
generics)
diazepam (Valium®, generics)
lorazepam (Ativan®, generics)
oxazepam (Serax®, generics)
MAXIMUM RECOMMENDED
DOSE
< 65 YEARS
anxiety: 4 mg daily
panic: 10 mg daily
mild, moderate anxiety: 40 mg daily
severe anxiety: 100 mg daily
seizures: 20 mg daily
panic: 4 mg daily
anxiety: 60 mg daily
seizures: 90 mg daily
oral (anxiety, MS conditions,
seizures): 40 mg daily
rectal gel (seizures):+ 0.2 mg/kg;
may be repeated once 4-12 hours
after initial dose
anxiety: 10 mg daily, in divided
doses
mild, moderate anxiety: 60 mg daily
severe anxiety: 120 mg daily
MAXIMUM RECOMMENDED
DOSE
> 65 YEARS*
anxiety: 4 mg daily
panic: 10 mg daily
anxiety: 20 mg daily
seizures: 20 mg daily
panic: 4 mg daily
anxiety: 60 mg daily
seizures: 90 mg daily
oral (anxiety, MS conditions,
seizures): 40 mg daily
rectal gel (seizures):+ 0.2 mg/kg;
may be repeated once 4-12 hours
after initial dose
anxiety: 10 mg daily, in divided
doses
anxiety: 60 mg daily
*In
elderly patients (patients > 65 years of age), the benzodiazepine dose should be reduced to the lowest effective dose, if possible, to
minimize oversedation, as these patients are more sensitive to the pharmacologic effects of these agents.
+ Dose rounded up to nearest commercially available dose (in multiples of 2.5 mg); should not be administered by caregivers outside the
hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to
minimize potential for development of tolerance
Pediatrics
Safety and effectiveness of alprazolam use in children less than 18 years of age have not been
established.
With the exception of alprazolam, non-sedative/hypnotic benzodiazepines are indicated for use in
pediatric patients to provide sedation, or manage anxiety or seizures. Pediatric dosages and age
limitations for benzodiazepines are summarized in Table 2.
Table 2
Pediatric Benzodiazepine Maximum Recommended Dosages
DRUG NAME
chlordiazepoxide
clonazepam
clorazepate
diazepam
lorazepam
oxazepam
MAXIMUM RECOMMENDED DOSE
anxiety:
> 6 years of age: 30 mg daily in divided doses, or 0.5 mg/kg daily in divided doses
seizures:
< 10 years of age or < 30 kg: 0.2 mg/kg daily in divided doses
> 10 years of age or > 30 kg: 20 mg daily in divided doses
seizures:
9-12 years: 60 mg daily in divided doses
> 12 years of age: 90 mg daily in divided doses
oral (sedation, MS conditions, seizures):
> 6 months of age: 0.8 mg/kg/day in divided
doses; alternately, for seizures, 30 mg daily in divided doses
rectal gel (seizures):+
2-5 years of age: 0.5 mg/kg/dose
6-11 years of age: 0.3 mg/kg/dose
> 12 years of age: 0.2 mg/kg/dose
anxiety, sedation:
> 12 years of age: 10 mg daily in divided doses (maximum, 2 mg/dose4)
anxiety:
6-12 years of age: dose not established; 1 mg/kg/day has been adequate5
> 12 years of age: 30-90 mg daily6-8
+Dose
rounded up to nearest commercially available dose (in multiples of 2.5 mg); should not be administered by caregivers outside the
hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to
minimize potential for development of tolerance
2.
Duration of Therapy
Anxiety disorders are considered chronic disorders with low spontaneous remission rates and high
rates of relapse. Pharmacotherapy for generalized anxiety disorder (GAD) in adults includes
antidepressants, benzodiazepines, buspirone, hydroxyzine and pregabalin. Treatment duration
for GAD ranges from 3 months to 12 months to accomplish treatment goals of symptom remission
and improvement in quality of life. Although antidepressants are now considered drugs of choice
for managing GAD, benzodiazepines are used frequently for short-term management of anxiety,
as an adjunct to initiating antidepressant therapy, or improvement in sleep disturbances
associated with GAD and/or antidepressant therapy. Benzodiazepines provide symptom
improvement more rapidly than antidepressants and are more effective in managing somatic
complaints rather than psychic symptoms. Although longer-term use is considered relatively safe
and effective for benzodiazepines, the potential for abuse, dependence and withdrawal does exist.
In pediatric patients, selective serotonin reuptake inhibitors (SSRIs) are agents of choice to
manage childhood anxiety disorders, with benzodiazepines prescribed as alternatives either alone
or concurrently with accepted antidepressant therapy.
Panic disorder (PD) is a chronic, recurring condition requiring drug therapy suitable for prolonged use.
The acute treatment phase for PD lasts approximately 12 weeks, and most patients require an
additional 12to 18 months of therapy to optimize treatment response and prevent relapse. SSRIs
are the agents of choice to manage PD, although benzodiazepines are frequently prescribed as
well, usually in combination with antidepressant therapy. While benzodiazepines are effective in
the short-term treatment of panic disorder due to rapid onset of action, long-term treatment may be less
desirable due to the potential for dependence. Unlike anxiety disorder patients, patients with panic
disorder are less successful at discontinuing benzodiazepine therapy. Additionally, there is a high
prevalence of comorbid depression and/or bipolar disorder in patients with panic disorder.
Benzodiazepines are less effective than other available agents when panic disorder coexists with other
mood disorders. Therefore, patients with panic disorder and other psychiatric comorbidities may benefit
from short-term therapy with a benzodiazepine, with chronic management incorporating mood
stabilizing or antidepressant agents that are also effective in panic disorder. Alprazolam has been
studied more than other available benzodiazepines for the treatment of panic disorder, although
clonazepam, lorazepam, and diazepam have also been evaluated. Most studies evaluating
benzodiazepine use in panic disorder have been short-term studies (< 8 weeks in duration). A few longterm panic disorder studies evaluating alprazolam have demonstrated sustained reductions in panic
attack frequency when alprazolam has been administered for 6 to 8 months.
Benzodiazepines should be tapered when discontinued, as patients may experience a withdrawal
syndrome if therapy is discontinued abruptly. Benzodiazepine elimination half-life and seizure
history for the patient also influence the taper duration. Patients receiving benzodiazepines in
lower doses for shorter times periods (less than six months) may be effectively tapered over two to
eight weeks, while patients receiving benzodiazepines with a short elimination half-life, in higher
doses, and/or for a longer duration (six months or longer) may require a slow taper over two to
four months.
Benzodiazepines are prescribed on a short-term basis to manage anxiety disorders. Patient
profiles documenting benzodiazepine use for anxiety lasting greater than four months will be
reviewed.
While concerns for benzodiazepine tolerance and withdrawal exist, patients may benefit from
long-term use of benzodiazepines in panic disorder to minimize symptom recurrence.
Additionally, significant problems with benzodiazepine dose escalation have not surfaced with
chronic use for panic disorder.
The use of benzodiazepines as an anti-epileptic is not limited in duration.
3.*
Duplicative Therapy
The combined use of two or more benzodiazepines is not supported in the literature and therefore is not
recommended. The concurrent use of two or more benzodiazepines will be reviewed.
4.*
Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant
drug-drug interactions.
The following drug-drug interactions are considered clinically relevant for benzodiazepines. Only those
drug-drug interactions identified as clinical significance level 1 or those considered life-threatening
which have not yet been classified will be reviewed:
a. Select CNS Depressants [clinical significance level – major (DrugReax); buprenorphine, opioid
analgesics: 1 (DIF)]
Concurrent administration of benzodiazepines with opioid analgesics, buprenorphine, chloral
hydrate, barbiturates, or centrally acting skeletal muscle relaxants may result in potentiation
of respiratory depression. Patients requiring concurrent therapy with benzodiazepines and
CNS depressants should be monitored for respiratory depression; dosages should be modified
as necessary. Concurrent administration of benzodiazepines with buprenorphine may also
increase the risk of cardiovascular collapse. Concurrent administration of benzodiazepines
with buprenorphine is not recommended and will be reviewed.
b. Benzodiazepines (oxidized) and Protease Inhibitors [e.g., indinavir (Crixivan®), ritonavir
(Norvir®)] [clinical significance level – alprazolam and indinavir: contraindicated (DrugReax);
other benzodiazepines and protease inhibitors: moderate (DrugReax); 1 (DIF)]
Concurrent administration of benzodiazepines that undergo oxidative metabolism with protease
inhibitors may result in enhanced benzodiazepine pharmacologic effects and/or risk of toxicity.
Patients may experience significant sedation and potentially respiratory depression when this drug
combination is utilized. Protease inhibitors inhibit hepatic metabolism of those benzodiazepines
subject to oxidative metabolism including alprazolam, chlordiazepoxide, clonazepam, clorazepate,
and diazepam. When concurrent administration of protease inhibitors and benzodiazepines is
necessary, a benzodiazepine metabolized by glucuronidation (e.g., oxazepam) may be considered.
Adjuvant administration of protease inhibitors and benzodiazepines that undergo oxidative
metabolism is not recommended and will be reviewed.
c. Benzodiazepines (oxidized) and Azole Antifungals [clinical significance level –alprazolam and
itraconazole: contraindicated (DrugReax); other benzodiazepines and itraconazole: major
(DrugReax); 2 (DIF); 3 (Hansten & Horn)]
The combined use of azole antifungals and benzodiazepines which undergo oxidative metabolism,
such as alprazolam, chlordiazepoxide, clonazepam, and diazepam may result in elevated serum
benzodiazepine levels and enhanced or prolonged CNS depression. It is presumed that itraconazole,
fluconazole, and ketoconazole inhibit metabolism of oxidized benzodiazepines at the cytochrome
P450 3A4 isozyme site. Concurrent use of azole antifungals and benzodiazepines that undergo
oxidative metabolism is not recommended and will be reviewed. When adjunctive azole antifungal
and benzodiazepine treatment is necessary, a lower benzodiazepine dose or a benzodiazepine
metabolized by glucuronidation (e.g., oxazepam) may be considered.
d. Benzodiazepines (oxidized) and Macrolide Antibiotics [e.g., clarithromycin (Biaxin®),
erythromycin, telithromycin (Ketek®)] [clinical significance level – moderate (DrugReax); 2
(DIF); 3 (Hansten & Horn)]
The combined use of certain macrolide antibiotics and benzodiazepines which undergo oxidative
metabolism, such as alprazolam, chlordiazepoxide, clonazepam, and diazepam may result in elevated
serum benzodiazepine levels and enhanced or prolonged CNS depression. It is presumed that
clarithromycin and erythromycin inhibit metabolism of oxidized benzodiazepines at the cytochrome
P450 3A4 isozyme site. Concurrent use of these macrolide antibiotics and benzodiazepines that
undergo oxidative metabolism is not recommended and will be reviewed. When adjunctive
macrolide and benzodiazepine treatment is necessary, a lower benzodiazepine dose or a
benzodiazepine metabolized by glucuronidation (e.g., oxazepam) may be considered. Alternately,
azithromycin does not significantly interfere with CYP3A4 metabolism and may be a suitable
alternative in patients prescribed benzodiazepines requiring macrolide antibiotics.
e. Alprazolam and Delavirdine (Rescriptor®), Efavirenz (Sustiva®) [clinical significance level –
contraindicated (DrugReax); 2 (DIF)]
Combined administration of alprazolam and non-nucleoside reverse transcriptase inhibitors
(NNRTs) such as delavirdine and efavirenz may result in inhibition of alprazolam metabolism and
the potential for serious and/or life-threatening events, including prolonged sedation and respiratory
depression. NNRTs inhibit the cytochrome P450 3A4 isoenzyme and compete with alprazolam for
metabolism by this enzyme, which results in increased serum alprazolam concentrations. Combined
administration of alprazolam and NNRTs is not recommended and will be reviewed.
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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and
the College of Pharmacy, The University of Texas at Austin.