Download Benzodiazepines (not including sedative/hypnotics*)

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; June 2011]
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 [*].
Dosage1-6
1.*
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), seizures (clonazepam, clorazepate, oral and rectal diazepam), and acute alcohol withdrawal
(chlordiazepoxide, clorazepate, oral diazepam, oxazepam). The adult maximum recommended doses for
non-sedative/hypnotic benzodiazepines are summarized in Table 1.
Table 11-6
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
alcohol withdrawal (AW): 300 mg
daily in divided doses
mild, moderate anxiety: 40 mg daily
severe anxiety: 100 mg daily
seizures: 20 mg daily
panic: 4 mg daily
anxiety: 60 mg daily
AW, seizures: 90 mg daily
oral (AW, 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
AW, severe anxiety: 120 mg daily
MAXIMUM RECOMMENDED
DOSE
> 65 YEARS*
anxiety: 4 mg daily
panic: 10 mg daily
AW: 300 mg daily in divided doses
anxiety: 20 mg daily
seizures: 20 mg daily
panic: 4 mg daily
anxiety: 60 mg daily
AW, seizures: 90 mg daily
oral (AW, 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
AW, 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
Pediatrics7-11
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 21-7
Pediatric Benzodiazepine Maximum Recommended Dosages
DRUG NAME
chlordiazepoxide
clonazepam
clorazepate
diazepam
lorazepam
oxazepam
MAXIMUM RECOMMENDED DOSE
AW (adolescents):
> 12 years of age: 300 mg daily in divided doses
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 (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:
> 12 years of age: 10 mg daily in divided doses (maximum, 2 mg/dose7)
anxiety:
6-12 years of age: dose not established; 1 mg/kg/day in divided doses has been adequate
> 12 years of age: 120 mg daily; 30-90 mg daily has also been used8-10
+
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 Therapy12-18
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 long-term 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 should be prescribed on a short-term basis to manage anxiety disorders.
Benzodiazepine doses should be tapered rather than discontinued abruptly to avoid withdrawal
symptoms. Patients receiving benzodiazepines for up to 6 months should be tapered over 2 to 8 weeks,
while patients treated with benzodiazepines for up to 12 months should be tapered over 2 to 4 months.
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.
Drug-drug interactions considered clinically relevant for nonsedative/hypnotic benzodiazepines are
summarized in Table 3. 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:
Table 31, 19, 20
Benzodiazepines (nonsedative/hypnotic) Drug-Drug Interactions
TARGET DRUG
INTERACTING DRUG
INTERACTION
RECOMMENDATIONS
CLINICAL SIGNIFICANCE
benzodiazepines
(BZDs)
CNS depressants
oxidized BZDs
(e.g., alprazolam,
chlordiazepoxide,
clonazepam, and
diazepam)
CYP3A4 inducers (e.g.,
carbamazepine, rifamycins)
CYP3A4 inhibitors (e.g., azole
antifungals, macrolides,
NNRT inhibitors, protease
inhibitors)
monitor for respiratory
depression; adjust doses as
necessary
monitor oxidized BZD clinical
response and adjust dose as
needed; may also consider
substituting a BZD metabolized
by glucuronidation (e.g.,
oxazepam)
avoid combined therapy with
most CYP3A4 inhibitors, if
possible
major (DrugReax)
3-moderate (CP*)
1 (DIF+)
moderate (DrugReax)
2-major, 3-moderate (CP)
2 (DIF)
alprazolam
concurrent administration may
potentiate respiratory depression,
especially with overdosage
combined use may result in increased
oxidized BZD clearance, reduced
oxidized BZD serum levels, and
decreased pharmacologic effects;
oxidized BZDs are metabolized by
CYP3A4
adjunctive administration may result in
enhanced oxidized BZD pharmacologic
effects and/or toxicity, including
significant sedation and/or respiratory
depression, as alprazolam is
metabolized by CYP3A4
other oxidized
BZDs
(chlordiazepoxide,
clonazepam,
diazepam)
CYP3A4 inhibitors (e.g., azole
antifungals, macrolides,
NNRT inhibitors, protease
inhibitors)
adjunctive administration may result in
enhanced oxidized BZD pharmacologic
effects and/or toxicity, including
significant sedation and/or respiratory
depression, as oxidized BZDs are
metabolized by CYP3A4
alprazolam
phenytoin
select BZDs
(chlordiazepoxide,
clonazepam,
diazepam)
phenytoin
combined use may induce alprazolam
metabolism and decrease alprazolam
pharmacologic effects
concomitant use may result in
unpredictable effects on serum
phenytoin levels (may increase,
decrease, or not change) due to
unknown effect on phenytoin
metabolism; phenytoin may induce
BZD metabolism, reduce BZD serum
levels, and decrease BZD
pharmacologic effects
avoid combined therapy, if
possible; if concurrent with
BZD necessary, monitor for
increased sedation, respiratory
depression, or consider a BZD
metabolized by glucuronidation
(e.g., oxazepam)
monitor for reduced alprazolam
clinical effects and adjust doses
as necessary
closely monitor serum
phenytoin levels and observed
for altered pharmacologic
effects (reduced efficacy,
increased toxicity); monitor for
reduced BZD clinical effects
and adjust doses as necessary
*CP = Clinical Pharmacology; +Drug Interaction Facts
contraindicated -azole antifungals,
NNRT inhibitors, protease inhibitors;
moderate -macrolides (DrugReax)
1 – severe (azole antifungals, NNRT
inhibitors, protease inhibitors); 3moderate (macrolides) (CP)
1-protease inhibitors; 2 - azoles,
macrolides, NNRT inhibitors (DIF)
moderate (DrugReax)
2-major (protease inhibitors); 3moderate (azoles, macrolides, NNRT
inhibitors) (CP)
1-protease inhibitors; 2 - azoles,
macrolides, NNRT inhibitors (DIF)
3-moderate (CP)
alprazolam – 2 (DIF)
moderate (DrugReax)
3-moderate (CP)
2 (DIF)
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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.