Benzodiazepines (Systemic)

This monograph includes information on the following:

1) Alprazolam
2) Bromazepam  *
3) Chlordiazepoxide
4) Clobazam *
5) Clonazepam
6) Clorazepate
7) Diazepam
8) Estazolam  
9) Flurazepam
10) Halazepam  
11) Ketazolam  * 
12) Lorazepam
13) Nitrazepam  *
14) Oxazepam
15) Prazepam  * 
16) Quazepam  
17) Temazepam
18) Triazolam

VA CLASSIFICATION
Alprazolam Oral
Primary: CN302

Bromazepam Oral
Primary: CN302

Chlordiazepoxide Oral
Primary: CN302

Chlordiazepoxide Parenteral
Primary: CN302

Clobazam Oral
Primary: CN400

Clonazepam Oral
Primary: CN302
Secondary: CN400

Clorazepate Oral
Primary: CN302
Secondary: CN400

Diazepam Oral
Primary: CN302
Secondary: CN400; MS200

Diazepam Parenteral
Primary: CN302
Secondary: CN400; MS200

Diazepam Rectal
Primary: CN400

Estazolam Oral
Primary: CN302

Flurazepam Oral
Primary: CN302

Halazepam Oral
Primary: CN302

Ketazolam Oral
Primary: CN302

Lorazepam Oral
Primary: CN302
Secondary: MS200

Lorazepam Parenteral
Primary: CN302
Secondary: CN400; MS200; GA609

Nitrazepam Oral
Primary: CN302
Secondary: CN400

Oxazepam Oral
Primary: CN302

Prazepam Oral
Primary: CN302

Quazepam Oral
Primary: CN302

Temazepam Oral
Primary: CN302

Triazolam Oral
Primary: CN302


Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule IV (all of the benzodiazepines in this monograph)
Commonly used brand name(s): Alprazolam Intensol1; Alti-Alprazolam1; Alti-Bromazepam2; Alti-Clonazepam5; Alti-Triazolam18; Apo-Alpraz1; Apo-Chlordiazepoxide3; Apo-Clonazepam5; Apo-Clorazepate6; Apo-Diazepam7; Apo-Flurazepam9; Apo-Lorazepam12; Apo-Oxazepam14; Apo-Temazepam17; Apo-Triazo18; Ativan12; Clonapam5; Dalmane9; Diastat7; Diazemuls7; Diazepam Intensol7; Dizac7; Doral16; Frisium4; Gen-Alprazolam1; Gen-Bromazepam2; Gen-Clonazepam5; Gen-Triazolam18; Halcion18; Klonopin5; Lectopam2; Librium3; Lorazepam Intensol12; Mogadon13; Novo-Alprazol1; Novo-Clopate6; Novo-Dipam7; Novo-Flupam9; Novo-Lorazem12; Novo-Poxide3; Novo-Temazepam17; Novo-Triolam18; Novoxapam14; Nu-Alpraz1; Nu-Loraz12; PMS-Clonazepam5; PMS-Diazepam7; Paxipam10; ProSom8; Restoril17; Rivotril5; Serax14; Somnol9; Tranxene6; Tranxene T-Tab6; Tranxene-SD6; Tranxene-SD Half Strength6; Valium7; Vivol7; Xanax1; Xanax TS1.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:

Note: All of the benzodiazepines have similar pharmacologic actions; however, clinical uses among specific agents may vary because of actual pharmacokinetic differences, availability of specific testing, and/or availability of clinical-use data.



Antianxiety agent—Alprazolam; Bromazepam; Chlordiazepoxide; Clorazepate; Diazepam; Halazepam; Ketazolam; Lorazepam; Oxazepam; Prazepam;

Sedative-hypnotic—Alprazolam; Bromazepam; Chlordiazepoxide; Clonazepam; Clorazepate; Diazepam; Estazolam; Flurazepam; Halazepam; Ketazolam; Lorazepam; Nitrazepam; Oxazepam; Prazepam; Quazepam; Temazepam; Triazolam;

Amnestic—Diazepam (parenteral only); Lorazepam (parenteral only);

Anticonvulsant—Clobazam; Clonazepam; Clorazepate; Diazepam; Lorazepam (parenteral only); Nitrazepam;

Antipanic agent—Alprazolam; Chlordiazepoxide (parenteral only); Clonazepam; Diazepam; Lorazepam;

Skeletal muscle relaxant adjunct—Diazepam; Lorazepam;

Antitremor agent—Alprazolam; Chlordiazepoxide (oral only); Diazepam (oral only); Lorazepam (oral only);

Antiemetic, in cancer chemotherapy—Lorazepam (parenteral only);

Indications

Note: Because ketazolam and prazepam are not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for these medications.

Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anxiety (treatment)—Alprazolam {61}2 {61}1 {61}0, bromazepam {55}9, chlordiazepoxide {55}8, clorazepate {55}7, diazepam {55}6 {55}5 {55}4 {55}3, halazepam {55}2, [ ketazolam {55}1]1 , lorazepam {55}0 {55}9, oxazepam {55}8, and [prazepam {55}7]1 are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Chlordiazepoxide {55}6 {55}5, [oral diazepam]1 , and sublingual {55}4 or intramuscular lorazepam {55}3 are indicated for treatment of preoperative apprehension and anxiety.
—Benzodiazepines are not indicated for the treatment of anxiety or tension associated with the stress of everyday life {55}2 {55}1 {55}0 {55}9 {55}8. Effectiveness of these medications for long-term management of anxiety has not been assessed in systematic clinical studies {55}7 {55}6. The medication's efficacy in an individual patient should be reassessed at periodic intervals {55}5.

Anxiety associated with mental depression (treatment adjunct)1—Alprazolam {55}4 {55}3, lorazepam (oral) {55}2, and oxazepam {55}1 are also indicated for the adjunctive management of anxiety associated with mental depression. Effectiveness of these medications for long-term use has not been assessed in systematic clinical studies {55}0 {55}9 {55}8. The medication's efficacy in an individual patient should be reassessed at periodic intervals {55}7 {55}6 {55}5.

Alcohol withdrawal (treatment)—Chlordiazepoxide {55}4, clorazepate {55}3, diazepam {55}2 {55}1 {55}0, [ lorazepam]1 , and oxazepam {55}9 are indicated for the relief of acute alcohol withdrawal symptoms such as acute agitation, tremor, impending or acute delirium tremens, and hallucinosis.

Anesthesia, adjunct—Parenteral chlordiazepoxide {55}8 and parenteral diazepam {55}7 {55}6 {55}5 are indicated as premedication to relieve anxiety and tension in patients who are to undergo surgical procedures. Also, parenteral lorazepam is indicated in adults as preanesthetic medication to produce sedation, relief of anxiety, and anterograde amnesia {55}4.

Amnesia, in cardioversion or
Anxiety, in cardioversion (treatment)—Parenteral diazepam is indicated for intravenous administration prior to cardioversion to relieve anxiety and tension and to produce anterograde amnesia {55}3 {55}2 {55}1 {55}0.

Amnesia, in endoscopic procedures or
Anxiety, in endoscopic procedures (treatment adjunct)—Parenteral diazepam {61}9 {61}8 {61}7 {61}6 and [parenteral lorazepam]1 are indicated as adjuncts prior to endoscopic procedures if apprehension, anxiety, or acute stress reactions are present and to diminish patient's recall of the procedure. Safety and efficacy have not been established for the use of diazepam prior to bronchoscopy or laryngoscopy {61}5.

[Sedation, conscious]1—Parenteral diazepam is used in dentistry to relieve anxiety and produce amnesia in prolonged or difficult dental procedures. It is used frequently with a local anesthetic. {61}4

Insomnia (treatment)—Estazolam {61}3, flurazepam {61}2 {61}1, nitrazepam {61}0, quazepam {55}9, temazepam {55}8, and triazolam {55}7 {55}6 are indicated for the short-term treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Lorazepam1 is indicated for insomnia due to anxiety or transient situational stress {55}5 {55}4. Other benzodiazepines, such as [alprazolam]1 , bromazepam1 , [ diazepam]1 {55}3, [ ketazolam]1 , [halazepam] , and [prazepam]1 , are also used in the treatment of insomnia. Failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric or medical illness {55}2 {55}1 {55}0. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder {33}9 {33}8 {33}7.
—[Short- and intermediate-acting benzodiazepine hypnotics may be useful in the prevention or treatment (short-term) {33}6 of transient insomnia associated with a sudden sleep schedule change, such as occurs in trans-meridian travel and shift-work rotation {33}5 {33}4 {33}3 .]1

Convulsions (treatment adjunct) or
Status epilepticus (treatment adjunct)—Diazepam injection {33}2, sterile emulsion1 {33}1, and [diazepam for rectal solution]1 {33}0 {35}9 {35}8 are indicated as adjuncts in status epilepticus and severe recurrent convulsive seizures. Lorazepam injection is indicated for the treatment of status epilepticus {35}7 {35}6 as part of a complex and sustained intervention that may include support of vital functions, administration of additional anticonvulsant medications, and/or correction of acute causes of status epilepticus {35}5. These medications are not recommended for maintenance anticonvulsant therapy; therefore, once seizures are controlled, appropriate maintenance anticonvulsant therapy should be instituted {35}4 {35}3.

Convulsive disorders (treatment adjunct)— Oral diazepam1is indicated as short-term (7 to 14 days) adjunctive therapy in convulsive disorders {35}2. It is not useful as sole therapy in convulsive disorders {35}1. [ Clonazepam may be effective as an adjunct in convulsive disorders such as eclamptic convulsions, infantile spasms {35}0 {61}9 , reading epilepsy {61}8 , and startle-induced seizures.]1 {61}7

Epilepsy (treatment adjunct)—Clobazam is indicated as an adjunct in the treatment of patients with epilepsy who are not adequately stabilized by their current anticonvulsant therapy {61}6.
—Diazepam rectal gel is indicated to control bouts of increased seizure activity in patients with refractory epilepsy who are on stable regimens of antiepileptic medications {61}5. Diazepam rectal gel may be administered in the home by a competent caregiver who has been instructed in its proper use and who can distinguish the characteristic seizure clusters that may be treated with diazepam rectal gel from the patient's usual seizure activity {61}4.

Epilepsy, Lennox-Gastaut syndrome (treatment) or
Epilepsy, akinetic seizure pattern (treatment) or
Epilepsy, myoclonic seizure pattern (treatment)— Clonazepam is indicated for use alone or, more frequently, as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic seizures, and myoclonic seizures {61}3.
—Nitrazepam also is indicated for the treatment of myoclonic seizures {61}2.

[Epilepsy, myoclonic seizure pattern (treatment adjunct)]1—Oral diazepam is used as adjunctive therapy in myoclonus. It is not useful as sole therapy in this condition. {61}1

Epilepsy, absence seizure pattern (treatment)— Clonazepam may be useful in the treatment of absence (petit mal) seizures refractory to the succinimide anticonvulsants {61}0 or valproic acid.

Epilepsy, simple partial seizure pattern (treatment adjunct)1 or
Epilepsy, complex partial seizure pattern (treatment adjunct)1—Clorazepate is indicated as adjunctive therapy in the management of partial seizures {33}9.

[Epilepsy, simple partial seizure pattern (treatment)]1or
[Epilepsy, complex partial seizure pattern (treatment)]1—Clonazepam may be effective in refractory seizures such as complex partial (psychomotor, temporal lobe) or elementary partial (focal) seizures {33}8.

[Epilepsy, tonic-clonic seizure pattern (treatment)]1—Clonazepam may be effective in tonic-clonic (grand mal) seizures. However, when clonazepam is used in patients in whom several types of seizure disorders coexist, it may increase the incidence or, rarely, precipitate the onset of generalized tonic-clonic (grand mal) seizures; addition of another anticonvulsant and/or an increase in dosage may be required {33}7.

Panic disorders (treatment)—Alprazolam {33}6 {33}5 {33}4, [ chlordiazepoxide (parenteral)] {33}3, clonazepam1 {33}2, [ diazepam]1 {33}1 {33}0, and [lorazepam]1 {35}9 are used in the treatment of panic disorders.

[Agoraphobia]1—Alprazolam is used in the treatment of agoraphobia.{35}8{35}7{35}6

Spasm, skeletal muscle (treatment adjunct)—Diazepam {35}5 {35}4 {35}3 and [ lorazepam]1 {35}2 are indicated as adjunctive therapy for the relief of skeletal muscle spasm due to reflex spasm of local pathology (such as inflammation of the muscles or joints, or secondary to trauma); spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; stiff-man syndrome; and tetanus {35}1 {35}0 {61}9 {61}8. [Diazepam also is used to relieve spasms of facial muscles associated with problems of occlusion and temporomandibular joint disorders.]1

[Nausea and vomiting, cancer chemotherapy–induced (prophylaxis)]1—Lorazepam injection, alone or in combination with other agents, reduces the severity and duration of nausea and vomiting associated with emetogenic cancer chemotherapy {61}7 {61}6. In addition, lorazepam-induced amnesia can reduce anticipatory anxiety, nausea, and vomiting {61}5.

[Headache, tension (treatment)]—Chlordiazepoxide {61}4, diazepam1 , lorazepam1 , and possibly other benzodiazepines1 are used in the treatment of tension headache {61}3.

[Tremors (treatment)]1—Oral alprazolam {61}2, chlordiazepoxide, diazepam, and lorazepam {61}1 are also used in the treatment of familial, senile, or essential action tremors.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics


Note: Whether the half-life of a benzodiazepine is considered to be long, intermediate, or short is determined by the half-lives of any active metabolites, as well as the half-life of the parent compound.



Drug
Protein
binding
(%)
Half-
life *
(hr)
Major active
metabolites
(half-life in hr)
Time to
peak plasma
concentration
(oral dose) (hr)
Elimination
(% excreted
unchanged)
Long half-life
 
         
Chlordiazepoxide
Very high (96) {61}0
5–30 {33}9
Desmethylchlordiazepoxide {33}8 (18)
Demoxepam (14–95 )
Desmethyldiazepam (40 {33}7–120 {33}6)
Oxazepam (5–15) {33}5
0.5–4
Renal (1–2) {33}4; 3–6%
as conjugate {33}3
Clorazepate §
Desmethyldiazepam: Very high (95–98) {33}2

Desmethyldiazepam (40 {33}1–120 {33}0)
Oxazepam (5–15) {35}9
0.5–2 {35}8
Renal {35}7; fecal {35}6
Diazepam
Very high (98) {35}5
20–80 {35}4 #
Desmethyldiazepam (40 {35}3–120 {35}2)
Temazepam (8–15) {35}1
Oxazepam (5–15) {35}0
1–2 {61}9
(injection: IM, 0.5–1.5;
IV, within 0.25 {61}8)
(sterile emulsion: IM, > 2 {61}7; IV, 0.13 {61}6–0.25 {61}5)
(rectal gel: 1.5 {61}4)
Renal {61}3
Flurazepam § **
Desalkylflurazepam: Very high (97) {61}2
2.3 {61}1
Desalkylflurazepam (47–100) {61}0
N-1-hydroxyethylflurazepam (2–4)
0.5–1 {56}9
Renal {56}8
Halazepam
Very high (97)
14 {56}7
Desmethyldiazepam (40 {56}6–120 {56}5)
1–3 {56}4
Renal (< 1) {56}3
Ketazolam
Very high (93)
2 {56}2
Desmethyldiazepam (40 {56}1–120 {56}0)
N-methylketazolam (34–52)
Diazepam (20–80) {56}9 #
3
Renal; fecal < 1%
Prazepam §
Desmethyldiazepam: Very high (95–98) {56}8

Desmethyldiazepam (40 {56}7–120 {56}6)
Oxazepam (5–15) {56}5
Desmethyldiazepam (single dose): 2.5–6
Renal
Quazepam
Very high (> 95) {56}4
39 {56}3
Desalkylflurazepam (47–100) {56}2
2-oxoquazepam (39) {56}1
2 {56}0
Renal (trace) {56}9; fecal {56}8
Short to intermediate
half-life
 
         
Alprazolam
High (80) {56}7
11 {56}6 (6.3–26.9) {56}5
None {56}4
1–2 {56}3
Renal {56}2
Bromazepam
High (70)
12 (8–19) {56}1
None
1–4 {56}0
Renal {56}9
Clobazam
High (85) {56}8
18 (10–30) {56}7
N-desmethylclobazam 42 (36–46) {56}6
1–4 {56}5
Renal {56}4
Clonazepam
High (85) {56}3
18–50 {56}2
None
1–2 {56}1 ††
Renal (< 2) {56}0
Estazolam
Very high (93) {68}9
10–24 {68}8
None
2 (0.5–6) {68}7
Renal (< 5) {68}6
Lorazepam ‡‡
High (85) {68}5
10–20
None {68}4
1–6 {68}3
(IM, 1–1.5 {68}2; sublingual, 1 {68}1)
Renal {68}0
Nitrazepam
High (87) {68}9
30 (18–57) {68}8
None {68}7
2–3 {68}6
Renal (about 1) {68}5; fecal {68}4
Oxazepam
Very high (97)
5–15 {68}3
None {68}2
1–4
Renal; fecal
Temazepam
Very high (96) {68}1 {68}0
8–15 {68}9 {68}8 {68}7
None {68}6
1–2 {68}5 {68}4 {68}3
Renal {68}2 (< 1) {68}1 §§
Triazolam
High (89) {68}0
1.5–5.5 {68}9
None {68}8
£ 2 {68}7
Renal (small
amount) {68}6 §§
* Elimination half-lives may be prolonged in children, especially premature and newborn infants, geriatric patients, and patients with hepatic disease; however, metabolic clearance of short to intermediate half-life benzodiazepines, especially lorazepam, oxazepam, temazepam, and triazolam, is affected less by age and hepatic disease than that of the long half-life benzodiazepines. The elimination half-life does not always predict the duration of clinical effects.
 With multiple dosing, steady-state plasma concentrations of long half-life benzodiazepines usually are achieved within 5 days to 2 weeks and those of short to intermediate half-life benzodiazepines within a few days.
 Benzodiazepines are not significantly removed from the body by hemodialysis.
§ Prodrugs or drug precursors; do not reach circulation in clinically significant amounts.
# Increases with age from approximately 20 hours in a 20-year-old patient to approximately 80 hours in an 80-year-old patient {68}5.
** Maximum effectiveness as a hypnotic may not be achieved for 2 to 3 days {68}4.
†† Following a single dose; in some patients peak concentrations may not be achieved for 4 to 8 hours.
‡‡ Peak amnestic effect: IM, within 2 hours; IV, 15 to 20 minutes {68}3.
§§ Appears to be biphasic in its time course {68}2 {68}1.

Physicochemical characteristics:
Molecular weight—
    Alprazolam: 308.77 {68}0
    Bromazepam: 316.16 {68}9
    Chlordiazepoxide: 299.76 {68}8
    Chlordiazepoxide hydrochloride: 336.22 {68}7
    Clonazepam: 315.72 {68}6
    Clorazepate dipotassium: 408.93 {68}5
    Diazepam: 284.75 {68}4
    Estazolam: 294.74 {68}3
    Flurazepam hydrochloride: 460.81 {68}2
    Halazepam: 352.74 {68}1
    Ketazolam: 368.82 {68}0
    Lorazepam: 321.16 {68}9
    Nitrazepam: 281.27 {68}8
    Oxazepam: 286.72 {68}7
    Prazepam: 324.81 {68}6
    Quazepam: 386.8 {68}5
    Temazepam: 300.75 {68}4
    Triazolam: 343.22 {68}3

Mechanism of action/Effect:

In general, benzodiazepines act as depressants of the central nervous system (CNS) {68}2, producing all levels of CNS depression from mild sedation to hypnosis to coma, depending on dose {68}1.

Although the precise mechanisms of action have not been completely established, it is believed that benzodiazepines enhance or facilitate the action of gamma-aminobutyric acid (GABA) {68}0 {44}9, the major inhibitory neurotransmitter in the CNS {44}8 {44}7, by causing it to bind more tightly to the GABA type A (GABA A) receptor {44}6.

Benzodiazepines reportedly act as agonists at the benzodiazepine receptors {44}5, which have been shown to form a component of a functional {44}4 {44}3 supramolecular unit {44}2 {44}1 known as the benzodiazepine-GABA receptor-chloride ionophore complex. This receptor complex, which resides on neuronal membranes {44}0 {44}9, functions mainly in the gating of the chloride channel {44}8. Activation of the GABA receptor results in the opening of the chloride channel {44}7 {44}6 {44}5, allowing the flow of chloride ions into the neuron {44}4. This results in hyperpolarization {44}3 {44}2 {44}1, which inhibits firing of the neuron {44}0 {44}9 {44}8 and translates into decreased neuronal excitability {44}7 {44}6 {44}5, thus attenuating the effects of subsequent depolarizing excitatory transmitters {44}4 {44}3. Benzodiazepines reportedly increase the frequency of chloride channel opening {44}2 {44}1 {44}0. There is also evidence that benzodiazepines may act at GABA-independent receptors {08}9.

Antianxiety agent; sedative-hypnotic—Believed to stimulate GABA receptors in the ascending reticular activating system. Since GABA is inhibitory, receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brain stem reticular formation. {08}8

Amnestic—Mechanism of action has not been determined. However, as may occur with all sedative-hypnotic medications, preanesthetic doses of diazepam and lorazepam impair recent memory and interfere with the establishment of the memory trace, thus producing anterograde amnesia for events occurring while therapeutic concentrations of the benzodiazepine are present. {08}7

Anticonvulsant—Hyperpolarization, which is enhanced by benzodiazepines, reduces the ability of the neuron to depolarize to the threshold required to produce an action potential {08}6. Thus, the seizure threshold is raised {08}5. Benzodiazepines suppress the spread of seizure activity produced by epileptogenic foci in the cortex, thalamus, and limbic structures but do not abolish the abnormal discharge of the focus {08}4.

Skeletal muscle relaxant adjunct—The exact mechanism of action of benzodiazepines has not been completely established but these medications appear to produce skeletal muscle relaxation primarily by inhibiting spinal polysynaptic afferent pathways; however, monosynaptic afferent pathways may also be inhibited {08}3. Benzodiazepines may also directly depress motor nerve and muscle function {08}2.

Absorption:

Following oral administration—Benzodiazepines are well absorbed from the gastrointestinal tract {08}1 {08}0, usually within 1 to 2 hours {44}9 {44}8. Diazepam and clorazepate are among the most rapidly absorbed, and prazepam and oxazepam are the least rapidly absorbed {44}7.

Following intramuscular administration—Lorazepam absorption is rapid and complete, whereas chlordiazepoxide and diazepam absorption may be slow and erratic {44}6, depending upon the site of administration {44}5. When diazepam is injected into the deltoid muscle, absorption is usually rapid and complete {44}4.

Following rectal administration—Absorption of diazepam rectal solution {44}3 {44}2 and rectal gel {44}1 is rapid.

Biotransformation:

Hepatic.


Long half-life benzodiazepines:

Chlordiazepoxide, flurazepam, halazepam, ketazolam, and quazepam are metabolized by oxidation to active, as well as inactive, metabolites before final inactivation as glucuronide conjugates {44}0 {44}9.

Diazepam undergoes hepatic demethylation and hydroxylation, involving the cytochrome P450 2C19 (CYP2C19) and CYP3A4 isoenzymes, followed by glucuronidation {44}8. Only one active metabolite, desmethyldiazepam, is present in clinically significant concentrations {44}7 {44}6.

Clorazepate and prazepam are metabolized in the stomach and liver, respectively, to desmethyldiazepam as a result of first-pass biotransformation prior to entering systemic circulation {44}5 {44}4 {44}3.



Short to intermediate half-life benzodiazepines:

Alprazolam undergoes hydroxylation {44}2, which is catalyzed by the CYP3A isoenzymes {44}1, and is eliminated as glucuronide conjugates {44}0 {25}9. One of alprazolam's metabolites has one half of the biological activity of alprazolam, but is present in very low plasma concentrations {25}8.

Bromazepam undergoes hepatic microsomal oxidation {25}7 and is eliminated primarily as glucuronide conjugates {25}6.

Clobazam undergoes hepatic demethylation and hydroxylation to active and inactive metabolites before inactivation by conjugation {25}5.

Clonazepam and nitrazepam undergo hepatic nitro-reduction to inactive metabolites {25}4 {25}3. Clonazepam also undergoes oxidative hydroxylation {25}2 and CYP3A isoenzymes may play an important role in clonazepam's metabolism {25}1.

Estazolam undergoes oxidative metabolism and hydroxylation to metabolites with little activity and low plasma concentrations in comparison with the parent compound {25}0.

Lorazepam, oxazepam, and temazepam are metabolized by direct conjugation with glucuronic acid {44}9 {44}8 {44}7 {44}6.

Triazolam undergoes hepatic microsomal oxidation to inactive hydroxylated metabolites that are eliminated primarily as glucuronide conjugates {44}5.


Accumulation

During repeated dosing with long half-life benzodiazepines, there is accumulation of the parent compound and/or any pharmacologically active metabolites {44}4 {44}3 {44}2 {44}1. Accumulation continues until a steady-state plasma concentration is reached, which usually takes 5 days to 2 weeks after initiation of therapy {44}0. Following termination of treatment, drug elimination is slow since active metabolites may remain in the blood for several days or even weeks, possibly resulting in persistent effects {25}9.

During repeated dosing with short to intermediate half-life benzodiazepines, accumulation is minimal {25}8 {25}7 {25}6, and a steady-state plasma concentration is usually attained within a few days after initiation of therapy {25}5. Following termination of treatment, blood concentrations are subclinical in 24 hours and return rapidly to zero (in about 4 days or less). {25}4

Onset of action:

After single oral doses, onset of action depends largely upon absorption rate. After multiple doses, effects depend partly upon rate and extent of drug accumulation, which in turn relate to elimination half-life and clearance. {25}3 {25}2

Duration of action:

After single oral doses, duration of action depends upon rate and extent of drug distribution, as well as rate of elimination once distribution is complete. After multiple doses, effects depend partly upon rate and extent of drug accumulation, which in turn relate to elimination half-life and clearance. {25}1 {25}0 The duration of clinical effects of the benzodiazepines is not always predictable from the elimination half-life {44}9.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one of the benzodiazepines may be sensitive to the other benzodiazepines also {44}8 {44}7.

Carcinogenicity/Tumorigenicity

Alprazolam—In a 24-month study in rats, alprazolam at doses of up to 150 times the maximum recommended human dose (MRHD) showed no evidence of carcinogenic potential {44}6.

Clobazam—Hepatomas, thyroid adenomas, and malignancies of the liver and thyroid gland were seen in rodent studies {44}5; the significance of this finding to humans is unknown {44}4.

Clonazepam—Studies on carcinogenic potential have not been done {44}3.

Diazepam—An increased incidence of liver tumors was seen in male mice and rats following oral administration of diazepam to mice and rats of both sexes at doses that were approximately 6 and 12 times, respectively, the MRHD (1 mg per kg of body weight [mg/kg] per day) on a mg per square meter of body surface area (mg/m 2) basis for 80 and 104 weeks, respectively {44}2.

Estazolam—Studies of 24-months duration in mice and rats showed no evidence of tumorigenicity {44}1. However, the female mice given 3 and 10 mg/kg per day of estazolam over the 2-year period showed an increase in hyperplastic liver nodules; the significance of this finding is unknown {44}0.

Halazepam—In oral oncogenicity studies in rats and mice, halazepam at doses 5 to 50 times the usual daily human dose of 120 mg showed no evidence of carcinogenicity {25}9.

Lorazepam—In an 18-month study in rats, lorazepam showed no evidence of carcinogenic potential {25}8.

Oxazepam—A 24-month study in rats given oxazepam at doses 30 times the MRHD showed an increase in benign thyroid follicular cell tumors, testicular interstitial cell adenomas, and prostatic adenomas. In a 9-month study in mice, oxazepam in doses 35 to 100 times the usual daily human dose caused dose-related increases in liver adenomas, some of which were classified as carcinomas after microscopic examination. {25}7

Quazepam—Oral oncogenicity studies in mice and hamsters showed no evidence of carcinogenicity {25}6.

Temazepam—Long-term studies in mice and rats showed no evidence of carcinogenicity. However, hyperplastic liver nodules occurred in female mice at the highest dose used (160 mg/kg per day); the clinical significance of this finding is unknown. {25}5

Triazolam—In a 24-month study in mice, triazolam in doses up to 4000 times the human dose showed no evidence of carcinogenic potential {25}4 {25}3.

Mutagenicity

Alprazolam—Mutagenicity was not demonstrated in appropriate tests on mice or bacteria {25}2.

Estazolam—Mutagenicity was not demonstrated in appropriate tests on mice, rats, and bacteria {25}1.

Diazepam—Data are insufficient to determine mutagenic potential {25}0.

Halazepam—Halazepam demonstrated no mutagenic activity in the Ames test {44}9.

Lorazepam, oxazepam, and temazepam—Studies on mutagenic potential have not been done {44}8 {44}7 {44}6.

Quazepam—Mutagenicity was not demonstrated in tests on mice or bacteria {44}5.

Pregnancy/Reproduction

Pregnancy—

All benzodiazepines

Chlordiazepoxide {44}4, clonazepam, diazepam {44}3 {44}2, estazolam, flurazepam {44}1, lorazepam {44}0 {33}9, nitrazepam {33}8, temazepam, and triazolam {33}7 cross the placenta. Alprazolam {33}6, bromazepam, clorazepate, halazepam, ketazolam {33}5, oxazepam, prazepam, and quazepam {33}4 are assumed to cross the placenta because of their similarity to the other benzodiazepines {33}3.

First trimester—Chlordiazepoxide and diazepam have been reported to increase the risk of congenital malformations when used during the first trimester of pregnancy {33}2 {33}1 {33}0. Because of the similarity of the benzodiazepines {33}9, the other benzodiazepines are assumed to be associated with this increased risk also {33}8 {33}7. Risk-benefit must be considered carefully. However, since the use of benzodiazepines (with the possible exception of anticonvulsant use) is rarely a matter of urgency, it should be avoided during pregnancy, especially during the first trimester {33}6 {33}5 {33}4 {33}3. The possibility that a woman of childbearing potential may already be pregnant should be considered when initiating benzodiazepine treatment {33}2 {33}1 {33}0 {08}9.

When benzodiazepines are used as anticonvulsants, risk-benefit must be considered {08}8. Reports suggest an increased incidence of congenital abnormalities in children whose mothers used anticonvulsants during pregnancy, although anticonvulsant medications have not been definitively shown to have a causative role and other factors, such as the epileptic condition itself, may be involved {08}7 {08}6. The severity of the seizure disorder and the potential harm to the mother or fetus in the event of a seizure must be considered when deciding whether to continue anticonvulsant treatment during pregnancy {08}5 {08}4.

Regular use of benzodiazepines during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate {08}3 {08}2 {08}1 {08}0 {33}9 {33}8.

Use of benzodiazepine hypnotics during the last weeks of pregnancy has resulted in neonatal CNS depression {33}7 {33}6 {33}5, neonatal flaccidity {33}4 {33}3 {33}2 {33}1, feeding difficulties {33}0 {33}9, hypothermia {33}8 {33}7, and respiratory problems {33}6 {33}5 {33}4.



Chlordiazepoxide

Reproduction studies in rats showed that chlordiazepoxide, at doses of 10, 20, and 80 mg per kg of body weight (mg/kg) per day, caused no congenital anomalies or adverse effects on the growth of the newborn animal. However, another study with chlordiazepoxide at doses of 100 mg/kg per day showed a significant decrease in the fertilization rate and a decrease in the viability and body weight of offspring, which may have been due to the sedative effect; also, one neonate in each of the first and second matings in this study showed skeletal deformities. {33}3

FDA pregnancy category not presently included in product labeling.



Clonazepam

Studies in rabbits have shown that clonazepam in oral doses of 0.2 to 10 mg/kg per day (low dose approximately 0.2 times the maximum recommended human dose [MRHD] for seizure disorders and approximately equivalent to the MRHD for panic disorder, on a mg/m 2 basis), given during organogenesis, caused a non–dose-related increased incidence of cleft palates, open eyelids, fused sternebrae, and limb defects {33}2.

Withdrawal of clonazepam anticonvulsant prior to or during pregnancy should be considered only when seizures are mild and infrequent in the absence of the medication and where the possibility of status epilepticus and withdrawal symptoms is considered low {33}1.

FDA Pregnancy Category D {33}0.



Diazepam

Rodent studies have shown that single oral doses ³ eight times the MRHD of 1 mg/kg per day on a mg/m 2 basis, administered during organogenesis, are teratogenic. Cleft palate and exencephaly were the most commonly and consistently reported malformations. Also, long-term changes in cellular immune response, brain neurochemistry, and behavior were seen in offspring of rodents given diazepam during pregnancy in doses similar to human clinical doses. {08}9

FDA Pregnancy Category D {08}8.



Lorazepam

Studies in rabbits have shown that lorazepam causes fetal resorption and increased fetal loss at oral doses of 40 mg/kg and intravenous doses of 4 mg/kg and higher; lorazepam was also shown to cause anomalies in rabbits without relationship to dosage {08}7.

FDA Pregnancy Category D (parenteral).



Quazepam

Reproduction studies in mice given 66 to 400 times the human dose of quazepam showed minor developmental variations including delayed ossification of the sternum, vertebrae, distal phalanges, and supraoccipital bones. Studies in mice given 60 to 180 times the human dose showed slight reductions in the pregnancy rate. {08}6

FDA Pregnancy Category X {08}5.



Temazepam

Studies in rats have shown that temazepam causes an increased incidence of fetal resorption at doses of 30 and 120 mg/kg, and an increased occurrence of rudimentary ribs (considered skeletal variants) at doses of 240 mg/kg or higher. Increased nursling mortality was seen in rats when oral doses of 60 mg/kg per day were given to the dam during the perinatal-postnatal period. Also, studies in rabbits have shown that temazepam causes an increased incidence of the 13th rib variant at doses of 40 mg/kg or higher, and occasional abnormalities such as exencephaly and fusion or asymmetry of ribs without relationship to dosage. {08}4

FDA Pregnancy Category X {08}3.


Alprazolam {08}2; Halazepam {08}1—FDA Pregnancy Category D.

Estazolam {08}0; Triazolam {08}9 {08}8—FDA Pregnancy Category X.


Clorazepate, flurazepam, and oxazepam

FDA pregnancy categories not presently included in product labeling.


Labor—

All benzodiazepines: Use of benzodiazepines just prior to or during labor may cause neonatal flaccidity {08}7 {08}6.

Delivery—

Diazepam: When diazepam is administered in doses of more than 30 mg (especially intramuscularly or intravenously) to women within 15 hours before delivery, the neonate may develop apnea, hypotonia, hypothermia, a reluctance to feed, and impaired metabolic response to cold stress {08}5.

Breast-feeding

Chlordiazepoxide, diazepam {08}4 {08}3, halazepam {08}2, quazepam {08}1, and their metabolites, including desmethyldiazepam {08}0 (which is also the metabolite of clorazepate {44}9 and prazepam {44}8) are distributed into breast milk; clobazam {44}7 and nitrazepam {44}6 are distributed into breast milk also; alprazolam {44}5, clonazepam, flurazepam, lorazepam {44}4, oxazepam, temazepam {44}3, and/or their metabolites are assumed to be distributed into breast milk because of their similarity to the other benzodiazepines. Although studies in humans have not been done, studies in rats have shown that bromazepam {44}2, estazolam {44}1, ketazolam {44}0, triazolam {26}9, and their metabolites are distributed into the milk of rats.

Chronic use of diazepam by nursing mothers has been reported to cause lethargy and weight loss in the infants {26}8. Since neonates metabolize benzodiazepines more slowly than adults and accumulation of the benzodiazepine and/or its metabolites may occur {26}7, use by nursing mothers may cause sedation, feeding difficulties, and/or weight loss in the infant.

Pediatrics

All benzodiazepines—Children, especially the very young, are usually more sensitive to the CNS effects of benzodiazepines. Prolonged CNS depression may be produced in the neonate because of inability to biotransform the benzodiazepine into inactive metabolites. {26}6 {26}5

Clonazepam—Risk-benefit must be considered in the long-term use of clonazepam to treat seizure disorders in pediatric patients because of the possibility that adverse effects on physical or mental development may occur and may not become apparent for many years {26}4.


Geriatrics


Geriatric patients are usually more sensitive to the CNS effects of benzodiazepines {26}3 {26}2 {26}1. It is recommended that dosage be limited to the smallest effective dose {26}0 {23}9 {23}8 and increased gradually {23}7, if necessary, to decrease the possibility of development of ataxia {23}6, dizziness {23}5 {23}4 {23}3, and oversedation {23}2 {23}1, which may lead to falls and other accidents {23}0 {26}9. A retrospective case-control study has shown that elderly patients receiving long-acting benzodiazepines are more likely than those receiving short-acting benzodiazepines to suffer falls and fall-related fractures {26}8. However, both groups had an increased risk of these sequelae as compared to older patients who did not receive benzodiazepines or who received other short-acting sedative-hypnotics {26}7.

The half-lives of benzodiazepines may be longer in elderly than in younger patients {26}6 {26}5 {26}4 {26}3.

Parenteral administration of benzodiazepines may be more likely to cause apnea, hypotension, bradycardia, or cardiac arrest in geriatric patients {26}2.


Pharmacogenetics

Diazepam—3 to 5% of white patients have little or no cytochrome P450 2C19 (CYP2C19) activity and are poor metabolizers of diazepam {26}1.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: The cytochrome P450 2C19 (CYP2C19) isoenzyme is known to be involved in diazepam's metabolism {26}0. Medications that inhibit CYP2C19, such as cimetidine, quinidine, and tranylcypromine, may decrease the rate of elimination of diazepam {23}9. Likewise, medications that induce CYP2C19, such as rifampin, may increase the rate of diazepam's elimination {23}8.
The CYP3A isoenzymes are known to be involved in the metabolism of alprazolam {23}7, clonazepam {23}6, diazepam {23}5, and triazolam {23}4 {23}3. Concurrent use with medications that inhibit CYP3A isoenzymes, other than those listed below, should be undertaken with caution, and reduction in benzodiazepine dosage should be considered {23}2 {23}1.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Addictive medications, other, especially CNS depressants with habituating potential    (prolonged concurrent use may increase the risk of habituation; caution is recommended)


» Alcohol or
» CNS depression–producing medications, other (see Appendix II )    (CNS depressant effects may be potentiated {23}0 {26}9 and the risk of apnea may be increased {26}8 {26}7; use of alcohol during treatment with a benzodiazepine is not recommended {26}6 {26}5 {26}4; caution is recommended when another CNS depression–producing medication is used with a benzodiazepine, and dosage of one or both agents should be reduced {26}3)

    (when a benzodiazepine is used with an opioid analgesic, the dosage of the opioid analgesic should be reduced by at least one third and administered in small increments {26}2 {26}1)


Antacids    (concurrent use may delay, but not reduce, the absorption of chlordiazepoxide and diazepam; whether this effect applies to other benzodiazepines has not been determined {26}0 {23}9)

    (concurrent use with clorazepate may decrease the rate of conversion of clorazepate to desmethyldiazepam, but does not affect the degree of absorption {23}8 {23}7)


Antidepressants, tricyclic    (in addition to possibly increasing CNS depressant effects, concurrent use with alprazolam in doses of up to 4 mg per day has been reported to increase steady-state plasma concentrations of imipramine and desipramine by an average of 31% and 20%, respectively; however, the clinical significance of these changes is unknown {23}6)


Carbamazepine    (induction of hepatic microsomal enzyme activity by carbamazepine may result in increased rate of metabolism, decreased serum concentrations, and reduced elimination half-lives of benzodiazepines metabolized via the hepatic enzyme system, such as clonazepam {23}5 {23}4; carbamazepine concentrations may be increased during concurrent use with a benzodiazepine {23}3; monitoring of carbamazepine blood concentrations as a guide to dosage is recommended, especially when carbamazepine is added to or withdrawn from existing benzodiazepine therapy {23}2 {23}1)


Cimetidine{23}0{26}9{26}8{26}7 or
Contraceptives, estrogen-containing, oral{26}6{26}5 or
Diltiazem{26}4 or
Disulfiram{26}3 or
Erythromycin{26}2 or
Fluoxetine{26}1{26}0 or
» Fluvoxamine{64}9{64}8 or
Grapefruit juice{64}7 or
» Itraconazole{64}6{64}5{64}4 or
» Ketoconazole{64}3{64}2{64}1 or
» Nefazodone{64}0{23}9 or
Propoxyphene{23}8 or
Ranitidine{23}7 or
Verapamil{23}6    (concurrent use may inhibit the hepatic metabolism of benzodiazepines that are metabolized by oxidation {23}5, resulting in delayed elimination {23}4 and increased plasma concentrations {23}3; however, the hepatic metabolism of benzodiazepines that undergo direct glucuronide conjugation, such as lorazepam {23}2, oxazepam {23}1, and temazepam {23}0, is probably not affected)

    (concurrent use of cimetidine or oral, estrogen-containing contraceptives may inhibit the hepatic metabolism of benzodiazepines that are metabolized primarily by nitro-reduction, such as nitrazepam, possibly resulting in delayed elimination, prolonged elimination half-life, and, during long-term use, increased serum concentrations {26}9 {26}8 {26}7)

    (alprazolam's peak plasma concentration [C max] has been almost doubled during concurrent use of cimetidine, fluvoxamine, or nefazodone; also, decreased psychomotor performance has been demonstrated during concurrent use of fluvoxamine; dosage reductions of alprazolam may be required [initial reductions of 50% are recommended in patients receiving fluvoxamine or nefazodone] {26}6 {26}5 {26}4; alprazolam's C max has been increased by approximately 50% during concurrent use of fluoxetine or propoxyphene; also, psychomotor performance has been decreased during concurrent use of fluoxetine {26}3 {26}2)

    (diazepam and desmethyldiazepam clearances have been reduced and patient psychomotor performance has been impaired during concurrent use of fluvoxamine; concurrent use is not recommended due to the potential for accumulation of diazepam and desmethyldiazepam {26}1)

    (triazolam's area under the plasma concentration–time curve [AUC] has been increased 22 and 27 times during concurrent use of ketoconazole and itraconazole, respectively; concurrent use is not recommended {26}0 {64}9; triazolam's AUC was increased fourfold and patient psychomotor performance was impaired during concurrent use of nefazodone {64}8; reductions in initial triazolam dosage of 75% are recommended in patients receiving nefazodone {64}7; triazolam's C max and half-life [t 1/2] have been doubled during concurrent use of cimetidine or erythromycin; dosage reductions may be necessary {64}6 {64}5; triazolam's C max, t 1/2, and AUC have been increased during concurrent use of ranitidine; caution is recommended {64}4; plasma concentration, AUC, and t 1/2 of triazolam have been increased by coadministration with grapefruit juice {64}3)


Clozapine{64}2{64}1{64}0    (collapse, sometimes accompanied by respiratory depression or arrest, has been reported in a few patients receiving clozapine concurrently with benzodiazepines. Caution is advised when clozapine is administered concomitantly with any agent that may depress respiration, and the dosage of clozapine should be titrated upward slowly. Some clinicians have recommended that benzodiazepines be discontinued at least 1 week prior to initiation of therapy with clozapine)


Fentanyl derivatives    (premedication with diazepam or lorazepam may decrease the dose of a fentanyl derivative required for induction of anesthesia and decrease the time to loss of consciousness with induction doses; also, administration of diazepam or lorazepam prior to or during surgery may decrease risk of patient recall of surgical events postoperatively; however, these potential benefits must be weighed against the potential risks of concurrent use, such as an increased risk of severe hypotension associated with decreases in systemic vascular resistance, increased risk of respiratory depression, and delayed recovery time, especially when the benzodiazepine is administered intravenously {26}9)


Hypotension-producing medications, other (see Appendix II )    (concurrent use may potentiate the hypotensive effects of benzodiazepine preanesthetics used in surgery; dosage adjustments may be necessary)

    (concurrent use of mecamylamine or trimethaphan with benzodiazepine preanesthetics used in surgery may potentiate the hypotensive response, with increased risk of severe hypotension, shock, and cardiovascular collapse during surgery {26}8 {26}7)

    (caution is advised during titration of calcium channel blocker dosage for those patients taking medication known to promote hypotension, such as benzodiazepine preanesthetics, since the combination may result in excessive hypotension)


Isoniazid    (concurrent use may inhibit the elimination of diazepam and triazolam, resulting in increased plasma concentrations {26}6; whether this effect applies to other benzodiazepines has not been determined {26}5; dosage adjustment may be necessary {26}4 {26}3)


Levodopa    (concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa {26}2)


Omeprazole{26}1{26}0    (concurrent use of omeprazole may prolong the elimination of diazepam)


Probenecid    (concurrent use may impair glucuronide conjugation of lorazepam, oxazepam, or temazepam, resulting in increased effects and possibly excessive sedation {23}9)


Rifampin    (concurrent use may enhance the elimination of diazepam, resulting in decreased plasma concentrations; whether this effect applies to other benzodiazepines has not been determined; dosage adjustment may be necessary {23}8)


Scopolamine, systemic    (concurrent use of scopolamine with parenteral lorazepam is reported to have no added beneficial effect and their combined effect may increase the incidence of sedation, hallucination, and irrational behavior {23}7)


» Tubing, infusion, plastic    (diazepam adheres to plastic infusion tubing; if parenteral diazepam must be administered through tubing, it should be injected as closely as possible to the insertion point {23}6 {23}5 {23}4)


Zidovudine{23}3{23}2    (concurrent use with benzodiazepines may, in theory, competitively inhibit hepatic glucuronidation and decrease the clearance of zidovudine; the toxicity of zidovudine potentially could be increased)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Metyrapone test    (chlordiazepoxide may interfere with the assay for urine 17-ketosteroids or 17-ketogenic steroids; in addition, the response to metyrapone may be decreased {23}1 {23}0)


Sodium iodide I 123 and
Sodium iodide I 131    (benzodiazepines may decrease thyroidal uptake of I 123 and I 131 {26}9)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcohol intoxication, acute, with depressed vital signs    (additive CNS depression {26}8 {26}7)


» Coma or
» Shock    (hypnotic or hypotensive effects may be prolonged or intensified by benzodiazepines administered parenterally {26}6 {26}5)


Drug abuse or dependence, history of    (patients predisposed to habituation and dependence {26}4 {26}3 {26}2 {26}1 {26}0 {23}9)


Epilepsy or
Seizures, history of    (initiation or abrupt withdrawal of clonazepam or diazepam therapy may increase frequency and/or severity of tonic-clonic [grand mal] seizures {23}8 {23}7 {23}6 {23}5; use of intravenous diazepam for absence [petit mal] status or Lennox-Gastaut syndrome [petit mal variant] status may precipitate tonic status epilepticus {23}4)

    (abrupt withdrawal of clonazepam or diazepam used to treat these disorders may precipitate seizures or status epilepticus {23}3 {23}2)


» Glaucoma, angle-closure, acute or predisposition to    (benzodiazepines may have anticholinergic effect {23}1 {23}0 {33}9 {33}8 {33}7)


Hepatic function impairment    (elimination half-life may be prolonged {33}6 {33}5 {33}4 {33}3 {33}2; minimal effect with oxazepam, lorazepam, and temazepam)


Hyperkinesis    (paradoxical reactions may occur {33}1)


Hypoalbuminemia{33}0    (may predispose patient to higher incidence of sedative side effects, especially with chlordiazepoxide and diazepam {33}9)


Mental depression, severe    (suicidal tendencies may be present; protective measures may be necessary; also benzodiazepines, when used alone, may increase depression {33}8 {33}7 {33}6 {33}5 {33}4; episodes of hypomania and mania reported with use of alprazolam in patients with mental depression {33}3 {33}2)


» Myasthenia gravis    (condition may be exacerbated {33}1 {33}0 {33}9 {33}8)


Organic brain disorders    (patients may be more prone to disinhibition and CNS depressant effects of benzodiazepines {33}7 {33}6)


Porphyria    (condition may be exacerbated with the use of chlordiazepoxide {33}5)


Psychoses    (benzodiazepines are rarely effective as primary treatment for psychosis; also, paradoxical reactions may be more likely to occur in psychotic patients {33}4 {33}3 {33}2)


» Pulmonary disease, severe chronic obstructive    (compromised respiratory function may be exacerbated and increased salivation and bronchial secretions occurring with benzodiazepine use may cause problems in these patients {33}1 {33}0 {64}9 {64}8; deaths occurring shortly after beginning treatment with alprazolam have been reported rarely in patients with severe pulmonary disease {64}7)


Renal function impairment    (accumulation of renally excreted metabolites may occur {64}6 {64}5 {64}4)


Sensitivity to benzodiazepines{64}3{64}2{64}1{64}0
Sleep apnea, established or suspected    (condition may be exacerbated {33}9 {33}8 {33}7)


Swallowing abnormality, in children    (condition may be exacerbated because drooling and aspiration induced by benzodiazepines, such as nitrazepam, may delay cricopharyngeal relaxation; patient should be closely monitored {33}6 {33}5)


Caution should also be used in surgical or nonambulatory patients because of the cough-suppressant effects of clonazepam{33}4{33}3 .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Assessment of amount and frequency of medication use    (recommended at periodic intervals during long-term therapy to detect signs of dependence or abuse {33}2)


Reassessment of medication's efficacy as an antianxiety agent or a sedative-hypnotic    (recommended at periodic intervals during therapy; see Indications {33}1 {33}0)




Side/Adverse Effects

Note: Although not all of these side effects have been attributed specifically to each benzodiazepine, a potential exists for their occurrence during the use of any benzodiazepine.
Psychological or physical dependence and tolerance may occur with benzodiazepine use, especially with high-dose or prolonged use {33}9.
Geriatric and debilitated patients, children (especially the very young), and patients with hepatic disease or low serum albumin are usually more sensitive to the CNS effects of benzodiazepines {33}8 {33}7 {33}6.
Parenteral administration of benzodiazepines may cause apnea, hypotension, bradycardia, or cardiac arrest, especially in geriatric or severely ill patients and in patients with limited pulmonary reserve or unstable cardiovascular status or if intravenous administration of medication is too rapid {33}5.
Parenteral benzodiazepines have produced hypotension or muscular weakness in some patients, especially when used concurrently with narcotics, barbiturates, or alcohol {33}4.
Coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm, and pain in throat and chest have been reported when parenteral diazepam was administered in peroral endoscopic procedures {33}3.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Anterograde amnesia{33}2{33}1{33}0 (lack of memory of events taking place after benzodiazepine is taken)
    
anxiety{33}9{33}8{33}7{33}6
    
confusion{33}5{33}4{33}3{33}2{33}1 —especially in the elderly and in patients with cerebral impairment{33}0
    
mental depression{33}9{33}8{33}7{33}6
    
tachycardia/palpitation{33}5{33}4{33}3 (fast, pounding, or irregular heartbeat)

Note: Anterograde amnesia may be dose-related {33}2 {33}1 and may occur at a higher rate with triazolam than with other benzodiazepines {33}0 {64}9 {64}8. “Traveler's amnesia,” which occurs in people taking benzodiazepines to avoid jet lag, may be associated with allowing insufficient time for sleep {64}7 {64}6 {64}5 {64}4 and/or concomitant use of alcohol {64}3.
Daytime anxiety, as well as wakefulness during the last third of the night, may develop over several weeks of nightly dosing with short to intermediate half-life benzodiazepines {64}2 {64}1 {64}0 {33}9. These effects are thought to be due to the development of tolerance or adaptation, which leads to a relative deficiency of benzodiazepine receptor binding between nightly doses {33}8 {33}7 {33}6 {33}5.


Incidence rare
    
Abnormal thinking{33}4{33}3
including delusions{33}2 (false beliefs that cannot be changed by facts), depersonalization{33}1{33}0{26}{75} (loss of sense of reality), or disorientation{75}
    
allergic reaction{03}{18}{23} (skin rash or itching)
    
behavior changes{18}{23}
including bizarre behavior{26}{75}
or decreased inhibition{26}{75}
    
blood dyscrasias, including agranulocytosis{41} (chills, fever, sore throat; unusual tiredness or weakness), anemia{18} (unusual tiredness or weakness), leukopenia{18}{55}{75} (chills, fever, sore throat), neutropenia{24} (chills, fever, and/or sore throat; ulcers or sores in mouth or throat, continuing; unusual tiredness or weakness), thrombocytopenia{18} (unusual bleeding or bruising)
    
extrapyramidal effects, dystonic{18}{23} (uncontrolled movements of body, including the eyes)
    
hepatic dysfunction{03}{18}{55} (yellow eyes or skin)
    
hypotension{03}{24}{75} (low blood pressure)
    
muscle weakness{24}
    
paradoxical reactions{03}{18}{23}
including agitation{03}{23}{26}{75}
aggressive behavior{03}{23}{26}{75}
hallucinations{03}{18}{23}{24}{75} (seeing, hearing, or feeling things that are not there), hostility or rage{03}{23}{75} (outbursts of anger), insomnia{03}{18}{23}{24} (trouble in sleeping), unusual excitement, irritability, or nervousness{03}{18}{23}{24}{75}
    
phlebitis or venous thrombosis{24}{113} (redness, swelling, or pain at injection site)—for parenteral dosage forms only
    
seizures{03}

Note: Behavioral disturbances associated with clonazepam are more likely to occur in children or in patients with pre-existing brain damage and/or mental retardation or a history of behavioral or psychiatric disturbances; if these effects occur, the medication should be discontinued.
Paradoxical reactions have occurred most often in patients who were receiving additional CNS-active medications {03}, or who had underlying psychiatric conditions {03} {18}, a history of violent or aggressive behavior {03} {75}, a history of alcohol or substance abuse {03}, or a history of unusual reactions to sedatives or alcohol {75}. Benzodiazepine treatment should be discontinued if a paradoxical reaction occurs {03} {23} {24} {75}.
Incidence of phlebitis or venous thrombosis is more common with diazepam, less common with lorazepam, and rare with chlordiazepoxide.
There may be an increased incidence and severity of seizures, especially on initiation or abrupt withdrawal of clonazepam and diazepam, in patients with epilepsy or history of seizures {05} {18}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Ataxia{18}{23}{38} (clumsiness or unsteadiness)—especially in elderly or debilitated patients{07}
    
dizziness or lightheadedness{03}{18}{23}{42}{75}
    
drowsiness, including residual daytime drowsiness when used as a hypnotic{03}{18}{23}{42}{75} —especially in elderly or debilitated patients{07}
    
slurred speech{18}{24}

Note: Ataxia and drowsiness are dose-related and are most severe during initial therapy {03}. They may decrease in severity or disappear with continued or long-term therapy {03} {18}.
Residual daytime drowsiness is dose-related {23}.


Incidence less frequent or rare
    
Abdominal or stomach cramps or pain{18}{38}
    
blurred vision or other changes in vision{03}{18}{23}{24}{75}
    
changes in libido{23}{75} (changes in sexual desire or ability)
    
constipation{18}{23}{24}{75}
    
diarrhea{18}{23}{38}{75}
    
dryness of mouth or increased thirst{03}{18}{23}
    
euphoria{23}{38} (false sense of well-being)
    
headache{18}{23}{24}{38}{75}
    
increased bronchial secretions or excessive salivation{03}{18}{75} (watering of mouth)
    
muscle spasm{05}
    
nausea or vomiting{18}{23}{24}{75}
    
problems with urination{03}{18}{23}{24}
    
tremor{18}{24} (trembling or shaking)
    
unusual tiredness or weakness{03}{18}{23}{75}

Note: Increased bronchial secretions and excessive salivation may pose a risk of aspiration in infants and young children, and in elderly or bedridden patients as well as in patients with chronic respiratory disease {18} {75}.




Those indicating possible withdrawal and the need for medical attention if they occur (usually within 2 to 3 days with short to intermediate half-life benzodiazepines and 10 to 20 days with long half-life benzodiazepines) after medication is discontinued
Incidence more frequent
    
Insomnia{03}{18}{23}{24}{60}{75} (trouble in sleeping)
    
irritability{03}{60}
    
nervousness{60}

Note: When a benzodiazepine has been used as a hypnotic, withdrawal of the medication may cause a transient recurrence of symptoms known as rebound insomnia {08} {23} {26} {75}. Rebound insomnia may be more severe than the insomnia that originally led to treatment {08} {23} {26} {75}.


Incidence less frequent
    
Abdominal or stomach cramps{03}{18}{23}{24}{60}{75}
    
confusion{03}
    
depersonalization{122}{124}{125} (loss of sense of reality)
    
increased sweating{03}{23}{24}{75}
    
mental depression{03}{124}{125}{126}
    
muscle cramps{03}{18}{23}{24}{75}
    
nausea or vomiting{03}{23}{24}{60}{75}
    
perceptual disturbances{120}{122}{124}{125}{126} , including hyperacusis{120} (increased sense of hearing), hypersensitivity to touch and pain{120}{124}
parasthesias{03}{120} (tingling, burning, or prickly sensations), or photophobia{120}{124} (sensitivity of eyes to light)
    
tachycardia{03}{127} (fast or pounding heartbeat)
    
tremor{03}{18}{23}{24}{60}{75} (trembling or shaking)

Incidence rare
    
Convulsions{03}{18}{23}{24}{60}{75}
    
delirium (confusion as to time, place, or person)
    
hallucinations{18}{125}
    
paranoid symptoms{125} (feelings of suspicion and distrust)



Note: Withdrawal symptoms are more common and often more severe in patients who have received high doses of a benzodiazepine over a prolonged period of time {03} {18} {23} {24} {75}. However, symptoms have occurred following abrupt discontinuation of benzodiazepines that have been taken continuously, at therapeutic doses, for as few as 1 to 2 weeks {08} {23} {75}. Abrupt discontinuation increases the chance of developing withdrawal symptoms, including life-threatening seizures {03}. In some patients, withdrawal symptoms have occurred during gradual discontinuation or tapering of benzodiazepines {84}. Withdrawal symptoms may be more likely to occur following the use of short-acting benzodiazepines than following the use of long-acting benzodiazepines {125} {127}.




Overdose
For specific information on the agents used in the management of benzodiazepine overdose, see:
   • Charcoal, Activated (Oral-Local) monograph;
   • Dopamine and/or Metaraminol and/or Norepinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Flumazenil (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: Serious sequelae are rare unless other drugs or alcohol have been coingested {18}. However, deaths have occurred after overdoses of benzodiazepines alone {03} {23}. Also, when benzodiazepines have been coingested with alcohol, deaths have occurred at benzodiazepine and alcohol plasma concentrations that were less than those usually associated with death by overdose with either agent alone {26}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Confusion, continuing{03}{05}{18}{23}
    
decreased reflexes{03}{05}{18}{60}
    
drowsiness, severe{03}{18}{23}{60} , or coma{03}{05}{18}{60}
    
seizures{23}
    
shakiness
    
slow heartbeat{75}
    
slurred speech, continuing{23}
    
staggering{05}{09}{60}
    
troubled breathing{23}{26}{75}
    
weakness, severe


Treatment of overdose


To decrease absorption:
If the patient is conscious (and not at risk of becoming obtunded, comatose, or convulsing based on ingestion {94}), emesis should be induced mechanically or with emetics {09} {44} {55}; also, activated charcoal may be administered orally to increase clearance as well as decrease absorption of the benzodiazepine {09}.

If the patient is unconscious, gastric lavage may be performed with a cuffed endotracheal tube in place to prevent aspiration of vomitus {03} {08}.



To enhance elimination:
Intravenous fluids may be administered to promote diuresis {08} {09} {42} {44}.



Specific treatment:
After airway, ventilation, and intravenous access have been secured, flumazenil, a specific benzodiazepine receptor antagonist, may be administered to reverse sedative effects {03} {18} {23}. Patients must be monitored for the return of sedation after the administration of flumazenil {03} {18} {23}. Flumazenil may precipitate seizures, especially in patients who have been using benzodiazepines long-term or who have coingested a cyclic antidepressant {18} {23} {55}. Because of the risk of seizure induction, flumazenil use is not recommended in epileptic patients who have been treated with benzodiazepines {18} {75}.

Oxygen should be administered if respiration is depressed.

Hypotension may be controlled, if necessary, by intravenous administration of vasopressors such as dopamine, norepinephrine {08} {23} {24} {55}, or metaraminol {04} {08} {18} {23}.



Monitoring:
Respiration, pulse, and blood pressure should be monitored {03} {18} {23} {24} {75}.



Supportive care:
Maintenance of adequate pulmonary ventilation is essential {08} {44}.

Intravenous fluids should be administered to maintain blood pressure {42}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Note: If excitation occurs, barbiturates should not be used {08} {41} {44} since they may exacerbate excitation and/or prolong CNS depression.
Dialysis is of no known value in the treatment of benzodiazepine overdose {03} {18} {23} {75}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Benzodiazepines (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to benzodiazepines

Pregnancy—Benzodiazepines reported to increase risk of congenital malformations when used during first trimester of pregnancy; chronic use may cause physical dependence in the neonate with resulting withdrawal symptoms; use during last weeks of pregnancy may cause neonatal CNS depression; use just prior to or during labor may cause neonatal flaccidity





Breast-feeding—Some benzodiazepines and their metabolites distributed into breast milk and others may be distributed into breast milk; use by nursing mothers may cause sedation, and possibly feeding difficulties and weight loss in the infant





Use in children—Children, especially the very young, usually more sensitive to CNS effects of benzodiazepines






Use in the elderly—Elderly patients usually more sensitive to CNS effects of benzodiazepines
Other medications, especially other CNS depression–producing medications, fluvoxamine, itraconazole, ketoconazole, or nefazodone
Other medical problems, especially acute angle-closure glaucoma, myasthenia gravis, or severe chronic obstructive pulmonary disease

Proper use of this medication

For caregiver administering diazepam rectal gel
Discussing with patient's physician when to use and proper administration

Discussing with patient's physician when to summon emergency help

Carefully reading instructions supplied with medication before use is needed

Monitoring patient after administration as instructed by physician

Proper administration
For extended-release dosage form of clorazepateSwallowing tablets whole

Not crushing, breaking, or chewing

For concentrated oral solution dosage form of alprazolam, diazepam, or lorazepamMeasuring each dose with dropper provided with medication

Diluting dose with liquid or semisolid food such as water, soda or soda-like beverages, applesauce, or pudding is recommended

Consuming entire mixture immediately; not saving for later use

For sublingual tablet dosage form of lorazepamNot chewing or swallowing tablet whole

Dissolving slowly under tongue; not swallowing for at least 2 minutes to allow sufficient absorption
» Importance of not taking more medication than the amount prescribed, because of habit-forming potential

» Not increasing dose if medication is less effective after a few weeks; checking with physician

For anticonvulsant use when on a regular dosing regimen
» Compliance with therapy; not missing any doses

For hypnotic use
» Taking only when schedule will allow a full night's sleep, to avoid amnesia and residual daytime sedation {44} {75}

For flurazepam only
» Maximum effectiveness of medication may not occur until 2 or 3 nights after initiation of therapy

» Proper dosing
Missed dose: If on scheduled dosing regimen (e.g., for epilepsy)—Taking right away if remembered within an hour or so; if remembered later, not taking at all; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during prolonged therapy (and during initial therapy for anticonvulsant use) and to evaluate need to continue benzodiazepine use

For anticonvulsant use
Carrying medical identification card or bracelet during therapy

For sedative-hypnotic use
Checking with physician if feel need to use medication for more than 7 to 10 days

Possibility of rebound insomnia after discontinuing medication
» Checking with physician if physical or psychological dependence is suspected

» Checking with physician before discontinuing medication after high-dose or prolonged use; gradual dosage reduction may be necessary to avoid the possibility of withdrawal symptoms and, in patients with epilepsy or history of seizures, the possibility of precipitating seizures

» Avoiding use of alcohol or other CNS depressants during therapy

» Suspected overdose: Getting emergency help at once

Caution if any laboratory tests required; possible interference with results of metyrapone test

» Not driving, riding a bicycle, or operating machinery until effects of medication are known or until effects of acute use have worn off, including residual daytime effects after use to treat insomnia, because of possible drowsiness, dizziness, lightheadedness, clumsiness, or unsteadiness; may be especially important for elderly patients


Side/adverse effects
Signs of potential side effects, especially anterograde amnesia, anxiety, confusion, mental depression, abnormal thinking, allergic reaction, behavior changes, blood dyscrasias, extrapyramidal symptoms, hepatic dysfunction, hypotension, muscle weakness, paradoxical reactions, or seizures

Most side/adverse effects are more likely to occur in children, especially the very young, and in elderly patients; these patients are usually more sensitive to effects of benzodiazepines

For patients receiving chlordiazepoxide, diazepam, or lorazepam injection: Checking with physician if redness, swelling, or pain at injection site occurs

Possibility of withdrawal symptoms


General Dosing Information
The possibility that a woman of childbearing potential may already be pregnant should be considered when initiating benzodiazepine treatment {26} {38} {42} {113}.

Geriatric or debilitated patients, children, or patients with hepatic or renal function impairment or low serum albumin should receive decreased initial dosage since elimination of benzodiazepines, especially those with long half-lives, may be decreased in these patients, resulting in increased CNS side effects such as oversedation, dizziness, or impaired coordination {03} {05} {09} {18} {75}.

Benzodiazepines may suppress respiration, especially in the elderly, the very ill, the very young, and patients with limited pulmonary reserve. Lower doses may be required for these patients. Deaths occurring shortly after beginning treatment with alprazolam have been reported rarely in patients with severe pulmonary disease {03}.

Optimal dosage of benzodiazepines varies with diagnosis and patient response. Individual dosage adjustments are important {75}. The minimum effective dose {03} {23} {75} should be used for the shortest period {75} {126}, with the need for continuing therapy with benzodiazepines reviewed regularly {03}.

If daytime anxiety appears in a patient being treated for insomnia, discontinuation of the benzodiazepine should be considered {26}.

Prolonged use and/or use of large doses of benzodiazepines increases the risk of developing psychological or physical dependence {03} {157}. However, withdrawal symptoms, including seizures, have occurred after short-term use at recommended doses of alprazolam {03}. The risk of dependence among patients taking > 4 mg per day of alprazolam may be greater than among patients taking lower doses {03}.

When a benzodiazepine is discontinued after treatment with a dose higher than the lowest dose for more than a few weeks, the medication should be withdrawn gradually to lessen the possibility of precipitating withdrawal symptoms, especially in patients with a history of seizures {03} {08} {23} {75}.

Depressed patients with suicidal tendencies, particularly those who use alcohol excessively, should not have access to large quantities of benzodiazepines {03} {08}.

For parenteral dosage forms only
Following administration of parenteral dosage forms, patients should be kept under observation for a period of 3 to 8 hours or longer, based on the patient's clinical response and rate of recovery {86}.

Too rapid intravenous administration may result in apnea, hypotension, bradycardia, or cardiac or respiratory arrest {151}.

Inadvertent intra-arterial injection of benzodiazepines may produce arteriospasm, resulting in gangrene {69}.

When parenteral benzodiazepines are to be administered intravenously, equipment necessary to support respiration should be immediately available and a patent airway should be maintained. This may be especially important in the elderly and in children. {113}

For treatment of dependence
Some clinicians substitute a long-acting benzodiazepine for short-acting agents before withdrawal is attempted {122} {126} {127}.

Benzodiazepines should be tapered gradually {119} {120} {122}, since there is some evidence that some withdrawal symptoms may be lessened in severity or avoided by gradual dosage reduction {42}. Withdrawal schedules ranging from 4 to 16 weeks are usually suggested {119} {126}; however, some practitioners believe withdrawal should be completed within 2 weeks, thus exposing patients to withdrawal symptoms for a shorter length of time {125}.

When necessary, the benzodiazepine may be reinstituted or another benzodiazepine may be substituted, at doses sufficient to suppress withdrawal symptoms, until restabilization allows continuance of the dosage taper, possibly at a slower rate {03}.

ALPRAZOLAM

Summary of Differences


Category:
In addition to being indicated as an antianxiety agent, indicated as an antipanic agent and used as an antitremor agent.



Indications:
Also indicated for adjunctive management of anxiety associated with mental depression.



Pharmacology/pharmacokinetics:
Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few (2 to 3) days.

Elimination rapid following discontinuation of therapy.



Precautions:
Drug interactions and/or related problems—Elevation of steady-state plasma concentrations of imipramine and desipramine reported with concurrent use of alprazolam.

Medical considerations/contraindications—Episodes of hypomania and mania reported with use of alprazolam in patients with mental depression; deaths shortly after alprazolam therapy initiation reported rarely in patients with severe pulmonary disease.



Additional Dosing Information
See also General Dosing Information .

Dosage should be reduced gradually when therapy is discontinued or the daily dosage is decreased. It is suggested that the daily dosage be decreased by no more than 500 mcg (0.5 mg) every 3 days {03}. However, some patients may need a slower reduction in dosage {03}.

The occurrence of early morning anxiety or the emergence of anxiety symptoms between doses of alprazolam in panic disorder patients may reflect the development of tolerance, or a time interval between doses that exceeds the duration of clinical action of the administered dose. The manufacturer states that when these effects occur, the prescribed dose is presumed to be insufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the course of the interdosing interval; they recommend that the same total daily dose be administered in more frequently divided doses. {03}


Oral Dosage Forms

ALPRAZOLAM ORAL SOLUTION

Usual adult dose
Antianxiety agent
Oral, initially 250 to 500 mcg (0.25 to 0.5 mg) three times a day, the dosage being titrated to the needs of the patient up to a maximum total dose of 4 mg per day {03} {52} {157}.

Note: Debilitated patients—Oral, initially 250 mcg (0.25 mg) two or three times a day, the dosage being increased as needed and tolerated {03} {52} {157}.
The starting dosage may be decreased if adverse effects occur {03}.


Antipanic or [ anti-agoraphobic]1agent
Oral, initially 500 mcg (0.5 mg) three times a day, the dosage being increased as needed and tolerated up to a maximum of 10 mg per day {03}{162}{163}{164}.


Usual pediatric dose
Antianxiety or antipanic agent
Children younger than 18 years of age: Safety and efficacy have not been established {03} {59}.


Usual geriatric dose
Antianxiety agent
Oral, initially 250 mcg (0.25 mg) two or three times a day, the dosage being increased as needed and tolerated {03} {52}.


Strength(s) usually available
U.S.—


0.1 mg per mL (Rx)[Generic]{157}


1 mg per mL (Rx) [Alprazolam Intensol{155}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. {155} {157}

Preparation of dosage form:
For concentrated oral solution (1 mg per mL)—Measure dose with calibrated dropper provided with product. It is recommended that each dose be gently stirred into liquid or semi-solid food, such as water, soda or soda-like beverage, applesauce, or pudding, immediately before taking. Entire mixture should be consumed; no mixture should be stored for later use. {155}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Patient or caregiver should be instructed in proper measurement and, for concentrated oral solution (1 mg per mL), preparation of dose.
Controlled substance in the U.S.



ALPRAZOLAM TABLETS USP

Usual adult dose
See Alprazolam Oral Solution .

Usual pediatric dose
See Alprazolam Oral Solution .

Usual geriatric dose
See Alprazolam Oral Solution .

Strength(s) usually available
U.S.—


0.25 mg (Rx) [Xanax (scored) (lactose ) (sodium benzoate){03}][Generic] (may be scored {52})


0.5 mg (Rx) [Xanax (scored) (docusate sodium) (lactose) (sodium benzoate){03}][Generic] (may be scored {52})


1 mg (Rx) [Xanax (scored) (docusate sodium) (lactose) (sodium benzoate){03}][Generic] ( may be scored {52})


2 mg (Rx) [Xanax (multi-scored) (docusate sodium) ( lactose) (sodium benzoate){03}][Generic]

Note: The multi-scored 2-mg tablet can be broken to provide doses of 0.5 or 1 mg {03}.


Canada—


0.25 mg (Rx) [Alti-Alprazolam (scored) ( lactose){33}] [Apo-Alpraz ( scored) (sodium < 0.14 mg){33}] [Gen-Alprazolam (lactose){33}] [Novo-Alprazol{33}] [Nu-Alpraz ( scored) (sodium < 0.14 mg){33}] [Xanax (scored) (lactose ){59}]


0.5 mg (Rx) [Alti-Alprazolam (scored) ( lactose){33}] [Apo-Alpraz ( scored) (sodium < 0.14 mg){33}] [Gen-Alprazolam (lactose){33}] [Novo-Alprazol{33}] [Nu-Alpraz ( scored) (sodium < 0.14 mg){33}] [Xanax (scored) (lactose ){59}]


1 mg (Rx) [Gen-Alprazolam (lactose){33}] [Xanax (scored) (lactose ){59}]


2 mg (Rx) [Gen-Alprazolam (lactose){33}] [Xanax TS (triscored) ( lactose){59}]

Note: The triscored 2-mg tablet can be broken into four equal parts of 0.5 mg each {59}.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



BROMAZEPAM

Summary of Differences


Category:
Indicated only as an antianxiety agent.



Pharmacology/pharmacokinetics:
Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few (2 to 3) days.

Elimination rapid following discontinuation of therapy.



Oral Dosage Forms

BROMAZEPAM TABLETS

Usual adult dose
Antianxiety agent
Oral, 6 to 30 mg per day in divided doses {60}.


Note: Dosages of up to 60 mg may be used in severe cases {60}.
Debilitated patients—Initial daily dosage should not exceed 3 mg in divided doses, the dosage being carefully adjusted as needed and tolerated {60}.


Usual pediatric dose
Antianxiety agent
Children younger than 18 years of age: Safety and efficacy have not been established {60}.


Usual geriatric dose
Antianxiety agent
Oral, initially up to 3 mg per day, the dosage being carefully adjusted as needed and tolerated {60}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1.5 mg (Rx) [Alti-Bromazepam (scored) ( lactose){33}] [Gen-Bromazepam ( scored) (lactose){33}] [Lectopam (scored) (lactose 96 mg){60}]


3 mg (Rx) [Alti-Bromazepam (scored) ( lactose){33}] [Gen-Bromazepam ( scored) (lactose){33}] [Lectopam (scored) (lactose 94 mg){60}]


6 mg (Rx) [Alti-Bromazepam (scored) ( lactose){33}] [Gen-Bromazepam ( scored) (lactose){33}] [Lectopam (scored) (lactose 91 mg){60}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


CHLORDIAZEPOXIDE

Summary of Differences


Category:
In addition to being indicated as an antianxiety agent and a sedative-hypnotic, oral chlordiazepoxide is used as an antitremor agent and parenteral chlordiazepoxide is used as an antipanic agent.



Indications:
Also indicated for relief of acute alcohol withdrawal symptoms and as a preoperative medication.

Also used in treatment of tension headache.



Pharmacology/pharmacokinetics:
Absorption of intramuscular chlordiazepoxide may be slow and erratic.

Long half-life benzodiazepine.

Accumulation of chlordiazepoxide and its active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 5 days to 2 weeks.

Elimination slow since metabolites remain in blood for several days or even weeks.



Precautions:


Drug interactions and/or related problems—
Antacids may delay the rate of but not reduce the extent of absorption of chlordiazepoxide.



Medical considerations/contraindications—
Hypoalbuminemia may predispose patient to an increased incidence of sedative side effects.

Porphyria may be exacerbated by use of chlordiazepoxide.




Side/adverse effects:
Intravenous chlordiazepoxide less likely to cause phlebitis or venous thrombosis than diazepam or lorazepam.



Additional Dosing Information
See also General Dosing Information.

For parenteral dosage forms only
Intramuscular injections should be administered deeply into the muscle {41}; absorption may be slow and erratic {02}, but effects are usually seen in 15 to 30 minutes {41}.

When more rapid effect is mandatory, chlordiazepoxide hydrochloride solution prepared with sterile physiological saline (0.9% sodium chloride injection) or sterile water for injection may be administered intravenously {41}.

Intravenous administration of the intramuscular preparation is not recommended by the manufacturer because of the air bubbles that may form when the intramuscular diluent is added to the chlordiazepoxide hydrochloride powder {41}.

Intravenous injections should be administered slowly over a 1-minute period {41}.

The chlordiazepoxide hydrochloride solution prepared with sterile physiological saline (0.9% sodium chloride injection) or sterile water for injection should not be administered intramuscularly because of pain on injection {41}.


Oral Dosage Forms

CHLORDIAZEPOXIDE HYDROCHLORIDE CAPSULES USP

Usual adult dose
Antianxiety agent
Oral, 5 to 25 mg three or four times a day {34}.

Note: Debilitated patients—Oral, 5 mg two to four times a day, the dosage being increased gradually as needed and tolerated {34}.


Sedative-hypnotic
Alcohol withdrawal: Oral, initially 50 to 100 mg {34}, repeated as needed, up to 400 mg per day, the dosage then reduced to maintenance levels {114}.


Usual pediatric dose
Antianxiety agent
Children younger than 6 years of age: Safety and efficacy have not been established {34}.

Children 6 years of age and older: Oral, 5 mg two to four times a day, the dosage being increased, if necessary, to 10 mg two or three times a day {34}.


Usual geriatric dose
Antianxiety agent
Oral, 5 mg two to four times a day, the dosage being increased gradually as needed and tolerated {34}.


Strength(s) usually available
U.S.—


5 mg (Rx) [Librium (lactose) (gelatin capsule shells may contain methyl and propyl parabens and potassium sorbate){34}{37}][Generic]


10 mg (Rx) [Librium (lactose) (gelatin capsule shells may contain methyl and propyl parabens and potassium sorbate){34}{37}][Generic]


25 mg (Rx) [Librium (lactose) (gelatin capsule shells may contain methyl and propyl parabens and potassium sorbate){34}{37}][Generic]

Canada—


5 mg (Rx) [Apo-Chlordiazepoxide] [Novo-Poxide (lactose){35}]


10 mg (Rx) [Apo-Chlordiazepoxide] [Novo-Poxide (lactose){35}]


25 mg (Rx) [Apo-Chlordiazepoxide] [Novo-Poxide (lactose){35}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.




Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CHLORDIAZEPOXIDE HYDROCHLORIDE FOR INJECTION USP

Usual adult dose
Antianxiety agent
Intramuscular or intravenous, initially 50 to 100 mg, then 25 to 50 mg three or four times a day, if necessary {41}.

Preoperative: Intramuscular, 50 to 100 mg one hour prior to surgery {41}.

Sedative-hypnotic
Alcohol withdrawal: Intramuscular or intravenous, initially 50 to 100 mg, repeated in two to four hours, if necessary {41}.

[Antipanic agent]
Intramuscular or intravenous, initially 50 to 100 mg, repeated in four to six hours if necessary {65}.


Note: Debilitated patients—Intramuscular or intravenous, 25 to 50 mg per dose {41}.


Usual adult prescribing limits
300 mg per day {41}.

Usual pediatric dose
Antianxiety agent or
Sedative-hypnotic
Children younger than 12 years of age: Safety and efficacy have not been established {41}.

Children 12 years of age and older: Intramuscular or intravenous, 25 to 50 mg per dose {41}.


Usual geriatric dose
Antianxiety agent or
Sedative-hypnotic
Intramuscular or intravenous, 25 to 50 mg per dose {41}.


Size(s) usually available:
U.S.—


100 mg, with 2 mL of special intramuscular diluent (Rx) [Librium ( benzyl alcohol 1.5%) (polysorbate 80 4%) (propylene glycol 20%) (maleic acid 1.6%) (sodium hydroxide){41}]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light {41}.

Note: Chlordiazepoxide injectable diluent should be stored between 2 and 8 °C (36 and 46 °F) {37}.


Preparation of dosage form:
Solutions of chlordiazepoxide hydrochloride for intramuscular or intravenous use should be prepared immediately before administration {41}.

To prepare solution for intramuscular use, add 2 mL of the special intramuscular diluent (supplied by manufacturer) to the ampul containing 100 mg of chlordiazepoxide hydrochloride. The diluent solution should not be used if it is opalescent or hazy. The diluent should be added carefully to the ampul of powder to avoid bubble formation. Agitate the ampul gently until the powder is completely dissolved. {41}

To prepare solution for intravenous use, add 5 mL of 0.9% sodium chloride injection or sterile water for injection to the ampul containing 100 mg of chlordiazepoxide hydrochloride. Agitate the ampul gently until the powder is completely dissolved {41}.

Stability:
If the diluent is stored at room temperature, it will remain stable for 18 to 20 months rather than until the expiration date, which reflects a stability period of 36 months. As the diluent alters, it develops slight opalescence; do not use if opalescent. Stability of diluent will not be affected by 2 to 4 weeks at room temperature. {37}

After reconstitution, solution should be used immediately {41}.

Any unused portion of the solution should be discarded {41}.

Sterilization by heating should not be done {41}.


Caution:
Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates (first 30 days of postnatal life). A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Note: Controlled substance in the U.S.



CLOBAZAM

Summary of Differences


Category:
Indicated as an anticonvulsant only.



Pharmacology/pharmacokinetics:
Intermediate half-life benzodiazepine.



Additional Dosing Information
See also General Dosing Information .

Daily dosages of up to 30 mg may be taken as a single dose at bedtime. If the daily dosage is divided, the larger portion should be taken at bedtime. {53}

There have been reports of development of tolerance to the anticonvulsant effects of clobazam with continuous, long-term use. There are insufficient data to predict which patients will develop tolerance or when this might occur. Some studies in catamenial epilepsy have indicated that efficacy may be maintained with intermittent use. However, long-term results from intermittent-use studies are not available. {53}


Oral Dosage Forms

CLOBAZAM TABLETS

Usual adult dose
Anticonvulsant
Oral, initially 5 to 15 mg per day. Dosage may be increased gradually as needed {53}.


Note: Dosage should be reduced in patients with impaired hepatic or renal function {53}.


Usual adult prescribing limits
80 mg per day {53}.

Usual pediatric dose
Anticonvulsant
Children younger than 2 years of age: Oral, initially 0.5 to 1 mg per kg of body weight per day {53}.

Children 2 to 16 years of age: Oral, initially 5 mg per day {53}. Dosage may be increased at five-day intervals {53}.


Usual pediatric prescribing limits
Children 2 to 16 years of age—40 mg per day {53}.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10 mg (Rx) [Frisium (scored) (lactose){53}]

Packaging and storage:
Store in original container at room temperature, below 25 °C (77 °F) {53}, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness or dizziness.
   • Avoid alcoholic beverages.


CLONAZEPAM

Summary of Differences


Category:
In addition to being indicated as an anticonvulsant, indicated as an antipanic agent.



Pharmacology/pharmacokinetics:
Intermediate half-life benzodiazepine.



Precautions:


Pregnancy—
Increased incidence of congenital abnormalities in children whose mothers used anticonvulsants during pregnancy; studies in animals have shown that clonazepam causes a non–dose-related increased incidence of cleft palates, open eyelids, fused sternebrae, and limb defects; withdrawal of clonazepam prior to or during pregnancy should be considered only when seizures are mild and infrequent in absence of medication and the possibility of status epilepticus and withdrawal symptoms is considered low.



Pediatrics—
It is possible that long-term use of clonazepam may result in adverse effects on physical or mental development that may not become apparent for many years.



Medical considerations/contraindications—
Initiation or abrupt withdrawal of clonazepam in patients with epilepsy or a history of seizures may precipitate seizures or status epilepticus.

Caution should be used in surgical or non-ambulatory patients because of cough suppressant effects of clonazepam.




Additional Dosing Information
See also General Dosing Information .

In some studies, up to 30% of patients have shown loss of anticonvulsant activity after a few (often within 3) months of therapy; dosage adjustment may restore efficacy of clonazepam {18}.

In order to maintain seizure control when clonazepam is used to replace other anticonvulsant therapy, the dosage of clonazepam should be increased gradually while the dosage of the other medication is decreased gradually; when clonazepam is used to supplement other anticonvulsant therapy, the dosage of clonazepam should be increased gradually until seizure activity is controlled adequately and then the dosage of the other medication may be decreased gradually if necessary {66}.

Also, clonazepam should be withdrawn gradually, especially in patients being treated for epilepsy and in patients who have received long-term, high-dose therapy, since abrupt withdrawal may precipitate seizures or status epilepticus. During withdrawal of clonazepam, the simultaneous administration of another anticonvulsant may be indicated in patients with epilepsy. The manufacturer recommends clonazepam dosage be decreased by 0.125 mg two times a day every 3 days. {18}


Oral Dosage Forms

CLONAZEPAM TABLETS USP

Usual adult dose
Anticonvulsant
Oral, initially up to 500 mcg (0.5 mg) three times a day; the dosage may be increased in increments of 500 to 1000 mcg (0.5 to 1 mg) every three days until seizures are controlled or until side effects prevent any further increase {18}.

Note: Maintenance dose must be individualized, depending on patient"s response {18}.


Antipanic agent1
Oral, initially 250 mcg (0.25 mg) two times a day, the dosage being increased to 1000 mcg (1 mg) per day after three days in most patients. The dosage may be increased in increments of 125 to 250 mcg (0.125 to 0.25 mg) two times a day every three days until panic disorder is controlled or until side effects prevent further dosage increases. One dose may be taken at bedtime to minimize daytime somnolence. {18}

Note: A fixed-dose study comparing dosages of 1, 2, 3, and 4 mg per day in the treatment of panic disorder found that a dosage of 1000 mcg (1 mg) per day was the most effective and best tolerated dosage for most patients {18}.



Usual adult prescribing limits
Anticonvulsant
20 mg per day {18}.

Antipanic agent1
4 mg per day {18}.


Usual pediatric dose
Anticonvulsant
Infants and children younger than 10 years of age or less than 30 kg of body weight: Oral, initially 10 to 30 mcg (0.01 to 0.03 mg), not to exceed 50 mcg (0.05 mg), per kg of body weight per day in two or three divided doses, the dosage being increased by no more than 250 to 500 mcg (0.25 to 0.5 mg) every third day until a maintenance dose of 100 to 200 mcg (0.1 to 0.2 mg) per kg of body weight per day is reached or until seizures are controlled or side effects prevent a further increase {13} {18}.


Note: The daily dose should be divided into three equal doses, if possible. If doses are not divided equally, the largest dose should be given at bedtime. {13} {18}

Antipanic agent1
Safety and efficacy have not been established in children up to 18 years of age {18}.


Strength(s) usually available
U.S.—


0.5 mg (Rx) [Klonopin (scored) (lactose ){18}][Generic] (may be scored {13})


1 mg (Rx) [Klonopin (lactose){18}][Generic] ( may be scored {13})


2 mg (Rx) [Klonopin (lactose){18}][Generic] ( may be scored {13})

Canada—


0.25 mg (Rx) [PMS-Clonazepam (lactose)]{33}


0.5 mg (Rx) [Alti-Clonazepam (scored) ( lactose)] [Apo-Clonazepam (scored)] [Clonapam (scored) (lactose)] [Gen-Clonazepam] [PMS-Clonazepam (scored) ( lactose)] [Rivotril (scored) ( lactose 122 mg)]{33}


1 mg (Rx) [Clonapam (scored) (lactose )] [PMS-Clonazepam (lactose)]{33}


2 mg (Rx) [Alti-Clonazepam (cross-scored) ( lactose)] [Apo-Clonazepam (scored)] [Clonapam (scored) (lactose)] [Gen-Clonazepam] [PMS-Clonazepam (lactose)] [Rivotril (scored) (lactose 122 mg)]{33}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {18}. Store in a tight, light-resistant container {13}.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



CLORAZEPATE

Summary of Differences


Category:
In addition to being indicated as an antianxiety agent and a sedative-hypnotic, indicated as an anticonvulsant.



Indications:
Also indicated for relief of acute alcohol withdrawal symptoms.



Pharmacology/pharmacokinetics:
Drug precursor; metabolized to desmethyldiazepam before absorption.

Orally, one of most rapidly absorbed benzodiazepines.

Long half-life benzodiazepine.

Accumulation of active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 5 days to 2 weeks.

Elimination slow since metabolites remain in blood for several days or even weeks.



Precautions:


Drug interactions and/or related problems—
Antacids may decrease rate of conversion to desmethyldiazepam but do not affect degree of absorption.




Additional Dosing Information
See also General Dosing Information .

When used for alcohol withdrawal, excessive reductions in the total amount of medication administered on successive days should be avoided.


Oral Dosage Forms

CLORAZEPATE DIPOTASSIUM CAPSULES

Usual adult and adolescent dose
Antianxiety agent
Oral, 7.5 to 15 mg two to four times a day; or 15 mg initially, as a single dose at bedtime, the dosage being adjusted as needed and tolerated {19}.

Note: Debilitated patients—Oral, initially 3.75 {67} to 15 mg per day, the dosage being increased gradually as needed and tolerated {19}.


Sedative-hypnotic
Alcohol withdrawal: Oral, 30 mg initially, followed by 15 mg two to four times a day the first day; 15 mg three to six times a day the second day; 7.5 to 15 mg three times a day the third day; 7.5 mg two to four times a day the fourth day; and thereafter, 3.75 mg two to four times a day. Discontinue when patient"s condition is stable. {19}

Anticonvulsant1
Oral, initially up to 7.5 mg three times a day, the dosage being increased by no more than 7.5 mg per week, not to exceed 90 mg per day {19}.


Usual adult prescribing limits
90 mg per day {19}.

Usual pediatric dose
Children younger than 9 years of age: Safety and efficacy have not been established {19}.
Anticonvulsant1
Children 9 to 12 years of age: Oral, initially up to 7.5 mg two times a day, the dosage being increased by no more than 7.5 mg per week, not to exceed 60 mg per day {19}.

Children 12 years of age and older: See Usual adult and adolescent dose {19} .


Usual geriatric dose
Antianxiety agent
Oral, initially 3.75 to 15 mg per day, the dosage being increased gradually as needed and tolerated {19}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


3.75 mg (Rx) [Apo-Clorazepate{33}] [Novo-Clopate{33}] [Tranxene{33}]


7.5 mg (Rx) [Apo-Clorazepate{33}] [Novo-Clopate{33}] [Tranxene{33}]


15 mg (Rx) [Apo-Clorazepate{33}] [Novo-Clopate{33}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


CLORAZEPATE DIPOTASSIUM TABLETS USP

Usual adult and adolescent dose
See Clorazepate Dipotassium Capsules.

Usual adult prescribing limits
See Clorazepate Dipotassium Capsules.

Usual pediatric dose
See Clorazepate Dipotassium Capsules.

Usual geriatric dose
See Clorazepate Dipotassium Capsules.

Strength(s) usually available
U.S.—


3.75 mg (Rx) [Tranxene T-Tab (scored){19}][Generic] (may be scored {58})


7.5 mg (Rx) [Tranxene T-Tab (scored){19}][Generic] (may be scored {58})


15 mg (Rx) [Tranxene T-Tab (scored){19}][Generic] (may be scored {58})

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container {39}, unless otherwise specified by manufacturer.

Stability:
Clorazepate dipotassium degrades in the presence of moisture. One of the degradation products is carbon dioxide gas, which tends to cause the tablets to “blow apart” and disintegrate very rapidly. The drug is also sensitive to heat and light. Pharmacists are advised to retain the desiccant when opening a new stock bottle of the product. If it is necessary to repackage the drug into unit doses, it is recommended that pharmacists be certain that the packaging materials used for unit-dose containers will produce a Class A package as defined in the USP. Multiple-dose containers should meet USP “tight” and “light-resistant” specifications. Pharmacists should consider using desiccant packets when dispensing a large number of tablets in a multiple-dose container. If shipping or mailing prescriptions, pharmacists should take into account these instability problems. Patients should be warned not to expose the product to moisture, light, or heat, and, when possible, to keep the tablets in the original containers. {87}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



CLORAZEPATE DIPOTASSIUM EXTENDED-RELEASE TABLETS

Usual adult and adolescent dose
Not intended for initiation of therapy. Single daily dose of 11.25 mg may be substituted for prompt-release dosage forms in patients already stabilized on a dosage of 3.75 mg three times a day. Single daily dose of 22.5 mg may be substituted for prompt-release dosage forms in patients already stabilized on a dosage of 7.5 mg three times a day. {19}

Usual pediatric dose
Children younger than 9 years of age—Safety and efficacy have not been established {19}.

Children 9 to 12 years of age—See Usual adult and adolescent dose.

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


11.25 mg (Rx) [Tranxene-SD Half Strength (lactose) (potassium carbonate) (potassium chloride ) (castor oil wax) (magnesium stearate) (magnesium oxide) ( talc) (FD&C Blue #2){19}]


22.5 mg (Rx) [Tranxene-SD (iron oxide) ( lactose) (potassium carbonate) ( potassium chloride) (castor oil wax) (magnesium stearate) (magnesium oxide ) (talc){19}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container {39}, unless otherwise specified by manufacturer.

Stability:
Clorazepate dipotassium degrades in the presence of moisture. One of the degradation products is carbon dioxide gas, which tends to cause the tablets to “blow apart” and disintegrate very rapidly. The drug is also sensitive to heat and light. Pharmacists are advised to retain the desiccant when opening a new stock bottle of the product. If it is necessary to repackage the drug into unit doses, it is recommended that pharmacists be certain that the packaging materials used for unit-dose containers will produce a Class A package as defined in the USP. Multiple-dose containers should meet USP “tight” and “light-resistant” specifications. Pharmacists should consider using desiccant packets when dispensing a large number of tablets in a multiple-dose container. If shipping or mailing prescriptions, pharmacists should take into account these instability problems. Patients should be warned not to expose the product to moisture, light, or heat, and, when possible, to keep the tablets in the original containers. {87}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Swallow tablets whole.

Note: Clorazepate dipotassium extended-release tablets are not intended to be used to initiate therapy, but to provide ease of dosing in patients who are already stabilized on clorazepate dipotassium at a dosage that allows direct substitution of the extended-release tablet for the prompt-release dosage forms {19}.
Controlled substance in the U.S.



DIAZEPAM

Summary of Differences


Category:
In addition to being indicated as an antianxiety agent and a sedative-hypnotic, indicated as an anticonvulsant and a skeletal muscle relaxant adjunct and used as an antipanic agent.

Parenteral diazepam also indicated as an amnestic.

Oral diazepam also used as an antitremor agent.



Indications:
Also indicated for relief of acute alcohol withdrawal symptoms, for the treatment of status epilepticus, and as a preoperative medication.

Parenteral diazepam also indicated as an adjunct prior to endoscopic procedures; indicated prior to cardioversion; and used in dentistry to produce conscious sedation.

Also used to relieve spasms of facial muscles associated with problems of occlusion and temporomandibular joint disorders, and for the treatment of tension headache.



Pharmacology/pharmacokinetics:
Orally, the most rapidly absorbed benzodiazepine.

Absorption of intramuscular diazepam may be slow and erratic, depending upon administration site; usually rapid and complete when injected into the deltoid muscle.

Absorption of rectal diazepam gel or solution is rapid.

Long half-life benzodiazepine.

Accumulation of diazepam and its active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 5 days to 2 weeks.

Elimination slow since metabolites remain in blood for several days or even weeks.



Precautions:


Sensitivity—
Sterile emulsion dosage form contains soybean oil.



Pregnancy—
Administration (especially intramuscular or intravenous) in doses of more than 30 mg within 15 hours before delivery may cause apnea, hypotonia, hypothermia, a reluctance to feed, and impaired metabolic response to cold stress in the neonate.



Drug interactions and/or related problems—
Antacids may delay but not reduce the absorption of diazepam.

Premedication with diazepam may decrease dose of a fentanyl derivative required for induction of anesthesia and decrease time to loss of consciousness with induction doses.

Diazepam in parenteral dosage forms adheres to plastic infusion tubing.

Isoniazid may inhibit elimination of diazepam, resulting in increased plasma concentrations.

Rifampin may enhance elimination of diazepam, resulting in decreased plasma concentrations.



Medical considerations/contraindications—
Initiation or abrupt withdrawal of diazepam in patients with epilepsy or a history of seizures may precipitate seizures or status epilepticus. Use of intravenous diazepam for absence status or Lennox-Gastaut syndrome status may precipitate tonic status epilepticus.

Hypoalbuminemia may predispose patient to increased incidence of sedative side effects.




Side/adverse effects:
Intravenous diazepam more likely to cause phlebitis or venous thrombosis than chlordiazepoxide or lorazepam.



Additional Dosing Information
See also General Dosing Information.

For oral dosage forms only
When diazepam is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of generalized tonic-clonic (grand mal) seizures may require an increase in dosage of standard anticonvulsant medication. Also, abrupt withdrawal of diazepam may result in a temporary increase in the frequency and/or severity of seizures. {43}

For parenteral dosage forms only
Intravenous administration of diazepam is usually preferred, since absorption may be slow and erratic following intramuscular administration {107} depending upon site of injection.

If intramuscular injections of diazepam are used, they should be administered deeply {113} into the deltoid muscle.

For intravenous injections of diazepam, small veins such as those on the back of the hand or wrist should not be used and care should be taken to avoid intra-arterial administration or extravasation in order to reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, and, rarely, vascular impairment. {04} {24}

For intravenous injections, the medication should be injected slowly into a large vein, taking at least 1 minute for each 5 mg (1 mL) of medication given {04} {24} {113}, due to the risk of thrombophlebitis {113}.

When subsequent doses are administered within 1 to 4 hours, consideration should be given to the possibility that active metabolites may still be present from the initial dose {24}.

Continuous intravenous infusion of diazepam is not recommended because of the possibility of precipitation of diazepam in intravenous fluids and adsorption of the medication to the plastic of infusion bags and tubing. {04}

If diazepam cannot be administered by direct intravenous injection, it may be injected slowly through an infusion tubing as close as possible to the insertion point to minimize adsorption of the medication to the plastic tubing {24} {69} {113}.

When intravenous diazepam is used to control seizures, a significant proportion of patients will return to seizure activity and will require additional doses {24}.

When parenteral diazepam is used for peroral endoscopic procedures, the use of a topical anesthetic and availability of necessary countermeasures are recommended since these procedures may cause an increase in cough reflex and laryngospasm {24} {113}.

For rectal gel dosage form only
Diazepam rectal gel should be administered only by caregivers who are able to distinguish the distinct cluster of seizures to be treated, or the events accompanying their onset, from the patient"s usual seizure activity, and who understand which seizure manifestations may or may not be treated with diazepam rectal gel. The caregiver also must be competent in the proper administration of the rectal gel and in monitoring the patient"s response, including recognizing when professional medical attention is required. {38}

Caregivers should be instructed to notify the physician immediately of any signs that are not typical of the patient"s characteristic seizure episode. {38}


Oral Dosage Forms

DIAZEPAM ORAL SOLUTION

Usual adult dose
Antianxiety agent
Oral, 2 to 10 mg two to four times a day {05} {96}.

Sedative-hypnotic
Alcohol withdrawal: Oral, 10 mg three or four times during the first twenty-four hours, the dosage being decreased to 5 mg three or four times a day as needed {05} {96}.

Anticonvulsant
Oral, 2 to 10 mg two to four times a day {96}.

Skeletal muscle relaxant adjunct
Oral, 2 to 10 mg three or four times a day {05} {96}.


Note: Debilitated patients—Oral, 2 to 2.5 mg one or two times a day, the dosage being increased gradually as needed and tolerated {05} {96}.


Usual pediatric dose
Antianxiety agent or
Anticonvulsant or
Skeletal muscle relaxant adjunct
Children younger than 6 months of age: Use is not recommended {05} {96}.

Children 6 months of age and older: Oral, 1 to 2.5 mg, or 40 to 200 mcg (0.04 to 0.2 mg) per kg of body weight, or 1.17 to 6 mg per square meter of body surface area, three or four times a day, the dosage being increased gradually as needed and tolerated {05}.


Usual geriatric dose
Antianxiety agent or
Sedative-hypnotic or
Anticonvulsant or
Skeletal muscle relaxant adjunct
Oral, 2 to 2.5 mg one or two times a day, the dosage being increased gradually as needed and tolerated {05} {96}.


Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Diazepam Intensol]{96}


5 mg per 5 mL (Rx)[Generic]{96}

Canada—


1 mg per mL (Rx) [PMS-Diazepam{47}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
For concentrated oral solution (5 mg per mL)—Measure dose with calibrated dropper provided with product. It is recommended that each dose be mixed with liquid or soft food, such as water, juice, soda, pudding, or applesauce, immediately before taking. The entire mixture should be consumed; none of the mixture should be stored for later use. {96}

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Patient or caregiver should be instructed in proper measurement of the dose and, for concentrated oral solution (5 mg per mL), preparation of the dose.
Controlled substance in the U.S.



DIAZEPAM TABLETS USP

Usual adult dose
See Diazepam Oral Solution.

Usual pediatric dose
See Diazepam Oral Solution.

Usual geriatric dose
See Diazepam Oral Solution.

Strength(s) usually available
U.S.—


2 mg (Rx) [Valium (scored){48}][Generic]


5 mg (Rx) [Valium (scored){48}][Generic]


10 mg (Rx) [Valium (scored){48}][Generic]

Canada—


2 mg (Rx) [Apo-Diazepam (scored){33}] [Novo-Dipam (scored){33}{35}] [Vivol (double-scored) (lactose) (sodium < 1 mmol [trace] ){33}]


5 mg (Rx) [Apo-Diazepam (scored){33}] [Novo-Dipam (scored){33}{35}] [Valium (scored) ( lactose){33}] [Vivol (double-scored) (lactose) (sodium < 1 mmol [trace] ){33}]


10 mg (Rx) [Apo-Diazepam (scored){33}] [Novo-Dipam (scored){33}{35}] [Valium (scored) ( lactose 100 mg){33}] [Vivol (double-scored ) (lactose) (sodium < 1 mmol [trace]){33}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.




Parenteral Dosage Forms

DIAZEPAM INJECTION USP

Usual adult dose
Antianxiety agent
Preoperative medication: Dosage must be individualized; however, as a general guideline—Intramuscular or intravenous, 5 to 10 mg prior to surgery {04} {112}.

Anxiety disorders or symptoms of anxiety: Intramuscular or intravenous, 2 to 10 mg (2 to 5 mg for moderate symptoms; 5 to 10 mg for severe symptoms), the dose being repeated in three or four hours, if necessary {04}.

Sedative-hypnotic
Alcohol withdrawal: Intramuscular or intravenous, initially 10 mg, followed by 5 to 10 mg in three or four hours, if necessary {04}.

Amnestic
Cardioversion: Intravenous, 5 to 15 mg five to ten minutes prior to the procedure {04}.

Endoscopic procedures:


Intravenous (preferred route), up to 20 mg, the dosage being titrated to give the desired sedative response and administered immediately prior to the procedure {04}.


Intramuscular, 5 to 10 mg approximately thirty minutes prior to the procedure {04}.

Anticonvulsant
Status epilepticus and severe recurrent convulsive seizures: Intravenous, initially 5 to 10 mg, the dose being repeated, if necessary, at ten- to fifteen-minute intervals up to a cumulative dose of 30 mg. If necessary, regimen may be repeated in two to four hours. {04}

Note: The intravenous route of administration is preferred; however, if intravenous administration is impossible, the intramuscular route of administration may be used {04}.
Some clinicians have used continuous intravenous infusions of diazepam in the treatment of selected patients with status epilepticus refractory to initial treatment {49} {74}. However, this method of administration is problematic due to inherent adsorption problems with plastic infusion bags and tubing {69}.


Skeletal muscle relaxant adjunct
Muscle spasm: Intramuscular or intravenous, initially 5 to 10 mg, the dose being repeated in three or four hours, if necessary. For tetanus, larger doses may be required. {04}


Note: Debilitated patients—Intramuscular or intravenous, initially 2 to 5 mg per dose, the dosage being increased gradually as needed and tolerated {04}.


Usual pediatric dose
Neonates 30 days of age and younger—Safety and efficacy have not been established {04}.
Anticonvulsant
Status epilepticus and severe recurrent convulsive seizures:


Infants older than 30 days of age and children younger than 5 years of age—Intravenous (slow), 200 to 500 mcg (0.2 to 0.5 mg) every two to five minutes up to a cumulative dose of 5 mg. If necessary, regimen may be repeated in two to four hours. {04}


Children 5 years of age and older—Intravenous (slow), 1 mg every two to five minutes up to a cumulative dose of 10 mg. If necessary, regimen may be repeated in two to four hours. {04}

Note: The intravenous route of administration is preferred; however, if intravenous administration is impossible, the intramuscular route of administration may be used {04}.


Skeletal muscle relaxant adjunct
Tetanus:


Infants older than 30 days of age and children younger than 5 years of age—Intramuscular or intravenous, 1 to 2 mg, the dose being repeated every three or four hours as needed {04}.


Children 5 years of age and older—Intramuscular or intravenous, 5 to 10 mg, the dose being repeated every three or four hours as needed {04}.


Note: In general, when the intravenous route is used in infants and children, it is recommended that the medication be administered slowly over a three-minute period in a dose not to exceed 250 mcg (0.25 mg) per kg of body weight. After an interval of fifteen to thirty minutes, a second dose may be administered. After an additional interval of fifteen to thirty minutes, a third dose may be administered. If the third administration does not provide relief of symptoms, adjunctive treatment appropriate to the condition being treated should be considered. {04}


Usual geriatric dose
Antianxiety agent or
Sedative-hypnotic or
Amnestic or
Anticonvulsant or
Skeletal muscle relaxant adjunct
Intramuscular or intravenous, initially 2 to 5 mg per dose, the dosage being increased gradually as needed and tolerated {04}.


Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Valium (benzoic acid) ( benzyl alcohol 1.5%) (ethyl alcohol 10%) (propylene glycol 40%) (sodium benzoate 5%){04}][Generic]

Canada—


5 mg per mL (Rx) [Valium (benzyl alcohol 16 mg) (ethyl alcohol 80 mg) (propylene glycol 414 mg) (sodium < 1 mmol) ( sodium benzoate) (benzoic acid)]{69}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Stability:
Do not mix or dilute this medication with other solutions, intravenous fluids, or medications {04}, because the resulting admixtures are unstable.

Diazepam is adsorbed to the plastic of intravenous infusion bags and tubing {69}.

Incompatibilities:
Diazepam injection is physically incompatible with aqueous solutions.


Caution:
Medications containing benzyl alcohol are not recommended for use in neonates (first 30 days of postnatal life). A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Note: Controlled substance in the U.S.



DIAZEPAM EMULSION STERILE

Usual adult dose
Antianxiety agent
Preoperative medication: Dosage must be individualized; however, as a general guideline—Intramuscular or intravenous, 10 mg one to two hours prior to surgery {113}.

Anxiety disorders or symptoms of anxiety: Intramuscular {113} or intravenous {24} {113}, 2 to 10 mg {113} (2 to 5 mg for moderate symptoms; 5 to 10 mg for severe symptoms {24}), the dose being repeated in three or four hours, if necessary {24} {113}.

Anticonvulsant1
Status epilepticus and severe recurrent convulsive seizures1: Intravenous, 5 to 10 mg, the dose being repeated at ten- to fifteen-minute intervals, if needed, up to a cumulative dose of 30 mg {24}. Regimen may be repeated in two to four hours, if needed, keeping in mind the persistence of active metabolites in the circulation {24}.

Sedative-hypnotic
Alcohol withdrawal: Intramuscular {113} or intravenous {24} {113}, initially 10 mg, followed by 5 to 10 mg in three or four hours, if necessary {24} {113}.

Amnestic
Cardioversion: Intravenous, 5 to 15 mg ten {14} to twenty {113} minutes prior to the procedure {24} {113}.

Endoscopic procedures: Intramuscular or intravenous, 5 to 10 mg about thirty minutes prior to procedure {113}. Intravenous dose may be titrated to desired sedative response with slow administration immediately prior to the procedure; although £ 10 mg is generally adequate, up to 20 mg may be given, particularly when no concomitant narcotics are administered {24}.

Skeletal muscle relaxant adjunct
Muscle spasm: Intramuscular {113} or intravenous {24} {113}, initially 5 to 10 mg, the dose being repeated in three or four hours, if necessary {24} {113}. Larger doses may be required in tetanus {24}.


Note: Debilitated patients and patients receiving other sedative medications—Intramuscular {113} or intravenous {24} {113}, initially 2 to 5 mg per dose, the dosage being increased gradually as needed and tolerated {24} {113}.


Usual pediatric dose
Antianxiety agent or
Amnestic
Neonates 30 days of age and younger: Safety and efficacy have not been established {24}.

Infants and children older than 30 days of age: Dosage must be individualized.

Anticonvulsant1
For status epilepticus and severe recurrent convulsive seizures1 :


Neonates 30 days of age and younger—Safety and efficacy have not been established {24}.


Infants older than 30 days of age and children younger than 5 years of age—Intravenous, 0.2 to 0.5 mg, administered slowly. May be repeated every two to five minutes, if needed, up to a cumulative dose of 5 mg. Regimen may be repeated in two to four hours, if needed, keeping in mind the persistence of active metabolites in the circulation. {24}


Children 5 years of age and older—Intravenous, 1 mg, administered slowly. May be repeated every two to five minutes, if needed, up to a cumulative dose of 10 mg. Regimen may be repeated in two to four hours, if needed, keeping in mind the persistence of active metabolites in the circulation. {24}

Skeletal muscle relaxant adjunct
For tetanus1 :


Neonates 30 days of age and younger—Safety and efficacy have not been established {24}.


Infants older than 30 days of age and children younger than 5 years of age—Intravenous, 1 to 2 mg, administered slowly. May be repeated every three to four hours, if needed. {24}


Children 5 years of age and older—Intravenous, 5 to 10 mg, administered slowly. May be repeated every three to four hours, if needed. {24}


Note: In general, when the intravenous route is used in infants and children, it is recommended that the medication be administered slowly over a three-minute period in a dose not to exceed 250 mcg (0.25 mg) per kg of body weight. After an interval of fifteen to thirty minutes, a second dose may be administered. After an additional interval of fifteen to thirty minutes, a third dose may be administered. If the third administration does not provide relief of symptoms, adjunctive treatment appropriate to the condition being treated should be considered. {24} {113}


Usual geriatric dose
Antianxiety agent or
Anticonvulsant1 or
Sedative-hypnotic or
Amnestic or
Skeletal muscle relaxant adjunct
Intramuscular {113} or intravenous {24} {113}, initially 2 to 5 mg per dose {24} {113}, the dosage being increased gradually as needed and tolerated {113}.


Strength(s) usually available
U.S.—


5 mg per mL (Rx) [Dizac (fractionated soybean oil 150 mg/mL ) (deacetylated monoglycerides 50 mg/mL) (fractionated egg yolk phospholipids 12 mg/mL) (glycerin 22 mg/mL) (water for injection ) (sodium hydroxide){24}]

Canada—


5 mg per mL (Rx) [Diazemuls (acetylated monoglycerides 50 mg/mL) (purified egg phospholipids 12 mg/mL) (purified soybean oil 150 mg/mL) ( glycerol 22 mg/mL) (sodium hydroxide)]{113}

Note: Sterile diazepam emulsion is an oil/water emulsion {113} with a pH of approximately 8 {24} {113}.


Packaging and storage:
Store below 25 °C (77 °F) {24} {113}, unless otherwise specified by manufacturer. Protect from freezing {24} {113}. Protect from light {24}.

Preparation of dosage form:
When administered intravenously, sterile diazepam emulsion should be administered without prior dilution or mixing with other products or solutions {24} {113}. However, it may be mixed or diluted with its emulsion base (Intralipid or Nutralipid) but the admixture should be used within 6 hours {113}.

Stability:
Sterile diazepam emulsion contains no preservatives {24} {113} and can support rapid microbial growth {24}. Administration should be completed within 6 hours after the ampul has been opened {24}.

Mixing or diluting sterile diazepam emulsion with products or solutions other than its own emulsion base (Intralipid or Nutralipid) may destabilize the emulsion. Although such an effect may not be recognized on visual inspection, it may result in potentially serious adverse reactions. {113}

Incompatibilities:
Sterile diazepam emulsion is incompatible with morphine and glycopyrrolate {24} {113}.

Infusion sets containing polyvinyl chloride should not be used for administration of sterile diazepam emulsion {24} {113}.

Note: For administration of sterile diazepam emulsion, polyethylene-lined or glass infusion sets and polyethylene/polypropylene plastic syringes are recommended {24} {113}.
Sterile diazepam emulsion should not be administered through a filter with a pore size of less than 5 microns, because the emulsion may be broken down {24}.
Strict aseptic technique is required in the handling of sterile diazepam emulsion {24}.
Controlled substance in the U.S.




Rectal Dosage Forms

DIAZEPAM FOR RECTAL SOLUTION

Usual adult and adolescent dose
Anticonvulsant
Status epilepticus and severe recurrent convulsive seizures: Rectal, 150 to 500 mcg (0.15 to 0.5 mg) of diazepam per kg of body weight {90} {93}, up to a maximum of 20 mg per dose {70} {73}.


Usual pediatric dose
Anticonvulsant
Status epilepticus and severe recurrent convulsive seizures: Rectal, 200 to 500 mcg (0.2 to 0.5 mg) of diazepam per kg of body weight {73} {92} {93}.


Usual geriatric dose
Rectal, 200 to 300 mcg (0.2 to 0.3 mg) of diazepam per kg of body weight {93}.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form:
For rectal administration, Diazepam Injection USP has been used. The parenteral preparation may be instilled via a cannula or catheter fitted to the syringe or directly from a needleless 1-mL syringe inserted 4 to 5 centimeters into the rectum to allow for optimum absorption. {88} {89} Alternatively, a dilution of Diazepam Injection USP with propylene glycol to make a solution containing 1 mg of diazepam per mL has been used {92}.

Stability:
Do not mix or dilute this medication with other solutions, intravenous fluids, or medications, because the resulting admixtures are unstable.

Diazepam is adsorbed to the plastic of intravenous infusion bags and tubing {04}.

Incompatibilities:
Diazepam injection is physically incompatible with aqueous solutions.


DIAZEPAM RECTAL GEL

Usual adult and adolescent dose
Anticonvulsant
Rectal, 200 mcg (0.2 mg) per kg of body weight rounded up to the next available unit dose {38}. Dose may be repeated, if needed, in four to twelve hours {38}.


Note: Geriatric or debilitated patients—Rounding down to the next available unit dose is recommended to avoid ataxia and oversedation {38}.


Usual pediatric dose
Anticonvulsant
Children younger than 2 years of age: Safety and efficacy have not been established {38}.

Children 2 to 6 years of age: Rectal, 500 mcg (0.5 mg) per kg of body weight rounded up to the next available unit dose {38}. Dose may be repeated, if needed, in four to twelve hours {38}.

Children 6 to 12 years of age: Rectal, 300 mcg (0.3 mg) per kg of body weight rounded up to the next available unit dose {38}. Dose may be repeated, if needed, in four to twelve hours {38}.

Children 12 years of age and older: See Usual adult and adolescent dose .


Strength(s) usually available
U.S.—


2.5 mg with pediatric (4.4 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]


5 mg with pediatric (4.4 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]


10 mg with pediatric (4.4 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]


10 mg with adult (6 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]


15 mg with adult (6 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]


20 mg with adult (6 cm) rectal tip size (Rx) [Diastat ( propylene glycol) (ethyl alcohol 10%) (hydroxypropyl methylcellulose) (sodium benzoate) (benzyl alcohol 1.5%) ( benzoic acid) (water){38}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {38}, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • For rectal use only.


Caution:
Medications containing benzyl alcohol are not recommended for use in neonates (first 30 days of postnatal life). A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

It is recommended that diazepam rectal gel be used no more frequently than every 5 days, and no more than five times a month {38}.

Note: Caregiver must be instructed in the proper use of diazepam rectal gel, including when use is appropriate, how to administer, how to monitor the patient after administration, and when immediate medical attention is required {38}.
Administration instructions for caregiver should be included with each prescription dispensed {38}.
If a child requires a dose of 15 mg and the pediatric rectal tip size is desired, unit doses of 5 and 10 mg must be dispensed since the 15 mg unit dose is available only in the adult rectal tip size {38}.
Controlled substance in the U.S.


Additional information:
The 2.5 mg unit dose size is intended for more precise dose titration or for the partial replacement of a dose that is expelled by the patient {38}.


ESTAZOLAM

Summary of Differences


Category:
Indicated only as a sedative-hypnotic.



Indications:
May be useful in prevention or treatment of transient insomnia associated with sudden sleep schedule changes.



Pharmacology/pharmacokinetics:
Intermediate half-life benzodiazepine {17}.

Small degree of accumulation during repeated dosing {85}.

Steady-state plasma concentration usually attained within a few days {86}.

Intermediate rate of elimination following discontinuation of therapy {85}.



Oral Dosage Forms

ESTAZOLAM TABLETS

Usual adult dose
Sedative-hypnotic
Oral, initially 1 mg at bedtime. A dose of 2 mg may be necessary in some patients {42}.


Usual pediatric dose
Sedative-hypnotic
Children younger than 18 years of age: Safety and efficacy have not been established {42}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 1 mg at bedtime. Dosage increases should be made cautiously {42}.


Note: Small or debilitated older patients may be started at 0.5 mg {42}.


Strength(s) usually available
U.S.—


1 mg (Rx) [ProSom (scored) (lactose ){154}][Generic] (may be scored){42}


2 mg (Rx) [ProSom (scored) (lactose ){154}][Generic] (may be scored){42}

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.



FLURAZEPAM

Summary of Differences


Category:
Indicated only as a sedative-hypnotic.



Pharmacology/pharmacokinetics:
Drug precursor; parent drug does not reach systemic circulation in significant amounts.

Long half-life benzodiazepine.

Accumulation of active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 7 to 10 days.

Elimination slow since metabolites remain in blood for several days.



Additional Dosing Information
See also General Dosing Information.

Flurazepam is increasingly effective on the second or third night of consecutive use, and for one or two nights after medication is discontinued both sleep latency and total wake time may still be decreased {46}.


Oral Dosage Forms

FLURAZEPAM HYDROCHLORIDE CAPSULES USP

Usual adult dose
Sedative-hypnotic
Oral, 15 or 30 mg at bedtime {46} {50}.


Note: The usual adult dose is 30 mg, but 15 mg may be sufficient for some patients {46}.
Debilitated patients—Oral, initially 15 mg at bedtime, the dosage being increased as needed and tolerated {46} {50}.


Usual pediatric dose
Sedative-hypnotic
Children younger than 15 years of age: Safety and efficacy have not been established {46}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 15 mg at bedtime, the dosage being increased as needed and tolerated {46} {50}.


Strength(s) usually available
U.S.—


15 mg (Rx) [Dalmane (lactose) ( gelatin capsules may contain methyl and propyl parabens){46}][Generic]


30 mg (Rx) [Dalmane (lactose) (gelatin capsules may contain methyl and propyl parabens){46}][Generic]

Canada—


15 mg (Rx) [Apo-Flurazepam{33}] [Dalmane (lactose 276 mg) (methylparaben) ( propylparaben){33}] [Novo-Flupam{33}]


30 mg (Rx) [Apo-Flurazepam] [Dalmane (lactose 263 mg) (methylparaben) (propylparaben)] [Novo-Flupam{33}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.



FLURAZEPAM HYDROCHLORIDE TABLETS

Usual adult dose
See Flurazepam Hydrochloride Capsules USP .

Usual pediatric dose
See Flurazepam Hydrochloride Capsules USP .

Usual geriatric dose
See Flurazepam Hydrochloride Capsules USP .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


15 mg (Rx) [Somnol (scored) (lactose ){50}]


30 mg (Rx) [Somnol (scored) (lactose ){50}]

Packaging and storage:
Store between 8 and 15 °C (46 and 59 °F), in a well-closed container {50}, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.


HALAZEPAM

Summary of Differences


Category:
Indicated only as an antianxiety agent.



Pharmacology/pharmacokinetics:
Long half-life benzodiazepine.

Accumulation of active metabolite is significant during repeated dosing.

Steady-state plasma concentration usually attained in 5 days to 2 weeks.

Elimination slow since metabolite remains in blood for several days or even weeks.



Oral Dosage Forms

HALAZEPAM TABLETS

Usual adult dose
Antianxiety agent
Oral, 20 to 40 mg three or four times a day. Dosage may be adjusted upward or downward after several days if needed. The optimal dosage is usually 80 to 160 mg per day. {06}


Note: Debilitated patients—Oral, 20 mg one or two times a day, the dosage being adjusted as needed and tolerated {06}.


Usual pediatric dose
Antianxiety agent
Children younger than 18 years of age: Safety and efficacy have not been established {06}.


Usual geriatric dose
Antianxiety agent
Oral, 20 mg one or two times a day, the dosage being adjusted as needed and tolerated {06}.


Strength(s) usually available
U.S.—


20 mg (Rx) [Paxipam (scored) (lactose ){06}]


40 mg (Rx) [Paxipam (scored) (lactose ){06}]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



KETAZOLAM

Summary of Differences


Category:
Formerly indicated in Canada as an antianxiety agent only.



Pharmacology/pharmacokinetics:
Long half-life benzodiazepine.

Accumulation of active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 7 to 10 days.

Elimination slow since metabolites remain in blood for several days.



Oral Dosage Forms

KETAZOLAM CAPSULES

Usual adult dose
[Antianxiety agent]1
Oral, 15 mg one or two times a day, the dosage being increased in 15-mg increments as needed and tolerated {63}.


Note: Debilitated patients—The recommended initial dosage is one half the lowest recommended initial adult dosage {63}.


Usual pediatric dose
[Antianxiety agent]1
Children younger than 18 years of age: Safety and efficacy have not been established {63}.


Note: Use in infants is not recommended {63}.


Usual geriatric dose
[Antianxiety agent]1
Oral, 15 mg once a day, the dosage being increased in 15-mg increments as needed and tolerated {63}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


LORAZEPAM

Summary of Differences


Category:
In addition to being indicated as an antianxiety agent and a sedative-hypnotic, lorazepam is indicated as an amnestic and an anticonvulsant (parenteral only), and is used as an antiemetic in cancer chemotherapy (parenteral only), an antipanic agent, an antitremor agent (oral only), and a skeletal muscle relaxant adjunct.



Indications:
Oral lorazepam also indicated for adjunctive management of anxiety associated with mental depression.

Parenteral lorazepam also indicated as a preanesthetic medication and for the treatment of status epilepticus; and used as an adjunct prior to endoscopic procedures and as prophylaxis of cancer chemotherapy–induced nausea and vomiting.

Oral and parenteral lorazepam also used for relief of acute alcohol withdrawal symptoms and for treatment of tension headache.



Pharmacology/pharmacokinetics:
Absorption of intramuscular lorazepam is rapid and complete.

Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few (2 to 3) days.

Elimination rapid following discontinuation of therapy.



Precautions:


Drug interactions and/or related problems—
Cimetidine, oral estrogen-containing contraceptives, diltiazem, disulfiram, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, nefazodone, propoxyphene, ranitidine, and verapamil, which inhibit the oxidative metabolism of benzodiazepines, are less likely to affect lorazepam, which undergoes glucuronide conjugation.

Premedication with lorazepam may decrease dose of a fentanyl derivative required for induction of anesthesia and reduce time to loss of consciousness with induction doses.

Probenecid may impair glucuronide conjugation of lorazepam, resulting in increased effects and possibly excessive sedation.



Medical considerations/contraindications—
Prolongation of elimination half-life due to hepatic function impairment may be minimal with lorazepam.




Side/adverse effects:
Intravenous lorazepam more likely than chlordiazepoxide but less likely than diazepam to cause phlebitis or venous thrombosis.



Additional Dosing Information
See also General Dosing Information.

For sublingual tablets only
Do not swallow for at least 2 minutes to allow sufficient time for absorption {09}.

For parenteral dosage forms only
Immediately prior to intravenous use, lorazepam injection must be diluted with an equal amount of a compatible diluent such as sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection {09}.

Following proper dilution, the medication may be injected directly into the vein or into the tubing of an intravenous infusion.

Intravenous injection should be made slowly and with repeated aspiration {09}.

The rate of the intravenous injection should not exceed 2 mg per minute {09}.

Intra-arterial injection and perivascular extravasation should be avoided. Intra-arterial injection may produce arteriospasm, possibly resulting in gangrene. {09}

When administered intramuscularly, the injection (undiluted) should be injected deeply into the muscle mass {09}.

When parenteral lorazepam is used for peroral endoscopic procedures, the use of topical or regional anesthesia is recommended to minimize the reflex activity associated with such procedures {54}.

When lorazepam is administered intravenously as premedication prior to regional or local anesthesia, potential excessive sleepiness or drowsiness may interfere with patient cooperation in determining levels of anesthesia. This is more likely to occur when doses greater than 0.05 mg per kg of body weight (mg/kg) are given and narcotic analgesics are used concomitantly with recommended doses. {09}


Oral Dosage Forms

LORAZEPAM ORAL CONCENTRATE USP

Usual adult and adolescent dose
Antianxiety agent
Oral, 1 to 3 mg two or three times a day {71}.

Sedative-hypnotic
Oral, 2 to 4 mg as a single dose at bedtime {71}.


Note: Debilitated patients—Oral, initially 1 to 2 mg per day in divided doses, the dosage being increased gradually as needed and tolerated {71}.


Usual adult prescribing limits
10 mg per day {71}.

Usual pediatric dose
Antianxiety agent or
Sedative-hypnotic1
Children younger than 12 years of age: Safety and efficacy have not been established {07} {71}.


Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Lorazepam Intensol{71}]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {71}, unless otherwise specified by manufacturer. Store in a well-closed container. Protect from light {71}.

Preparation of dosage form:
The manufacturer recommends that each dose be mixed with water, juice, soda or soda-like beverages, or semisolid food, such as applesauce or pudding. The entire amount of the mixture should be consumed immediately after mixing; no part of the mixture should be saved for later use. {71}

Auxiliary labeling:
   • Refrigerate.
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: The patient or caregiver should be instructed in proper measurement of the dose using the calibrated dropper provided with the medication, and in preparation of the dose.
Controlled substance in the U.S.



LORAZEPAM TABLETS USP

Usual adult and adolescent dose
Antianxiety agent
Oral, 1 to 3 mg two or three times a day {07} {09}.

Note: Debilitated patients—Oral, initially 0.5 to 2 mg per day in divided doses, the dosage being increased gradually as needed and tolerated {07} {09}.


Sedative-hypnotic1
Oral, 2 to 4 mg as a single dose at bedtime {07}.

Note: Elderly and debilitated patients may require a lower dose {160}.



Usual pediatric dose
Antianxiety agent or
Sedative-hypnotic1
Children younger than 12 years of age: Safety and efficacy have not been established {07}.


Usual geriatric dose
Antianxiety agent
Oral, initially 0.5 to 2 mg per day in divided doses, the dosage being increased gradually as needed and tolerated {07} {09}.


Strength(s) usually available
U.S.—


0.5 mg (Rx) [Ativan (lactose){07}][Generic] (may be scored ){57}


1 mg (Rx) [Ativan (scored) (lactose ){07}][Generic] (may be scored){57}


2 mg (Rx) [Ativan (scored) (lactose ){07}][Generic] (may be scored){57}

Canada—


0.5 mg (Rx) [Apo-Lorazepam (sodium < 1 mmol [0.06 mg]){33}] [Ativan (lactose){09}] [Novo-Lorazem{33}] [Nu-Loraz (sodium < 1 mmol [0.06 mg]){33}]


1 mg (Rx) [Apo-Lorazepam (scored) ( sodium < 1 mmol [0.13 mg]){33}] [Ativan ( scored) (lactose){09}] [Novo-Lorazem (scored){33}] [Nu-Loraz (scored) (sodium < 1 mmol [0.13 mg]){33}]


2 mg (Rx) [Apo-Lorazepam (scored) ( sodium < 1 mmol [0.16 mg]){33}] [Ativan ( scored) (lactose){09}] [Novo-Lorazem (scored){33}] [Nu-Loraz (scored) (sodium < 1 mmol [0.16 mg]){33}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



LORAZEPAM SUBLINGUAL TABLETS

Usual adult dose
Antianxiety agent
Sublingual, 2 to 3 mg per day in divided doses, the dosage being adjusted as needed, usually not exceeding 6 mg per day {09}.

Note: Debilitated patients—Sublingual, initially 500 mcg (0.5 mg) per day, the dosage being gradually adjusted as necessary {09}.


Preoperative: Sublingual, 50 mcg (0.05 mg) per kg of body weight, up to a maximum of 4 mg, one to two hours before surgery {09}.


Usual pediatric dose
Antianxiety agent
Children younger than 18 years of age: Safety and efficacy have not been established {09}.


Usual geriatric dose
Antianxiety agent
Sublingual, initially 500 mcg (0.5 mg) per day, the dosage being gradually adjusted as necessary {09}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


0.5 mg (Rx) [Ativan (lactose){09}]


1 mg (Rx) [Ativan (lactose){09}]


2 mg (Rx) [Ativan (lactose){09}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Dissolve tablets under tongue.
   • Avoid alcoholic beverages.
   • May cause drowsiness.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

LORAZEPAM INJECTION USP

Usual adult dose
Antianxiety agent or
Sedative-hypnotic or
Amnestic
Intramuscular, 50 mcg (0.05 mg) per kg of body weight, up to a maximum of 4 mg. Dose should be administered at least two hours prior to surgery for optimum amnestic effect. {09}

Intravenous, initially 44 mcg (0.044 mg) per kg of body weight or a total dose of 2 mg, whichever is less {09}. For greater amnestic effect, up to 50 mcg (0.05 mg) per kg of body weight, not to exceed a maximum of 4 mg, may be administered. Dose should be administered fifteen to twenty minutes prior to surgery for optimum amnestic effect {09}.

Anticonvulsant
Status epilepticus: Intravenous, initially 4 mg administered slowly {161} (at a rate not to exceed 2 mg per minute {09}). If seizures continue or recur after ten to fifteen minutes, the dose may be repeated {09} {161}. If seizure control is not evident after another ten to fifteen minutes, other measures to control status epilepticus should be used {09}. The total cumulative dose should not exceed 8 mg of lorazepam in a twelve-hour period {09}. Experience with additional doses is extremely limited {161}.

[Antiemetic, in cancer chemotherapy]1
Intravenous, initially 2 mg thirty minutes before initiation of chemotherapy, followed by 2 mg every four hours as needed {130}.


Usual pediatric dose
Antianxiety agent or
Sedative-hypnotic or
Anticonvulsant or
Amnestic
Children younger than 18 years of age: Safety and efficacy have not been established {09}.


Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Ativan (benzyl alcohol 2%) (polyethylene glycol 400 0.18 mL in propylene glycol)][Generic]{153}


4 mg per mL (Rx) [Ativan (benzyl alcohol 2%) (polyethylene glycol 400 0.18 mL in propylene glycol)][Generic]{153}

Canada—


4 mg per mL (Rx) [Ativan (benzyl alcohol 2%) (polyethylene glycol 18%) (propylene glycol 80%){09}]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form:
For intravenous administration—Immediately prior to use, lorazepam injection must be diluted with an equal volume of a compatible diluent, such as sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection {09}.

Stability:
Do not use if solution is discolored or contains a precipitate {09}.

Incompatibilities:
Lorazepam injection is physically incompatible with buprenorphine injection.


Caution:
Medications containing benzyl alcohol are not recommended for use in neonates (first 30 days of postnatal life). A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Note: Controlled substance in the U.S.



NITRAZEPAM

Summary of Differences


Category:
In addition to being indicated as a sedative-hypnotic, indicated as an anticonvulsant.



Pharmacology/pharmacokinetics:
Absorption of nitrazepam is rapid.

Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few (2 to 3) days.

Elimination rapid following discontinuation of therapy.



Precautions:
Drug interactions and/or related problems—Cimetidine or oral estrogen-containing contraceptives may inhibit the nitro-reduction of nitrazepam, resulting in delayed elimination and prolonged elimination half-life; serum concentrations may also be increased during long-term use.

Medical considerations/contraindications—Nitrazepam may delay cricopharyngeal relaxation, exacerbating swallowing abnormalities in children.



Oral Dosage Forms

NITRAZEPAM TABLETS

Usual adult dose
Sedative-hypnotic
Oral, 5 or 10 mg at bedtime {75}.


Note: Debilitated patients—Oral, initially 2.5 mg, the dosage being increased as needed and tolerated up to 5 mg {75}.


Usual pediatric dose
Sedative-hypnotic
Dosage has not been established {75}.

Anticonvulsant
Children up to 30 kg: Oral, initially the dosage should be below the usual recommended dosage range of 300 mcg (0.3 mg) to 1 mg per kg of body weight per day given in three divided doses, to determine response and tolerance. The dosage may be increased above the recommended range gradually, as needed and tolerated. {75}

Note: If doses are not equally divided, the larger dose should be given at bedtime {75}.



Usual geriatric dose
Sedative-hypnotic
Oral, initially 2.5 mg, the dosage being increased as needed and tolerated up to 5 mg {75}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


5 mg (Rx) [Mogadon (scored) (lactose ){75}]


10 mg (Rx) [Mogadon (scored) (lactose ){75}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light {75}.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


OXAZEPAM

Summary of Differences


Indications:
Also indicated for adjunctive management of anxiety associated with mental depression and relief of acute alcohol withdrawal symptoms.



Pharmacology/pharmacokinetics:
Orally, one of least rapidly absorbed benzodiazepines.

Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few days.

Elimination rapid following discontinuation of therapy.



Precautions:


Drug interactions and/or related problems—
Cimetidine, oral estrogen-containing contraceptives, diltiazem, disulfiram, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, nefazodone, propoxyphene, ranitidine, and verapamil, which inhibit the oxidative metabolism of benzodiazepines, are less likely to affect oxazepam, which undergoes glucuronide conjugation.

Probenecid may impair glucuronide conjugation of oxazepam, resulting in increased effects and possibly excessive sedation.



Medical considerations/contraindications—
Prolongation of elimination half-life due to hepatic function impairment may be minimal with oxazepam.




Oral Dosage Forms

OXAZEPAM CAPSULES USP

Usual adult dose
Antianxiety agent
Oral, 10 to 30 mg three or four times a day {55}.

Sedative-hypnotic
Alcohol withdrawal: Oral, 15 or 30 mg three or four times a day {55}.


Usual pediatric dose
Antianxiety agent or
Sedative-hypnotic
Children younger than 6 years of age: Safety and efficacy have not been established {55}.

Children 6 to 12 years of age: Dosage has not been established {55} {61}.


Usual geriatric dose
Antianxiety agent
Oral, initially 10 mg three times a day, the dosage being increased as needed and tolerated to 15 mg three or four times a day {55}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Serax (lactose){55}][Generic]


15 mg (Rx) [Serax (lactose){55}][Generic]


30 mg (Rx) [Serax (lactose){55}][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



OXAZEPAM TABLETS USP

Usual adult dose
See Oxazepam Capsules USP.

Usual pediatric dose
See Oxazepam Capsules USP.

Usual geriatric dose
Antianxiety agent
Oral, initially 10 mg three times a day, the dosage being increased as needed and tolerated to 15 mg three or four times a day {55}. Alternatively, an initial dosage of 5 mg one or two times a day has been recommended {61}.


Strength(s) usually available
U.S.—


15 mg (Rx) [Serax (tartrazine) (lactose ){55}][Generic]

Canada—


10 mg (Rx) [Apo-Oxazepam (scored){33}] [Novoxapam (scored){35}] [Serax (scored) (lactose){61}]


15 mg (Rx) [Apo-Oxazepam (scored){33}] [Novoxapam (scored){35}] [Serax (scored) (lactose){61}]


30 mg (Rx) [Apo-Oxazepam (scored) ( sodium < 1 mmol [0.49 mg]){33}] [Novoxapam ( scored){35}] [Serax (scored ) (lactose){61}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



PRAZEPAM

Summary of Differences


Category:
Formerly indicated in the U.S. as an antianxiety agent only.



Pharmacology/pharmacokinetics:
Drug precursor; metabolized to desmethyldiazepam before reaching systemic circulation.

Orally, one of least rapidly absorbed benzodiazepines.

Long half-life benzodiazepine.

Accumulation of active metabolites is significant during repeated dosing.

Steady-state plasma concentration usually attained in 5 days to 2 weeks.

Elimination slow since metabolites remain in blood for several days.



Oral Dosage Forms

PRAZEPAM CAPSULES USP

Usual adult dose
[Antianxiety agent]1
Oral, 10 mg three times a day (range, 20 to 60 mg per day); or 20 to 40 mg at bedtime {56}.


Note: Debilitated patients—Oral, initially 10 to 15 mg per day in divided doses, the dosage being increased gradually as needed and tolerated {56}.


Usual pediatric dose
[Antianxiety agent]1
Children younger than 18 years of age: Safety and efficacy have not been established {56}.


Usual geriatric dose
[Antianxiety agent]1
Oral, initially 10 to 15 mg per day in divided doses, the dosage being increased gradually as needed and tolerated {56}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


QUAZEPAM

Summary of Differences


Category:
Indicated only as a sedative-hypnotic.



Pharmacology/pharmacokinetics:
Long half-life benzodiazepine.

Accumulation of active metabolites may occur during repeated dosing.

Steady-state plasma concentrations usually attained within 7 to 13 days.

Elimination slow since metabolites remain in blood for several days.



Oral Dosage Forms

QUAZEPAM TABLETS

Usual adult dose
Sedative-hypnotic
Oral, initially 15 mg, the dose being reduced to 7.5 mg as needed {68}.


Note: Debilitated patients—Because of increased sensitivity to benzodiazepines, it is suggested that the nightly dose be reduced after one or two nights of treatment {68}.


Usual pediatric dose
Sedative-hypnotic
Children younger than 18 years of age: Safety and efficacy have not been established {68}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 15 mg, the dose being reduced to 7.5 mg after one or two nights {68}.


Strength(s) usually available
U.S.—


7.5 mg (Rx) [Doral (lactose){68}]


15 mg (Rx) [Doral (lactose){68}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.



TEMAZEPAM

Summary of Differences


Category:
Indicated only as a sedative-hypnotic.



Indications:
May be useful in prevention or treatment of transient insomnia associated with sudden sleep schedule changes.



Pharmacology/pharmacokinetics:
Short to intermediate half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Steady-state plasma concentration usually attained within a few (about 3) days.

Elimination rapid following discontinuation of therapy.



Precautions:


Drug interactions and/or related problems—
Cimetidine, oral estrogen-containing contraceptives, diltiazem, disulfiram, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, nefazodone, propoxyphene, ranitidine, and verapamil, which inhibit the oxidative metabolism of the benzodiazepines, are less likely to affect temazepam, which undergoes glucuronide conjugation.

Probenecid may impair glucuronide conjugation of temazepam, resulting in increased effects and possibly excessive sedation.



Medical considerations/contraindications—
Prolongation of elimination half-life due to hepatic function impairment may be minimal with temazepam.




Oral Dosage Forms

TEMAZEPAM CAPSULES USP

Usual adult dose
Sedative-hypnotic
Oral, usually 15 mg at bedtime, although 7.5 mg may be sufficient for some patients and others may need 30 mg {44}.


Note: In transient insomnia, 7.5 mg may be sufficient to improve sleep latency {44}.
Debilitated patients—Oral, initially 7.5 mg, the dosage being adjusted as needed and tolerated {44}.


Usual pediatric dose
Sedative-hypnotic
Children younger than 18 years of age: Safety and efficacy have not been established {08} {44}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 7.5 mg, the dosage being adjusted as needed and tolerated {44}.


Strength(s) usually available
U.S.—


7.5 mg (Rx) [Restoril (lactose){25}][Generic]{44}


15 mg (Rx) [Restoril (lactose){25}][Generic]{44}


30 mg (Rx) [Restoril (lactose){25}][Generic]{44}

Canada—


15 mg (Rx) [Apo-Temazepam{33}] [Novo-Temazepam{33}] [Restoril (lactose){08}]


30 mg (Rx) [Apo-Temazepam{33}] [Novo-Temazepam{33}] [Restoril (lactose){08}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant {08} {44} container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.



TRIAZOLAM

Summary of Differences


Category:
Indicated only as a sedative-hypnotic.



Indications:
May be useful in prevention or treatment of transient insomnia associated with sudden sleep schedule change.



Pharmacology/pharmacokinetics:
Short half-life benzodiazepine.

Accumulation is minimal during repeated dosing.

Elimination rapid following discontinuation of therapy.



Precautions:


Drug interactions and/or related problems—
Itraconazole and ketoconazole greatly increase the area under the plasma concentration–time curve (AUC) of triazolam; concurrent use is not recommended.

Nefazodone increases the AUC of triazolam fourfold, resulting in impairment of psychomotor function; a 75% reduction in triazolam dosage is recommended during concurrent use.

Cimetidine and erythromycin may inhibit the hepatic metabolism of triazolam, resulting in increased plasma concentrations and delayed clearance of triazolam; dosage reductions may be necessary.

Isoniazid may inhibit the elimination of triazolam, resulting in increased plasma concentrations.




Side/adverse effects:
Anterograde amnesia may be more likely to occur with triazolam than with most other benzodiazepines.

Because of the potency of triazolam, symptoms of overdose may occur at doses as low as 2 mg {26}.



Oral Dosage Forms

TRIAZOLAM TABLETS USP

Usual adult dose
Sedative-hypnotic
Oral, 125 to 250 mcg (0.125 to 0.25 mg) at bedtime {23} {26}.


Note: A dose of 500 mcg (0.5 mg) may be necessary in some patients. However, this dose should be reserved for patients who do not respond adequately to lower doses, since the risk of side effects increases with dosage increases. {23} {26}
Debilitated patients—Oral, initially 125 mcg (0.125 mg) at bedtime, the dosage being increased as needed and tolerated {23} {26}.


Usual pediatric dose
Sedative-hypnotic
Children younger than 18 years of age: Safety and efficacy have not been established {64}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 125 mcg (0.125 mg) at bedtime, the dosage being increased as needed and tolerated {23} {26} {64}.


Strength(s) usually available
U.S.—


125 mcg (0.125 mg) (Rx) [Halcion (docusate sodium) (lactose) (sodium benzoate){26}][Generic]( may contain docusate sodium, lactose, and/or sodium benzoate){23}


250 mcg (0.25 mg) (Rx) [Halcion (scored) (docusate sodium) ( lactose) (sodium benzoate){26}][Generic] (may be scored)(may contain docusate sodium, lactose, and/or sodium benzoate){23}

Canada—


125 mcg (0.125 mg) (Rx) [Alti-Triazolam (scored) (docusate sodium) (erythrosine sodium ) (lactose){33}] [Apo-Triazo (scored) (sodium < 1 mmol [0.32 mg]){33}] [Gen-Triazolam (scored){33}] [Halcion (scored) ( docusate sodium) (lactose){64}] [Novo-Triolam (scored){33}][Generic]


250 mcg (0.25 mg) (Rx) [Alti-Triazolam (scored) (docusate sodium) (lactose){33}] [Apo-Triazo (scored) ( sodium < 1 mmol [0.32 mg]){33}] [Gen-Triazolam (scored){33}] [Halcion ( scored) (docusate sodium) ( lactose){64}] [Novo-Triolam (scored){33}][Generic]

Packaging and storage:
Store between 15 and 30° C (59 and 86° F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause daytime drowsiness.

Note: Controlled substance in the U.S.




Revised: 04/05/2001



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  1. Reviewer comment, 7/90.
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  1. Panelist comment, 4/90. Ref: Kaplan SA, Jack ML, Weinfeld RE, et al. Biopharmaceutical and clinical pharmacokinetic profile of bromazepam. J Pharmacokinet Biopharm 1976 Feb; 4(1): 1-16.
  1. Ochs HR, Greenblatt DJ, Friedman H, et al. Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol. Clin Pharmacol Ther 1987 May; 41(5): 562-70.
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  1. Panel consensus, 4/90.
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  1. Dommisse CS, Hayes PE. Current concepts in clinical therapeutics: anxiety disorders, Part 2. Clin Pharm 1987 Mar; 6: 196-215.
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  1. Essentials of Nuclear Medicine. p. 204.
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  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, l989. p. 402-3; 712-3; 715; 719; 720; 726-34; 740-3; 746-8; 755-7; 762; 765; 768; 773.
  1. Carbamazepine update. Lancet 1989 Sep 9; 2(8663): 595-7.
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  1. Lorazepam injection package insert (Ativan, Wyeth—US), Rev 8/30/88, Rec 1/89.
  1. Estazolam tablets package insert (ProSom, Abbott—US), Rev 3/97, Rec 1/98.
  1. Alprazolam oral solution concentrate package insert (Alprazolam Intensol, Roxane—US), Rev 10/93, Rec 12/97.
  1. Chlordiazepoxide HCl capsules package insert (Lederle—US), Rev 6/86, Rec 12/88.
  1. Alprazolam oral solution package insert (Roxane—US), Rev 1/97, Rec 12/97.
  1. Alfentanil hydrochloride injection package insert (Alfenta, Janssen—US), Issued 12/86.
  1. Trimethaphan camsylate injection package insert (Arfonad, Roche—US), Rev 2/88, Rec 11/91.
  1. Personal communication, Drug Infomation, Wyeth—US, 5/12/98.
  1. Lorazepam injection package insert (Ativan, Wyeth—US), Rev 7/98, Rec 12/98.
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  1. Reviewers' consensus on monograph revision of 10/17/2000.
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