Professional Information

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 ^{03} ^{52} ^{59}, bromazepam ^{60}, chlordiazepoxide ^{41}, clorazepate ^{19}, diazepam ^{04} ^{24} ^{96} ^{113}, halazepam ^{06}, [ ketazolam ^{63}]¹ , lorazepam ^{07} ^{09}, oxazepam ^{55}, and [prazepam ^{56}]¹ are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Chlordiazepoxide ^{34} ^{41}, [oral diazepam]¹ , and sublingual ^{09} or intramuscular lorazepam ^{09} 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 ^{03} ^{07} ^{24} ^{55} ^{60}. Effectiveness of these medications for long-term management of anxiety has not been assessed in systematic clinical studies ^{03} ^{07}. The medication's efficacy in an individual patient should be reassessed at periodic intervals ^{07}.

Anxiety associated with mental depression (treatment adjunct)¹—Alprazolam ^{03} ^{52}, lorazepam (oral) ^{71}, and oxazepam ^{55} 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 ^{03} ^{55} ^{71}. The medication's efficacy in an individual patient should be reassessed at periodic intervals ^{03} ^{55} ^{71}.

Alcohol withdrawal (treatment)—Chlordiazepoxide ^{41}, clorazepate ^{19}, diazepam ^{04} ^{24} ^{113}, [ lorazepam]¹ , and oxazepam ^{55} 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 ^{41} and parenteral diazepam ^{04} ^{24} ^{113} 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 ^{54}.

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 ^{04} ^{24} ^{69} ^{113}.

Amnesia, in endoscopic procedures or
Anxiety, in endoscopic procedures (treatment adjunct)—Parenteral diazepam ^{04} ^{24} ^{69} ^{113} 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 ^{113}.

[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. ^{01}

Insomnia (treatment)—Estazolam ^{42}, flurazepam ^{46} ^{50}, nitrazepam ^{75}, quazepam ^{68}, temazepam ^{44}, and triazolam ^{23} ^{26} 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 ^{07} ^{71}. Other benzodiazepines, such as [alprazolam]¹ , bromazepam¹ , [ diazepam]¹ ^{97}, [ 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 ^{23} ^{44} ^{75}. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder ^{23} ^{44} ^{75}.
—[Short- and intermediate-acting benzodiazepine hypnotics may be useful in the prevention or treatment (short-term) ^{121} of transient insomnia associated with a sudden sleep schedule change, such as occurs in trans-meridian travel and shift-work rotation ^{17} ^{76} ^{150} .]¹

Convulsions (treatment adjunct) or
Status epilepticus (treatment adjunct)—Diazepam injection ^{04}, sterile emulsion¹ ^{24}, and [diazepam for rectal solution]¹ ^{93} ^{09} ^{161} are indicated as adjuncts in status epilepticus and severe recurrent convulsive seizures. Lorazepam injection is indicated for the treatment of status epilepticus ^{09} ^{161} 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 ^{161}. These medications are not recommended for maintenance anticonvulsant therapy; therefore, once seizures are controlled, appropriate maintenance anticonvulsant therapy should be instituted ^{24} ^{161}.

Convulsive disorders (treatment adjunct)— Oral diazepam¹is indicated as short-term (7 to 14 days) adjunctive therapy in convulsive disorders ^{96}. It is not useful as sole therapy in convulsive disorders ^{96}. [ Clonazepam may be effective as an adjunct in convulsive disorders such as eclamptic convulsions, infantile spasms ^{78} ^{145} , reading epilepsy ^{98} , and startle-induced seizures.]¹ ^{111}

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 ^{53}.
—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 ^{38}. 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 ^{38}.

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 ^{18}.
—Nitrazepam also is indicated for the treatment of myoclonic seizures ^{75}.

[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. ^{111}

Epilepsy, absence seizure pattern (treatment)— Clonazepam may be useful in the treatment of absence (petit mal) seizures refractory to the succinimide anticonvulsants ^{18} 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 ^{39}.

[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 ^{78}.

[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 ^{18}.

Panic disorders (treatment)—Alprazolam ^{03} ^{59} ^{117}, [ chlordiazepoxide (parenteral)] ^{65}, clonazepam¹ ^{18}, [ diazepam]¹ ^{116} ^{117}, and [lorazepam]¹ ^{85} are used in the treatment of panic disorders.

[Agoraphobia]¹—Alprazolam is used in the treatment of agoraphobia.^{162}^{163}^{164}

Spasm, skeletal muscle (treatment adjunct)—Diazepam ^{04} ^{24} ^{96} and [ lorazepam]¹ ^{29} 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 ^{04} ^{24} ^{96} ^{113}. [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 ^{131} ^{132}. In addition, lorazepam-induced amnesia can reduce anticipatory anxiety, nausea, and vomiting ^{130}.

[Headache, tension (treatment)]—Chlordiazepoxide ^{65}, diazepam¹ , lorazepam¹ , and possibly other benzodiazepines¹ are used in the treatment of tension headache ^{36}.

[Tremors (treatment)]¹—Oral alprazolam ^{104}, chlordiazepoxide, diazepam, and lorazepam ^{28} 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) ^{02}	5–30 ^{11}	Desmethylchlordiazepoxide ^{02} (18) Demoxepam (14–95 ) Desmethyldiazepam (40 ^{19}–120 ^{113}) Oxazepam (5–15) ^{10}	0.5–4	Renal (1–2) ^{34}; 3–6% as conjugate ^{34}
Clorazepate ^§	Desmethyldiazepam: Very high (95–98) ^{38}	—	Desmethyldiazepam (40 ^{19}–120 ^{113}) Oxazepam (5–15) ^{10}	0.5–2 ^{14}	Renal ^{19}; fecal ^{19}
Diazepam	Very high (98) ^{113}	20–80 ^{113} ^#	Desmethyldiazepam (40 ^{19}–120 ^{113}) Temazepam (8–15) ^{20} Oxazepam (5–15) ^{10}	1–2 ^{05} (injection: IM, 0.5–1.5; IV, within 0.25 ^{69}) (sterile emulsion: IM, > 2 ^{113}; IV, 0.13 ^{24}–0.25 ^{113}) (rectal gel: 1.5 ^{38})	Renal ^{113}
Flurazepam ^§ ^**	Desalkylflurazepam: Very high (97) ^{02}	2.3 ^{46}	Desalkylflurazepam (47–100) ^{46} N-1-hydroxyethylflurazepam (2–4)	0.5–1 ^{46}	Renal ^{46}
Halazepam	Very high (97)	14 ^{06}	Desmethyldiazepam (40 ^{19}–120 ^{113})	1–3 ^{06}	Renal (< 1) ^{06}
Ketazolam	Very high (93)	2 ^{63}	Desmethyldiazepam (40 ^{19}–120 ^{113}) N-methylketazolam (34–52) Diazepam (20–80) ^{113} ^#	3	Renal; fecal < 1%
Prazepam ^§	Desmethyldiazepam: Very high (95–98) ^{38}	—	Desmethyldiazepam (40 ^{19}–120 ^{113}) Oxazepam (5–15) ^{10}	Desmethyldiazepam (single dose): 2.5–6	Renal
Quazepam	Very high (> 95) ^{68}	39 ^{68}	Desalkylflurazepam (47–100) ^{46} 2-oxoquazepam (39) ^{68}	2 ^{68}	Renal (trace) ^{68}; fecal ^{68}
Short to intermediate half-life
Alprazolam	High (80) ^{03}	11 ^{59} (6.3–26.9) ^{03}	None ^{03}	1–2 ^{03}	Renal ^{03}
Bromazepam	High (70)	12 (8–19) ^{60}	None	1–4 ^{60}	Renal ^{60}
Clobazam	High (85) ^{23}	18 (10–30) ^{23}	N-desmethylclobazam 42 (36–46) ^{23}	1–4 ^{23}	Renal ^{23}
Clonazepam	High (85) ^{18}	18–50 ^{13}	None	1–2 ^{13} ^††	Renal (< 2) ^{18}
Estazolam	Very high (93) ^{42}	10–24 ^{42}	None	2 (0.5–6) ^{42}	Renal (< 5) ^{42}
Lorazepam ^‡‡	High (85) ^{07}	10–20	None ^{07}	1–6 ^{09} (IM, 1–1.5 ^{09}; sublingual, 1 ^{09})	Renal ^{07}
Nitrazepam	High (87) ^{75}	30 (18–57) ^{75}	None ^{75}	2–3 ^{75}	Renal (about 1) ^{75}; fecal ^{75}
Oxazepam	Very high (97)	5–15 ^{10}	None ^{55}	1–4	Renal; fecal
Temazepam	Very high (96) ^{08} ^{44}	8–15 ^{20} ^{27} ^{62}	None ^{44}	1–2 ^{20} ^{62} ^{85}	Renal ^{44} (< 1) ^{08} ^§§
Triazolam	High (89) ^{02}	1.5–5.5 ^{26}	None ^{64}	£ 2 ^{23}	Renal (small amount) ^{26} ^§§

^* 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 ^{113}.
^** Maximum effectiveness as a hypnotic may not be achieved for 2 to 3 days ^{53}.
^†† 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 ^{153}.
^§§ Appears to be biphasic in its time course ^{08} ^{26}.

Physicochemical characteristics:
Molecular weight—
    Alprazolam: 308.77 ^{12}
    Bromazepam: 316.16 ^{12}
    Chlordiazepoxide: 299.76 ^{12}
    Chlordiazepoxide hydrochloride: 336.22 ^{12}
    Clonazepam: 315.72 ^{12}
    Clorazepate dipotassium: 408.93 ^{12}
    Diazepam: 284.75 ^{12}
    Estazolam: 294.74 ^{12}
    Flurazepam hydrochloride: 460.81 ^{12}
    Halazepam: 352.74 ^{12}
    Ketazolam: 368.82 ^{12}
    Lorazepam: 321.16 ^{12}
    Nitrazepam: 281.27 ^{12}
    Oxazepam: 286.72 ^{12}
    Prazepam: 324.81 ^{12}
    Quazepam: 386.8 ^{12}
    Temazepam: 300.75 ^{12}
    Triazolam: 343.22 ^{12}

Mechanism of action/Effect:

In general, benzodiazepines act as depressants of the central nervous system (CNS) ^{08}, producing all levels of CNS depression from mild sedation to hypnosis to coma, depending on dose ^{02}.

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) ^{08} ^{18}, the major inhibitory neurotransmitter in the CNS ^{18} ^{38}, by causing it to bind more tightly to the GABA type A (GABA _A) receptor ^{38}.

Benzodiazepines reportedly act as agonists at the benzodiazepine receptors ^{08}, which have been shown to form a component of a functional ^{136} ^{139} supramolecular unit ^{133} ^{139} known as the benzodiazepine-GABA receptor-chloride ionophore complex. This receptor complex, which resides on neuronal membranes ^{135} ^{137}, functions mainly in the gating of the chloride channel ^{140}. Activation of the GABA receptor results in the opening of the chloride channel ^{133} ^{141} ^{142}, allowing the flow of chloride ions into the neuron ^{38}. This results in hyperpolarization ^{136} ^{141} ^{142}, which inhibits firing of the neuron ^{137} ^{141} ^{147} and translates into decreased neuronal excitability ^{134} ^{135} ^{136}, thus attenuating the effects of subsequent depolarizing excitatory transmitters ^{138} ^{142}. Benzodiazepines reportedly increase the frequency of chloride channel opening ^{02} ^{08} ^{133}. There is also evidence that benzodiazepines may act at GABA-independent receptors ^{02}.

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. ^{156}

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. ^{02}

Anticonvulsant—Hyperpolarization, which is enhanced by benzodiazepines, reduces the ability of the neuron to depolarize to the threshold required to produce an action potential ^{38}. Thus, the seizure threshold is raised ^{75}. 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 ^{02}.

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 ^{145}. Benzodiazepines may also directly depress motor nerve and muscle function ^{111}.

Absorption:

Following oral administration—Benzodiazepines are well absorbed from the gastrointestinal tract ^{08} ^{75}, usually within 1 to 2 hours ^{03} ^{08}. Diazepam and clorazepate are among the most rapidly absorbed, and prazepam and oxazepam are the least rapidly absorbed ^{02}.

Following intramuscular administration—Lorazepam absorption is rapid and complete, whereas chlordiazepoxide and diazepam absorption may be slow and erratic ^{02}, depending upon the site of administration ^{147}. When diazepam is injected into the deltoid muscle, absorption is usually rapid and complete ^{147}.

Following rectal administration—Absorption of diazepam rectal solution ^{72} ^{92} and rectal gel ^{38} 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 ^{02} ^{115}.

Diazepam undergoes hepatic demethylation and hydroxylation, involving the cytochrome P450 2C19 (CYP2C19) and CYP3A4 isoenzymes, followed by glucuronidation ^{38}. Only one active metabolite, desmethyldiazepam, is present in clinically significant concentrations ^{38} ^{113}.

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 ^{02} ^{109} ^{110}.

Short to intermediate half-life benzodiazepines:

Alprazolam undergoes hydroxylation ^{03}, which is catalyzed by the CYP3A isoenzymes ^{03}, and is eliminated as glucuronide conjugates ^{02} ^{115}. One of alprazolam's metabolites has one half of the biological activity of alprazolam, but is present in very low plasma concentrations ^{03}.

Bromazepam undergoes hepatic microsomal oxidation ^{106} and is eliminated primarily as glucuronide conjugates ^{105}.

Clobazam undergoes hepatic demethylation and hydroxylation to active and inactive metabolites before inactivation by conjugation ^{53}.

Clonazepam and nitrazepam undergo hepatic nitro-reduction to inactive metabolites ^{13} ^{75}. Clonazepam also undergoes oxidative hydroxylation ^{13} and CYP3A isoenzymes may play an important role in clonazepam's metabolism ^{18}.

Estazolam undergoes oxidative metabolism and hydroxylation to metabolites with little activity and low plasma concentrations in comparison with the parent compound ^{42}.

Lorazepam, oxazepam, and temazepam are metabolized by direct conjugation with glucuronic acid ^{02} ^{07} ^{44} ^{115}.

Triazolam undergoes hepatic microsomal oxidation to inactive hydroxylated metabolites that are eliminated primarily as glucuronide conjugates ^{64}.

Accumulation

During repeated dosing with long half-life benzodiazepines, there is accumulation of the parent compound and/or any pharmacologically active metabolites ^{23} ^{42} ^{44} ^{75}. Accumulation continues until a steady-state plasma concentration is reached, which usually takes 5 days to 2 weeks after initiation of therapy ^{14}. 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 ^{156}.

During repeated dosing with short to intermediate half-life benzodiazepines, accumulation is minimal ^{23} ^{42} ^{75}, and a steady-state plasma concentration is usually attained within a few days after initiation of therapy ^{44}. Following termination of treatment, blood concentrations are subclinical in 24 hours and return rapidly to zero (in about 4 days or less). ^{97}

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. ^{146} ^{147}

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. ^{146} ^{147} The duration of clinical effects of the benzodiazepines is not always predictable from the elimination half-life ^{02}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one of the benzodiazepines may be sensitive to the other benzodiazepines also ^{18} ^{23}.

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 ^{03}.

Clobazam—Hepatomas, thyroid adenomas, and malignancies of the liver and thyroid gland were seen in rodent studies ^{53}; the significance of this finding to humans is unknown ^{53}.

Clonazepam—Studies on carcinogenic potential have not been done ^{18}.

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 ^{38}.

Estazolam—Studies of 24-months duration in mice and rats showed no evidence of tumorigenicity ^{42}. 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 ^{42}.

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 ^{06}.

Lorazepam—In an 18-month study in rats, lorazepam showed no evidence of carcinogenic potential ^{07}.

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. ^{55}

Quazepam—Oral oncogenicity studies in mice and hamsters showed no evidence of carcinogenicity ^{68}.

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. ^{44}

Triazolam—In a 24-month study in mice, triazolam in doses up to 4000 times the human dose showed no evidence of carcinogenic potential ^{23} ^{26}.

Mutagenicity

Alprazolam—Mutagenicity was not demonstrated in appropriate tests on mice or bacteria ^{03}.

Estazolam—Mutagenicity was not demonstrated in appropriate tests on mice, rats, and bacteria ^{154}.

Diazepam—Data are insufficient to determine mutagenic potential ^{38}.

Halazepam—Halazepam demonstrated no mutagenic activity in the Ames test ^{06}.

Lorazepam, oxazepam, and temazepam—Studies on mutagenic potential have not been done ^{07} ^{44} ^{55}.

Quazepam—Mutagenicity was not demonstrated in tests on mice or bacteria ^{68}.

Pregnancy/Reproduction

Pregnancy—

All benzodiazepines

Chlordiazepoxide ^{21}, clonazepam, diazepam ^{24} ^{38}, estazolam, flurazepam ^{46}, lorazepam ^{07} ^{09}, nitrazepam ^{75}, temazepam, and triazolam ^{23} cross the placenta. Alprazolam ^{03}, bromazepam, clorazepate, halazepam, ketazolam ^{63}, oxazepam, prazepam, and quazepam ^{68} are assumed to cross the placenta because of their similarity to the other benzodiazepines ^{03}.

First trimester—Chlordiazepoxide and diazepam have been reported to increase the risk of congenital malformations when used during the first trimester of pregnancy ^{23} ^{24} ^{68}. Because of the similarity of the benzodiazepines ^{03}, the other benzodiazepines are assumed to be associated with this increased risk also ^{03} ^{18}. 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 ^{03} ^{07} ^{18} ^{24}. The possibility that a woman of childbearing potential may already be pregnant should be considered when initiating benzodiazepine treatment ^{26} ^{38} ^{42} ^{113}.

When benzodiazepines are used as anticonvulsants, risk-benefit must be considered ^{18}. 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 ^{18} ^{38}. 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 ^{18} ^{38}.

Regular use of benzodiazepines during pregnancy may cause physical dependence with resulting withdrawal symptoms in the neonate ^{03} ^{08} ^{18} ^{23} ^{38} ^{75}.

Use of benzodiazepine hypnotics during the last weeks of pregnancy has resulted in neonatal CNS depression ^{08} ^{26} ^{46}, neonatal flaccidity ^{18} ^{23} ^{38} ^{75}, feeding difficulties ^{18} ^{38}, hypothermia ^{18} ^{38}, and respiratory problems ^{03} ^{18} ^{38}.

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. ^{41}

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 ^{18}.

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 ^{18}.

FDA Pregnancy Category D ^{18}.

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. ^{38}

FDA Pregnancy Category D ^{38}.

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 ^{07}.

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. ^{68}

FDA Pregnancy Category X ^{68}.

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. ^{44}

FDA Pregnancy Category X ^{44}.

Alprazolam ^{03}; Halazepam ^{06}—FDA Pregnancy Category D.

Estazolam ^{42}; Triazolam ^{23} ^{26}—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 ^{18} ^{38}.

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 ^{148}.

Breast-feeding

Chlordiazepoxide, diazepam ^{38} ^{113}, halazepam ^{06}, quazepam ^{68}, and their metabolites, including desmethyldiazepam ^{38} (which is also the metabolite of clorazepate ^{19} and prazepam ^{02}) are distributed into breast milk; clobazam ^{53} and nitrazepam ^{75} are distributed into breast milk also; alprazolam ^{03}, clonazepam, flurazepam, lorazepam ^{07}, oxazepam, temazepam ^{08}, 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 ^{60}, estazolam ^{42}, ketazolam ^{63}, triazolam ^{26}, 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 ^{03}. Since neonates metabolize benzodiazepines more slowly than adults and accumulation of the benzodiazepine and/or its metabolites may occur ^{22}, 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. ^{24} ^{113}

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 ^{18}.

Geriatrics

Geriatric patients are usually more sensitive to the CNS effects of benzodiazepines ^{53} ^{60} ^{113}. It is recommended that dosage be limited to the smallest effective dose ^{08} ^{23} ^{75} and increased gradually ^{60}, if necessary, to decrease the possibility of development of ataxia ^{38}, dizziness ^{08} ^{23} ^{75}, and oversedation ^{60} ^{113}, which may lead to falls and other accidents ^{08} ^{75}. 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 ^{118}. 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 ^{118}.

The half-lives of benzodiazepines may be longer in elderly than in younger patients ^{03} ^{38} ^{42} ^{75}.

Parenteral administration of benzodiazepines may be more likely to cause apnea, hypotension, bradycardia, or cardiac arrest in geriatric patients ^{09}.

Pharmacogenetics

Diazepam—3 to 5% of white patients have little or no cytochrome P450 2C19 (CYP2C19) activity and are poor metabolizers of diazepam ^{38}.

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 ^{38}. Medications that inhibit CYP2C19, such as cimetidine, quinidine, and tranylcypromine, may decrease the rate of elimination of diazepam ^{38}. Likewise, medications that induce CYP2C19, such as rifampin, may increase the rate of diazepam's elimination ^{38}.
The CYP3A isoenzymes are known to be involved in the metabolism of alprazolam ^{03}, clonazepam ^{18}, diazepam ^{38}, and triazolam ^{26} ^{64}. 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 ^{26} ^{64}.
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 ^{18} ^{113} and the risk of apnea may be increased ^{24} ^{113}; use of alcohol during treatment with a benzodiazepine is not recommended ^{03} ^{18} ^{26}; caution is recommended when another CNS depression–producing medication is used with a benzodiazepine, and dosage of one or both agents should be reduced ^{113})

    (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 ^{24} ^{113})

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 ^{141} ^{142})

    (concurrent use with clorazepate may decrease the rate of conversion of clorazepate to desmethyldiazepam, but does not affect the degree of absorption ^{108} ^{141})

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 ^{03})

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 ^{18} ^{53}; carbamazepine concentrations may be increased during concurrent use with a benzodiazepine ^{53}; monitoring of carbamazepine blood concentrations as a guide to dosage is recommended, especially when carbamazepine is added to or withdrawn from existing benzodiazepine therapy ^{97} ^{149})

Cimetidine^{03}^{23}^{24}^{113} or
Contraceptives, estrogen-containing, oral^{03}^{26} or
Diltiazem^{26} or
Disulfiram^{142} or
Erythromycin^{23} or
Fluoxetine^{03}^{31} or
» Fluvoxamine^{03}^{26} or
Grapefruit juice^{26} or
» Itraconazole^{03}^{26}^{64} or
» Ketoconazole^{03}^{26}^{64} or
» Nefazodone^{26}^{30} or
Propoxyphene^{03} or
Ranitidine^{26} or
Verapamil^{26}    (concurrent use may inhibit the hepatic metabolism of benzodiazepines that are metabolized by oxidation ^{64}, resulting in delayed elimination ^{24} and increased plasma concentrations ^{03}; however, the hepatic metabolism of benzodiazepines that undergo direct glucuronide conjugation, such as lorazepam ^{152}, oxazepam ^{152}, and temazepam ^{44}, 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 ^{100} ^{102} ^{121})

    (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] ^{03} ^{30} ^{32}; 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 ^{03} ^{31})

    (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 ^{32})

    (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} ^{64}; triazolam's AUC was increased fourfold and patient psychomotor performance was impaired during concurrent use of nefazodone ^{64}; reductions in initial triazolam dosage of 75% are recommended in patients receiving nefazodone ^{30}; 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 ^{23} ^{95}; triazolam's C _max, t _1/2, and AUC have been increased during concurrent use of ranitidine; caution is recommended ^{26}; plasma concentration, AUC, and t _1/2 of triazolam have been increased by coadministration with grapefruit juice ^{26})

Clozapine^{77}^{79}^{83}    (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 ^{158})

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 ^{51} ^{159})

    (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}; whether this effect applies to other benzodiazepines has not been determined ^{03}; dosage adjustment may be necessary ^{100} ^{142})

Levodopa    (concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa ^{80})

Omeprazole^{128}^{129}    (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 ^{123})

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 ^{100})

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 ^{09})

» 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 ^{24} ^{69} ^{113})

Zidovudine^{81}^{82}    (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 ^{15} ^{99})

Sodium iodide I 123 and
Sodium iodide I 131    (benzodiazepines may decrease thyroidal uptake of I 123 and I 131 ^{144})

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 ^{24} ^{113})

» Coma or
» Shock    (hypnotic or hypotensive effects may be prolonged or intensified by benzodiazepines administered parenterally ^{24} ^{113})

Drug abuse or dependence, history of    (patients predisposed to habituation and dependence ^{07} ^{18} ^{24} ^{26} ^{38} ^{113})

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 ^{05} ^{13} ^{18} ^{38}; use of intravenous diazepam for absence [petit mal] status or Lennox-Gastaut syndrome [petit mal variant] status may precipitate tonic status epilepticus ^{24})

    (abrupt withdrawal of clonazepam or diazepam used to treat these disorders may precipitate seizures or status epilepticus ^{05} ^{18})

» Glaucoma, angle-closure, acute or predisposition to    (benzodiazepines may have anticholinergic effect ^{03} ^{04} ^{07} ^{23} ^{24})

Hepatic function impairment    (elimination half-life may be prolonged ^{03} ^{18} ^{38} ^{60} ^{75}; minimal effect with oxazepam, lorazepam, and temazepam)

Hyperkinesis    (paradoxical reactions may occur ^{40})

Hypoalbuminemia^{141}    (may predispose patient to higher incidence of sedative side effects, especially with chlordiazepoxide and diazepam ^{141})

Mental depression, severe    (suicidal tendencies may be present; protective measures may be necessary; also benzodiazepines, when used alone, may increase depression ^{03} ^{18} ^{23} ^{26} ^{42}; episodes of hypomania and mania reported with use of alprazolam in patients with mental depression ^{03} ^{91})

» Myasthenia gravis    (condition may be exacerbated ^{08} ^{60} ^{75} ^{113})

Organic brain disorders    (patients may be more prone to disinhibition and CNS depressant effects of benzodiazepines ^{08} ^{64})

Porphyria    (condition may be exacerbated with the use of chlordiazepoxide ^{41})

Psychoses    (benzodiazepines are rarely effective as primary treatment for psychosis; also, paradoxical reactions may be more likely to occur in psychotic patients ^{53} ^{60} ^{113})

» 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 ^{18} ^{38} ^{42} ^{64}; deaths occurring shortly after beginning treatment with alprazolam have been reported rarely in patients with severe pulmonary disease ^{03})

Renal function impairment    (accumulation of renally excreted metabolites may occur ^{18} ^{24} ^{38})

Sensitivity to benzodiazepines^{03}^{08}^{60}^{75}
Sleep apnea, established or suspected    (condition may be exacerbated ^{08} ^{23} ^{68})

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 ^{121} ^{143})

Caution should also be used in surgical or nonambulatory patients because of the cough-suppressant effects of clonazepam^{101}^{103} .

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 ^{16})

Reassessment of medication's efficacy as an antianxiety agent or a sedative-hypnotic    (recommended at periodic intervals during therapy; see Indications ^{07} ^{44})

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 ^{16}.
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 ^{03} ^{05} ^{141}.
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 ^{113}.
Parenteral benzodiazepines have produced hypotension or muscular weakness in some patients, especially when used concurrently with narcotics, barbiturates, or alcohol ^{113}.
Coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm, and pain in throat and chest have been reported when parenteral diazepam was administered in peroral endoscopic procedures ^{113}.

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^{03}^{23}^{26} (lack of memory of events taking place after benzodiazepine is taken)

anxiety^{26}^{42}^{44}^{75}

confusion^{03}^{18}^{23}^{24}^{75} —especially in the elderly and in patients with cerebral impairment^{75}

mental depression^{18}^{23}^{24}^{75}

tachycardia/palpitation^{18}^{23}^{75} (fast, pounding, or irregular heartbeat)

Note: Anterograde amnesia may be dose-related ^{64} ^{75} and may occur at a higher rate with triazolam than with other benzodiazepines ^{23} ^{26} ^{64}. “Traveler's amnesia,” which occurs in people taking benzodiazepines to avoid jet lag, may be associated with allowing insufficient time for sleep ^{23} ^{26} ^{64} ^{75} and/or concomitant use of alcohol ^{26}.
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 ^{26} ^{42} ^{44} ^{75}. 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 ^{26} ^{42} ^{44} ^{75}.

Incidence rare

Abnormal thinking^{26}^{75}
including delusions^{23} (false beliefs that cannot be changed by facts), depersonalization^{03}^{23}^{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}

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