Clorazolam - General Information

Withdrawn in the United Kingdom due to risk of psychiatric adverse drug reactions. This drug continues to be available in the U.S. Internationally, triazolam is a Schedule IV drug under the Convention on Psychotropic Substances.


Pharmacology of Clorazolam

A short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Clorazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites.


Clorazolam for patients


Patient Package Insert

The text of the patient insert for triazolam is set forth below.

Introduction: Triazolam is intended to help you sleep. It is one of several benzodiazepine sleeping pills that have generally similar properties. Anyone who is considering using one of these medications should be aware of both their benefits and several important risks and limitations, including diminishing effectiveness with continued use and the possible development of dependence (addiction) and possibly mental changes particularly when the drugs are used for more than a few days to a week. This patient information statement is intended to provide you with knowledge about this class of medications in general and about triazolam in particular that will be useful to guide you in the safe use of this product, BUT IT SHOULD NOT REPLACE A DISCUSSION BETWEEN YOU AND YOUR PHYSICIAN ABOUT THE RISKS AND BENEFITS OF TRIAZOLAM.

This leaflet will focus on the beneficial and adverse effects of all members of this class of medications, as well as some specific information about triazolam. There are some differences among these products, and your physician may wish to discuss any specific advantages and disadvantages of particular members of this drug class with you.

Effectiveness Of Benzodiazepine Sleeping Pills: Benzodiazepine sleeping pills are effective medications and are relatively free of serious problems when they are used for short-termmanagement of sleep problems (insomnia). insomnia is not always the same. It may be reflected in difficulty in falling asleep, frequent awakening during the night, and/or early morning awakening. Insomnia is often transient in nature, responding to brief treatment with sleeping pills. Use for more than a short while requires discussion with your physician about the risks and benefits of prolonged use.

Side Effects

Common Side Effects: The most common side effects of benzodiazepine sleeping pills are related to the ability of the medications to make you sleepy; drowsiness, dizziness, lightheadedness, and difficulty with coordination. Users must be cautious about engaging in hazardous activities requiring complete mental alertness, e.g. operating machinery or driving a motor vehicle. Do not take alcohol while using triazolam. Benzodiazepine sleeping pills should not be used with other medications or substances that may cause drowsiness, without discussing said use with your physician.

How sleepy you are the day after you use one of these sleep medications depends on your individual response and on how quickly the product is eliminated from your body. The larger the dose, the more likely an individual will experience next day residual effects such as drowsiness. For this reason, it is important to use the lowest effective dose for each individual patient. Benzodiazepines that are eliminated rapidly, (e.g., triazolam) tend to cause less next day drowsiness but may cause more withdrawal problems the day after use.

Special Concerns

Memory Problems: All benzodiazepine sleeping pills can cause a special type of amnesia (memory loss) in which a person may not recall events occurring during some period of time, usually several hours, after taking a drug. This is ordinarily not a problem, because the person taking a sleeping pill intends to be asleep during this vulnerable period of time. It can be a problem when the drugs are taken to induce sleep while traveling, such as during an airplane flight, because the person may awake before the effect of the drug is gone. This has been called "traveler's amnesia". Triazolam is more likely than other members of the class to cause this problem.

Tolerance/Withdrawal Phenomena: Some loss of effectiveness or adaptation to the sleep inducing effects of these medications may develop after nightly use for more than a few weeks and there may be a degree of dependence that develops. For the benzodiazepine sleeping pills that are eliminated quickly from the body, a relative deficiency of the drug may occur at some point in the interval between each night's use. This can lead to (1) increased wakefulness during the last third of the night, and (2) the appearance of increased signs of daytime anxiety or nervousness. These two events have been reported in particular for triazolam.

There can be more severe `withdrawal' effects when a benzodiazepine sleeping pill is stopped. Such effects can occur after discontinuing these drugs following use for only a week or two, but may be more common and more severe after longer periods of continuous use. One type of withdrawal phenomenon is the occurrence of what is known as `rebound insomnia'. That is, on the first few nights after the drug is stopped, insomnia is actually worse than before the sleeping pill was given. Other withdrawal phenomena following abrupt stopping of benzodiazepine sleeping pills range from mild unpleasant feelings to a major withdrawal syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely, convulsions. These more severe withdrawal phenomena are uncommon.

Dependence/Abuse Phenomena: All benzodiazepine sleeping pills can cause dependence (addiction), especially when used regularly for more than a few weeks or at higher doses. Some people develop a need to continue taking these drugs, either at the prescribed dose or at increasing doses, not so much for continued therapeutic effect, but rather, to avoid withdrawal phenomena and/or to achieve nontherapeutic effects. Individuals who have been dependent on alcohol or other drugs may be at particular risk of becoming dependent on drugs in this class, but all people appear to be at some risk. This possibility must be considered before extending the use of these drugs for more than a few weeks.

Mental and Behavioral Changes: A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine sleeping pills. Some of these changes are like the release of inhibition seen in association with alcohol, e.g. aggressiveness and extroversion that seem out of character. Others, however, can be more unusual and more extreme, such as confusion, bizarre behavior, agitation, hallucinations, depersonalization, and worsening of depression, including suicidal thinking. It is rarely clear whether such events are induced by the drug being taken, are caused by some underlying illness or are simply spontaneous happenings. In fact, worsened insomnia may in some cases be associated with illnesses that were present before the medication was used. In any event, the most important fact is to understand that regardless of the cause, users of these medications should promptly report any mental or behavioral changes to their doctor.

Effects on Pregnancy: Certain benzodiazepines have been linked to birth defects when administered during the early months of pregnancy. In addition, the administration of benzodiazepines during the last weeks of pregnancy has been associated with sedation of the fetus. Consequently, the use of this drug should be avoided at any time during pregnancy.

Interactions with Other Medications
HALCION should not be taken with ketoconazole, itraconazole and nefazodone. Taking HALCION with certain other medications may cause increased levels of the drug in the blood and result in an excessive effect. Always tell your doctor about all medications you are taking.

Safe Use Of Benzodiazepine Sleeping Pills: To assure the safe and effective use of triazolam, you should adhere to the following cautions:

  1. Triazolam is a prescription medication and therefore, should be used only as directed by your doctor. Follow your doctor's advice about how to take it, when to take it, and how long to take it. As with other prescription medication, triazolam should be taken only by the individual for whom it is prescribed.
  2. Do not extend your use of triazolam beyond 7-10 days without first consulting your physician.
  3. If you develop any unusual and disturbing thoughts or behavior during treatment with triazolam, you should discuss such problems with your physician.
  4. Inform your physician about any alcohol consumption and medicine you are taking now, including drugs you may buy without a prescription. Do not use alcohol while taking triazolam.
  5. Do not take triazolam in circumstances where a full night's sleep and elimination of the drug from the body are not possible before you would again need to be active and functional, e.g. an overnight flight of less than 7-8 hours, because amnestic episodes have been reported in such situations.
  6. Do not increase the prescribed dose except on the advice of your physician.
  7. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
  8. Be aware that you may experience an increase in sleep difficulties (rebound insomnia) on the first night or two after discontinuing triazolam.
  9. Inform your physician if you are planning to become pregnant, if you are pregnant, or if you become pregnant while you are taking this medicine. The use of triazolam should be avoided at any time during pregnancy.
  10. Always tell your doctor about all medications you are taking.

Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, Michigan 49001, USA
Revised January 2003      812 110 831


Clorazolam Interactions

Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression.

Drugs that inhibit triazolam metabolism via cytochrome P450 3A: The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam.

Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the basis of clinical studies involving triazolam (caution is recommended during coadministration with triazolam):

Isoniazid Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%.

Oral contraceptives Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%.

Grapefruit juice Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%.

Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam): Available data from clinic a l studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interact ion with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during coadministration of any of these drugs with triazolam.

Drugs that affect triazolam pharmacokinetics by other mechanisms:

Ranitidine Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam.


Clorazolam Contraindications

Triazolam tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines.

Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.

Triazolam is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving triazolam, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.

HALCION is contraindicated with ketoconazole, itraconazole, and nefazodone, medicat ions that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A).


Additional information about Clorazolam

Clorazolam Indication: For the short-term treatment of insomnia.
Mechanism Of Action: Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Triazolam
Synonyms: DEA No. 2887; Triazolamum [Inn-Latin]
Drug Category: Anti-anxiety Agents; Adjuvants, Anesthesia; GABA Modulators; Benzodiazepines
Drug Type: Small Molecule; Illicit; Approved; Withdrawn

Other Brand Names containing Triazolam: Alti-Triazolam; Apo-Triazo; Clorazolam; Gen-Triazolam; Halcion; Novidorm; Novo-Triolam; Novodorm; Songar;
Absorption: Bioavailability is 44% (oral) and 53% (sublingual).
Toxicity (Overdose): Symptoms of overdose include drowsiness, slurred speech, motor inco-ordination, coma, and respiratory depression.
Protein Binding: Not Available
Biotransformation: Hepatic. Small amounts of unmetabolized triazolam appear in the urine.
Half Life: 1.5-5.5 hours
Dosage Forms of Clorazolam: Tablet Oral
Chemical IUPAC Name: 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Chemical Formula: C17H12Cl2N4
Triazolam on Wikipedia:
Organisms Affected: Humans and other mammals