Pharmacokinetics

• Long half-life compared to other benzodiazepine anxiolytics (elimination half-life approximately 30–40 hours)

Drug Interactions

• Increased depressive effects when taken with other CNS depressants

• Inhibitors of CYP450 3A4 may affect the clearance of clonazepam, but dosage adjustment usually not necessary

• Flumazenil (used to reverse the effects of benzodiazepines) may precipitate seizures and should not be used in patients treated for seizure disorders with clonazepam

• Use of clonazepam with valproate may cause absence status

Other Warnings/Precautions

• Dosage changes should be made in collaboration with prescriber

• Use with caution in patients with pulmonary disease; rare reports of death after initiation of benzodiazepines in patients with severe pulmonary impairment

• History of drug or alcohol abuse often creates greater risk for dependency

• Clonazepam may induce grand mal seizures in patients with multiple seizure disorders

• Use only with extreme caution if patient has obstructive sleep apnea

• Some depressed patients may experience a worsening of suicidal ideation

• Some patients may exhibit abnormal thinking or behavioral changes similar to those caused by other CNS depressants (i.e., either depressant actions or disinhibiting actions)

Do Not Use

• If patient has angle-closure glaucoma

• If patient has severe liver disease

• If there is a proven allergy to clonazepam or any benzodiazepine

CLONAZEPAM: SPECIAL POPULATIONS

Renal Impairment

• Dose should be reduced

Hepatic Impairment

• Dose should be reduced

Cardiac Impairment

• Benzodiazepines have been used to treat anxiety associated with acute myocardial infarction

Elderly

• Should receive lower doses and be monitored

Children and Adolescents

• Seizures – up to 10 years or 30 kg – 0.01–0.03 mg/kg per day divided into 2–3 doses; maximum dose 0.05 mg/kg per day

• Safety and efficacy not established in panic disorder

• For anxiety, children and adolescents should generally receive lower doses and be more closely monitored

• Long-term effects of clonazepam in children/adolescents are unknown

Pregnancy

• Risk Category D [positive evidence of risk to human fetus; potential benefits may still justify its use during pregnancy, especially for seizure disorders]

• Possible increased risk of birth defects when benzodiazepines taken during pregnancy

• Because of the potential risks, clonazepam is not generally recommended as treatment for anxiety during pregnancy, especially during the first trimester

• Drug should be tapered if discontinued

• Infants whose mothers received a benzodiazepine late in pregnancy may experience withdrawal effects

• Neonatal flaccidity has been reported in infants whose mothers took a benzodiazepine during pregnancy

• Seizures, even mild seizures, may cause harm to the embryo/fetus

Breast Feeding

• Some drug is found in mother’s breast milk

✽ Recommended either to discontinue drug or bottle feed

• Effects on infant have been observed and include feeding difficulties, sedation, and weight loss

CLONAZEPAM: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Rapid onset of action

• Less sedation than some other benzodiazepines

• Longer duration of action than some other benzodiazepines

• Availability of oral disintegrating wafer

Potential Disadvantages

• Development of tolerance may require dose increases, especially in seizure disorders

• Abuse especially risky in past or present substance abusers

Primary Target Symptoms

• Frequency and duration of seizures

• Spike and wave discharges in absence seizures (petit mal)

• Panic attacks

• Anxiety

Pearls

✽ One of the most popular benzodiazepines for anxiety, especially among psychiatrists

• Is a very useful adjunct to SSRIs and SNRIs in the treatment of numerous anxiety disorders

• Not effective for treating psychosis as a monotherapy, but can be used as an adjunct to antipsychotics

• Not effective for treating bipolar disorder as a monotherapy, but can be used as an adjunct to mood stabilizers and antipsychotics

• Generally used as second-line treatment for petit mal seizures if succinimides are ineffective

• Can be used as an adjunct or as monotherapy for seizure disorders

• Clonazepam is the only benzodiazepine that is used as a solo maintenance treatment for seizure disorders

✽ Easier to taper than some other benzodiazepines because of long half-life

✽ May have less abuse potential than some other benzodiazepines

✽ May cause less depression, euphoria, or dependence than some other benzodiazepines

✽ Clonazepam is often considered a “longer-acting alprazolam-like anxiolytic” with improved tolerability features in terms of less euphoria, abuse, dependence, and withdrawal problems, but this has not been proven

• When using to treat insomnia, remember that insomnia may be a symptom of some other primary disorder itself, and thus warrant evaluation for comorbid psychiatric and/or medical conditions

• Though not systematically studied, benzodiazepines have been used effectively to treat catatonia and are the initial recommended treatment

Suggested Reading

Davidson JR, Moroz G. Pivotal studies of clonazepam in panic disorder. Psychopharmacol Bull 1998;34:169–74.

DeVane CL, Ware MR, Lydiard RB. Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull 1991;27:463–73.

Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002;53:39–49.

Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3:379–403.

CLONIDINE

CLONIDINE: THERAPEUTICS

Brands

• Duraclon (injection)

• Catapres

• Kapvay

see index for additional brand names

Generic?

Yes (not for transdermal)

Class

• Antihypertensive; centrally acting alpha 2 agonist hypotensive agent, nonstimulant for ADHD

Commonly Prescribed for

(bold for FDA approved)

• Hypertension

• Attention deficit hyperactivity disorder (ADHD) (Kapvay)

• Attention deficit hyperactivity disorder (ADHD)

• Tourette’s syndrome

• Substance withdrawal, including opiates and alcohol

• Anxiety disorders, including posttraumatic stress disorder (PTSD) and social anxiety disorder

• Clozapine-induced hypersalivation

• Menopausal flushing

• Severe pain in cancer patients that is not adequately relieved by opioid analgesics alone (combination with opiates)