Category

Medications

Triazolam – TRIAZOLAM®

Brand name

  • TRIAZOLAM®

Drug Class

  • Benzodiazepine Hypnotic

Preparations

  • Triazolam Tablets USP125 mg and 0.25 mg

Indications

  • Symptomatic relief of transient and short-term insomnia in patients who have difficulty falling asleep.

Pharmacology

  • Pharmacokinetics:
    • Half-life: 1.5-5.5 hours
    • Peak plasma time: 2 hours
    • Onset of action: 15-30 min
    • Duration of action: 6-7 hours
    • Metabolism: metabolized via hepatic microsomal oxidation
    • Excretion: primarily in the urine

Metabolism

  • Depresses all level of CNS possibly by increasing membrane permeability to chloride ions, which in turn increase the inhibitory activity of GABA on neuronal excitability.

Dosing

  • Dosage in all patients:
    1. Initial dose: 0.125 mg (immediately before retiring)
    2. Duration: should usually not exceed 7-10 consecutive days.
    3. Max dose: Should not be exceeded 0.25 mg (0.5mg is used only for exceptional patients who do not respond to a trial of the lower dose.)
  • Dosage in elderly or debilitated patients and patients with disturbed liver/kidney function:
    1. Should not exceed 0.125 mg before retiring (0.25 mg is used only for exceptional patients who do not respond to a trial of the lower dose.)

Drug Interactions

  1. alcohol, antihistamines, anticonvulsants, or psychotropic medications: co-administration produces additive CNS depressant effects
  2. Cimetidine, erythromycin: interfere with triazolam metabolism

Adverse Effects

  • Most frequent:
    • Sedation (morning drowsiness, somnolence), dizziness, nervousness, irritability and impaired coordination.
  • Most serious:
    • memory impairment, abnormal thinking, abnormal behavior, confusion, anxiety, and depression
  • Rare:
    • Dysesthesia, paresthesia, dream abnormalities, drug abuse/habituation, drug withdrawal symptoms, hallucinations, muscle tone disorder, tremor, tinnitus, hearing impairment, eye irritation/redness, edema, chest pain, hot/cold flashes, hypertension, syncope, dyspnea, constipation, flatulence, oral irritation, micturition difficulties, dermatitis, diaphoresis, muscular cramps, muscular weakness, malaise, sexual dysfunction, Elevated levels of SGOT, bilirubin, and alkaline phosphatase

Contraindications

  1. Hypersensitivity to this drug or other benzodiazepines.
  2. Paradoxical reactions to alcohol or sedative medications, and history of substance or alcohol abuse.
  3. Pregnancy
  4. Myasthenia Gravis
  5. Uncorrected narrow-angle glaucoma.

Pregnancy and Breastfeeding

  • Pregnancy: category X
  • Lactation: not recommended in nursing mothers

Precautions

  1. Rebound” Insomnia:
    1. On the first or second night after drug discontinuance, total time asleep, and percentage of time spent sleeping frequently might significantly decrease.
  2. Treatment with triazolam should usually not exceed 7-10 consecutive days.
  3. Use in elderly:
    1. Degree of sedation and impairment of psychomotor performance are more pronounced in the elderly.
  4. Use in patients with severe liver disease:
    1. Greater psychomotor impairment than with minimal liver dysfunction.
  5. Over-dosage:
    1. Manifestations: somnolence, confusion, impaired coordination, slurred speech, coma, respiratory depression and apnea.
    2. Treatment: supportive care
    3. Antidote: flumazenil (‘Anexate’), a benzodiazepine antagonist.
  6. Failure of insomnia to remit after 7-10 days of treatment:
    1. Indicate the presence of a primary psychiatric or medical illness.
  7. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior:
    1. Indicate consequence of an unrecognized psychiatric or physical disorder.
  8. Memory disturbance
    1. Anterograde amnesia:
      1. varying severity
      2. dose-related phenomenon
      3. Elderly subjects at a particular risk.
    2. Transient global amnesia and “traveler’s amnesia”:
      1. Unpredictable
      2. Not necessarily dose-related phenomena.
  9. Abnormal thinking and psychotic behavioral changes:
    1. Characterized by decreased inhibition, e.g., aggressiveness or extroversion
    2. Particular caution in patients with a history of violent behavior.
    3. Psychotic behavioral include:
    4. Bizarre behavior, hallucinations, and depersonalization.
    5. Abnormal behaviors are more with chronic use or high doses.
  10. Confusion:
    1. Triazolam affect mental efficiency, e.g., concentration, attention and vigilance.
    2. The risk of confusion is greater in elderly and patients with cerebral impairment.
  11. Anxiety, restlessness:
    1. Increase in daytime anxiety (interdose rebound anxiety) and restlessness
  12. Depression:
    1. Caution in patients with signs or symptoms of depression >>> because Suicidal tendencies e.g., intentional overdose, is more common in these patients,
  13. Complex sleep-related behaviors:
    1. Caution patients about dangerous sleep-related behaviors such as “sleep- driving – patients usually do not remember these events.
    2. Caution in concomitant use with alcohol and other CNS-depressants increase the risk of such behaviors
  14. Severe Anaphylactic and Anaphylactoid Reactions:
    1. Patients should be informed about angioedema
    2. Patients who develop angioedema after treatment with Triazolam should not be re-challenged with the drug.
  15. Drug abuse, dependence and withdrawal:
    1. Withdrawal symptoms:
      1. convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia
    2. Abrupt discontinuation should be avoided.
    3. Gradual dosage tapering is recommended in any patient taking more than the lowest dose for more than a few weeks.
    4. High risk of dependence:
      1. in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders
  16. caution in Patients with specific conditions:
    1. Impaired hepatic function,
    2. Impaired renal function,
    3. severe pulmonary insufficiency,
    4. Sleep apnea.
  17. Patients requiring mental alertness:
    1. Patients should be cautioned about:
    2. Engaging in hazardous occupations such as operating machinery or driving a motor vehicle.
    3. Concomitant ingestion of triazolam and alcohol or CNS depressant drugs.
  18. Use in children:
    1. Not recommended in children below the age of 18.
  19. Use in the elderly:
    1. Lowest possible dose should be used >>> elderly patients are susceptible to dose-related adverse effects

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Quazepam, DORAL®

Brand name

  • DORAL®

Drug Class

Benzodiazepines

Preparations

  • Tablets: 7.5 mg and 15 mg

Indications

  • Insomnia (Difficulty Sleeping)

Pharmacology

Pharmacodynamics:

Exact mechanism is not known >>> 1,4-benzodiazepine class presumably exerts their effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS).

Metabolism

Pharmacokinetics:

  •  Absorption: Gastrointestinal tract
  • Distribution: Peak plasma concentration of quazepam is approximately 20 ng/mL after a 15 mg dose after about 2 hours. Plasma protein binding: >95%
  • Metabolism: Metabolized in liver. Half-life of about 30 minutes. Two major metabolites: 2-oxoquazepam and N-desalkyl-2-oxoquazepam.
  • Excretion: Urine + Feces

Dosing

1. Insomnia: (Adults)

  • Initial dose:5 mg orally at bedtime
  • Maintenance dose: May increase to 15 mg orally at bedtime (Reduce the dose after 2 consecutive nights)

(Use the lowest effective dose, as adverse effects are dose related)


2. Insomnia: (Geriatrics)

  • Start at the lowest dose possible (Which is clinically effective)

3. Renal Dysfunction

No dose adjustment recommended.

(Monitor the patient closely for any signs of overdose like sedation)


4. Liver Dose Adjustments

No dose adjustment recommended.

(Monitor the patient closely for any signs of overdose like sedation)


5. Dialysis

  • Hemodialysis: No dose adjustment recommended.
  • Peritoneal dialysis: No available data

Drug Interactions

  1. Psychoactive drugs (Opioids, Benzodiazepines, Anti- Psychotics and etc.)
  2. Alcohol (Ethanol)
  3. Quazepam Increases the plasma concentrations of drugs that are substrates of CYP2B6 (e.g., efavirenz and bupropion) may result if co­ administered with Quazepam (Enzyme inhibitor effect) >>> Quazepam does not inhibit CYP2C8 and CYP2E1
  4. Anticonvulsants
  5. Antihistamines

Adverse Effects

More Frequent:

  • Drowsiness
  • Headache

Less frequent:

  • Dizziness
  • Dry mouth (Xerostomia)
  • Dyspepsia

Contraindications

  1. Known hypersensitivity to Quazepam or Benzodizepines.
  2. Patients with established or suspected sleep apnea, or with pulmonary insufficiency.
  3. Sodium-Oxybate

Pregnancy and Breastfeeding

Pregnancy: Category X

Lactation: NOT recommended in nursing mother

Precautions

1. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.


2. Avoid using dangerous machinery vehicles while taking Quazepam! Due to its sedative hypnotic effect.


3. Avoid driving while taking Quazepam! Due to its seeative hypnotic effect.


4. Caution in concomitant use with CNS-depressant medications! May cause synergistic effect >>> may increase sedation.


5. Caution in concomitant use with Alcohol! >>> Increases sedative effects.


6. Watch for possible Complex Behaviors: preparing and eating food, making phone calls, or having sex. (Patients usually do not remember these events)


7. Caution for Severe anaphylactic and anaphylactic reactions


8. Abuse: Caution in administering Quazepam to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative.


9. Dependence: The use of benzodiazepines may lead to dependence as defined by the presence of a withdrawal syndrome on discontinuation of the drug.


10. Tolerance: As defined by a need to increase the dose in order to achieve the same therapeutic effect seldom occurs in-patients receiving recommended doses under medical supervision >>> Caution for Tolerance to sedation may occur with benzodiazepines especially in those with drug seeking behaviour.


11. Caution in Patients with major depressive disorder: Risk that the signs and symptoms of depression may be intensified. Appropriate precautions (e.g, limiting the total prescription size and increased monitoring for suicidal ideation) should be considered.


12. Educate, Counsel the patient, caregivers, family for the associated benefit and risks.


13. If benzodiazepines are taken on a prolonged and regular basis (even for periods as brief as 6 weeks), patients should be advised not to stop taking them >>> do a gradual tapering to discontinuation:

 

  • Withdrawal symptoms: convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating, dysphoria and insomnia.

14. Pediatric Use: Safety and effectiveness in children below the age of 18 years have not been established.


15. Geriatric Use: Dose selection for an elderly patient should be cautious (Start with lower doses due to higher chances of hepatic and renal diseases).


16. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, Quazepam should be discontinued >>> Rebound phenomena.


17. Over dosage:

 Symptoms:

  • Sedation, somnolence, confusion, impaired, coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest.

Treatment:

  • Continuous monitoring of vital signs including EKG immediately.
  • Immediate attention should be given to the maintenance of an adequate airway and support of ventilation.
  • Cardiopulmonary resuscitation may be required
  • Flumazenil (Benzodiazepine antagonist –Specific antidote) >>> 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr (contact your regional Poison Control Centre for more information)

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Clobazam, FRISIUM®

Brand name

  • FRISIUM®

Drug Class

  • Benzodiazepines
  • Anti-Epileptics

Preparations

  • Tablets 10 mg

Indications

  • Epilepsy: Adjunctive therapy in patients with epilepsy who are not adequately stabilized with their current anticonvulsant therapy.

Pharmacology

Pharmacodynamics:

  • Mechanism of Action: The exact mechanisem of action is unknown. Clobazam is a 1,5-benzodiazepine with anticonvulsant properties >>> involve potentiation of GABAergic (gamma-Aminobutyric acid ) neurotransmission resulting from greater binding at the benzodiazepine site of the GABA receptor >>> resulting in a decrease in the firing rate of critical neurons in many regions of the brain.

Metabolism

Pharmacokinetics:

 

  • Absorption: Fast absorption, at least 87% absorbed after orally used. Maximum plasma concentration: 222 to 709 ng/ml after 0.25 to 4 hours.
  • Distribution: highly lipophilic and distributes rapidly throughout the body ( Fat and Gray matter). plasma protein binding of Clobazam and N- desmethylclobazam is approximately 80-90% and 70% respectively.
  • Metabolism: Active metabolite => N-desmethylclobazam. Primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6
  • Excretion: 90% Urine. (Half-life of N-desmethylclobazam = mean 42 hours)

Dosing

1. Adults:

  • Initial dose: 5-15 mg/day ( Do a gradual increase)
  • Maximum dose 80 mg/day

2. Children from 2 to 16 years:

  • Initial dose 5 mg/day (Do a gradual increase at 5-day intervals)
  • Maximum dose: of 40 mg/day

3. Infants ≤ 2 years:

  • Initial dose:5-1 mg/kg/day.

4. Elderly: Due to decreased organ function in elderly patients, lower initial doses and gradual dose increments are recommended and patients should be monitored for responsiveness and adverse events.


5. CYP2C19 Poor metabolizers: In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased:

  • Starting dose: lowest initial recommended dose and dose (titration should proceed slowly- half the maximum dose described-).
  • Maximum dose: (depending on the age group) may be started on day 21.

6. Hepatic Impairment:

  • Starting dose: lowest initial recommended dose and dose (titration should proceed slowly- half the maximum dose described-).
  • Maximum dose: (depending on the age group) may be started on day 21.

Drug Interactions

1. Clobazam is weak CYP3A4 (Cytochrome P-450) inducer:

  • Possible decrease in dosage of other medications especially Oral Contraceptive Pills in concomitatnt use with Clobazam! >>> Dose adjustment may be necessary.

2. Carbamazepine, phenytoin, phenobarbital, and valproate >>> decrease the blood level of Clobazam >>> dose adjustment may be necessary.

3. Diphenylhydantoin >>> decrease the blood level of Clobazam

4. Fluconazole, fluvoxamine, ticlopidine, Omeprazole (Moderate- Stong Cytochrome P-450 inhibitors) >>> Increase the dose of Clobazam

5. Alcohol >>> increase plasma clobazam levels by approximately 50%

6. Other central nervous system depressant drugs

7. Lithium: Mutually potentiating effect

8. Narcotic Analgesics: Possible euphoria may be enhanced

9. Muscle relaxants and nitrous oxide >>> The effects may be enhanced

Adverse Effects

Most common:

  1. Drowsiness
  2. Dizziness
  3. Fatigue

 


Less Common:

  1. Blood and lymphatic system disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
  2. Eye disorders: Double vision, nystagmus
  3. Gastrointestinal disorders: Dry mouth, constipation, loss of appetite, nausea, weight gain, increased appetite, vomiting, abdominal distention
  4. General disorders and administration site conditions: Unsteadiness of gait and other motor functions, fatigue, sedation leading to tiredness and sleepiness, especially at the beginning of treatment and when higher doses are used, slowing of reaction time, drowsiness, slow or indistinct speech, irritability, hypothermia
  5. Immune system disorders: Hypersensitivity
  6. Investigations: Hepatic enzyme increased
  7. Infections and infestations: Pneumonia
  8. Musculoskeletal and connective tissue disorders: Muscle weakness, frequent muscle spasms
  9. Nervous system disorders: Altered state of consciousness, anterograde amnesia, somnolence, lethargy hyporesponsive to stimuli, disorientation, confusion, headaches, tremor, fine tremor of the fingers, dysarthria, psychomotor hyperactivity
  10. Renal and urinary disorders: Urinary retention
  11. Psychiatric disorders: Suicidal behaviour and ideation, psychotic reactions, hallucination, delusion, acute agitational states, anxiety, emotional disorder, flat affect, aggressiveness, anger, fits of rage, restlessness, difficulty falling asleep or sleeping through, insomnia, nightmare, loss of libido
  12. Serious skin reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
  13. Respiratory, thoracic and mediastinal disorders: Respiratory distress, respiratory depression, aspiration pneumonia, cough

Contraindications

  1. Known hypersensitivity to Clobazam or to any ingredient in the formulation.
  2. Myasthenia gravis (risk of aggravation of muscle weakness)
  3. Narrow angle glaucoma
  4. Any history of drug or alcohol dependence (increased risk of development of dependence)
  5. Severe respiratory insufficiency
  6. Sleep apnoea syndrome (risk of deterioration)
  7. Severe impairment of liver function (risk of precipitating Hepatic encephalopathy)

Pregnancy and Breastfeeding

Pregnancy: Category C

Lactation: Not recommended in nursing mother.

Precautions

1. The efficacy of FRISIUM in adults aged 65 and over has not been established >>> Use with caution!


2. FRISIUM is contraindicated in patients with Myasthenia Gravis. In patients with pre-existing muscle weakness or with spinal or cerebellar ataxia, special observation is required and a dose reduction may be necessary.


3. Additive effects are to be expected if FRISIUM (Clobazam) is combined with alcohol or drugs with central nervous system depressant effects. >>> Concomitant consumption of alcohol can increase the serum levels of FRISIUM by 50%. >>> Recommend not drinking alcohol while taking Clobazam!


4. Avoid driving or working with dangerous operating machineries while taking Clobazam due to sedative effect.


5. Physical and psychological dependence are known to occur in persons taking benzodiazepines. FRISIUM should not be administered to individuals prone to drug abuse.

 

  • In case of physical dependence, do not do abrupt discontinuation! >>> May lead to withdrawal symtoms >>> include headaches, insomnia, sleep disturbances, increased dreaming, restlessness, tension, mental impairment, confusion, extreme anxiety, excitability, irritability, nervousness, agitation, derealization, depersonalization, hallucinations and symptomatic psychoses (e.g. withdrawal delirium), numbness and tingling sensations in the extremities, muscle pain, tremors, sweating, diarrhea, abdominal cramps, vomiting, nausea, hyperacusis, hypersensitivity to light, noise and physical contact, convulsions, as well as epileptic seizures.

6. Caution for rebound phenomenon: The rebound phenomenon is characterized by a recurrence in enhanced form of the symptoms, which originally led to FRISIUM treatment (i.e. seizures). This may be accompanied by other reactions including mood changes, anxiety, or sleep disturbances and restlessness.


7. Clobazam is contraindicated in biliary, hepatic and pancreatic dysfunction >>> Do low initial doses and gradual dose increments under careful observation!


8. Monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants.


9. Caution for Suicidal Ideation and Behaviour in use of Clobazam! >>> Do a close observation in patient with major depressive disorder.


10. Clobazam or its active metabolite, N-desmethylclobazam, is dialyzable. In long-term treatment, renal function must be checked regularly.


11. FRISIUM can cause respiratory depression >>> caution inpatients with bronchial asthma/ Chronic obstructive pulmonary disorder/ brain damage.


12. Caution for Serious skin reactions >>> Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) >>> closely monitor the patients!


13. Attention: If Clobazam is administered for repeated cycles of therapy, periodic blood counts and liver, renal and thyroid function tests are advisable. (CBC, BUN, Cr, NA K, LFT, TSH)


14. Lithium: Mutually potentiating effect >>> Special precaution is necessary


15. Narcotic Analgesics: Possible euphoria may be enhanced >>> Special precaution is necessary


16. Muscle relaxants and nitrous oxide >>> The effects may be enhanced >>> Special precaution is necessary


17. Overdosage:

 Symptoms:

  • Sedation, somnolence, confusion, impaired, coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest.

Treatment:

  • Continuous monitoring of vital signs including EKG immediately.
  • Immediate attention should be given to the maintenance of an adequate airway and support of ventilation.
  • Cardiopulmonary resuscitation may be required
  • Flumazenil (Benzodiazepine antagonist –Specific antidote) >>> 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr (contact your regional Poison Control Centre for more information)

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Flurazepam Hydrochloride – FLURAZEPAM®

Brand name

  • FLURAZEPAM®

Drug Class

  • Benzodiazepine

Preparations

  • Flurazepam Hydrochloride Capsules USP 15 mg and 30 mg

Indications

  • Sleep disturbance:
    • Symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.
    • Treatment should usually not exceed 7-10 consecutive days.

Pharmacology

Pharmacodynamics:

  • Mechanism of action: Long acting benzodiazepine that depresses all level of CNS (e.g. limbic and reticular formation) by increasing activity of GABA.

Metabolism

Pharmacokinetics: 

  • Metabolism: Flurazepam undergoes rapid and pronounced metabolism to two pharmacologically active metabolites via glucuronic acid conjugation
  • Excretion: mainly urine
  • Half-life elimination: 48-120 hours
  • Peak plasma time:5-3 hours
  • Peak plasma concentration: 0.5-4 ng/ml

Dosing

  • Treatment should be as short as possible, and should not exceed 7-10 consecutive days.
  • Dosage should be individualized for maximal beneficial effects.
  • Adults:
    • Usual adult dosage: 30 mg before retiring
  • Elderly and/or Debilitated Patients:
    • Initial recommended dosage: 15 mg

Drug Interactions

1. Produce additive CNS depressant effects when co-administered with:

  • Alcohol,
  • Sedative Antihistamines,
  • Narcotic Analgesics,
  • Anticonvulsants,
  • Psychotropic Medications.

2. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) enhance the activity of Flurazepam:

  • Cimetidine
  • Erythromycin

Adverse Effects

  • Most Common:
    • Dizziness, drowsiness, lightheadedness, and ataxia.
  • Less Common:
    • headache, heartburn, upset stomach, nausea, vomiting, amnesia, constipation, diarrhea, gastrointestinal pain, nervousness, apprehension, irritability, weakness, palpitations, chest pains, genitourinary complaints
  • Rare symptoms:
    • leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations, nightmares, numbed emotions, reduced alertness, changes in libido, inappropriate behavior and elevated SGOT, SGPT, total and direct bilirubin, and alkaline phosphatase, Paradoxical reactions such as excitement, stimulation, agitation, aggressiveness, rages, psychoses and hyperactivity.

Contraindications

  1. Hypersensitivity to benzodiazepines or any component of its formulation
  2. Severe impairment of respiratory function (sleep apnea syndrome)
  3. Myasthenia gravis
  4. Severe hepatic insufficiency

Pregnancy and Breastfeeding

  • Pregnancy: category C
  • Lactation: not recommended in nursing mothers.

Precautions

  1. Concomitant use with alcohol: should be used with extreme caution in patients with a history of alcohol abuse.
  2. Elderly:
    1. Inappropriate and heavy sedation in the elderly, may result in accidental events/falls >>> the smallest possible effective dose should be prescribed.
    2. The lowest possible dose (15 mg) should be used in these subjects.
  3. Failure of insomnia remission after 7-10 days: indicate the presence of a primary psychiatric and/or medical illness or the presence of sleep- state misperception.
  4. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior: may be the consequence of an unrecognized psychiatric or physical disorder.
  5. Caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.
  6. Anterograde amnesia:
    1. in the most common type of memory problem in patients using flurazepam,
    2. dose-related phenomenon,
    3. elderly are high risk group
  7. Transient global amnesia and “traveler’s amnesia”:
    1. Especially in individuals who have taken benzodiazepines, often in the middle of the night, to induce sleep while travelling.
    2. Unpredictable
    3. Not necessarily dose-related phenomena.
  8. Abnormal thinking and psychotic behavioral changes:
    1. Changes characterized by decreased inhibition, e.g., aggressiveness or extroversion
    2. Particular caution in patients with a history of violent behavior and unusual reactions to sedatives including alcohol and the benzodiazepines.
    3. Psychotic behavioral changes include: bizarre behavior, hallucinations, and depersonalization.
  9. Confusion:
    1. The benzodiazepines affect mental efficiency (e.g., concentration, attention and vigilance.)
    2. The risk of confusion is in greater in: elderly, patients with cerebral impairment.
  10. Anxiety & Restlessness: especially daytime anxiety and/or restlessness
  11. Depression: Caution in patients with signs or symptoms of depression because:
    1. Flurazepam could intensify the disease,
    2. There is a potential risk for self-harm (e.g., intentional overdose)
  12. Complex Sleep-related Behaviors:
    1. Complex sleep-related behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken flurazepam hydrochloride. Other potentially dangerous behaviors have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events.
  13. Usage of alcohol and other CNS-depressants with flurazepam:
    1. Flurazepam should not to be taken with alcohol.
    2. Caution is needed with concomitant use of other CNS depressant drugs.
  14. Severe Anaphylactic and Anaphylactoid Reactions:
    1. A severe and rare side effect involving the tongue, glottis or larynx
    2. Additional symptoms include dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis.
    3. If angioedema involves the throat, glottis or larynx >>> airway obstruction may occur and be fatal >>> Patients with history of angioedema after treatment should not be re-challenged with the drug.
  15. Flurazepam additive CNS depressant effect:
    1. When co-administered with alcohol, sedative antihistamines, narcotic analgesics, anticonvulsants, or psychotropic medications.
  16. Concomitant use with compounds which inhibit certain hepatic enzymes:
    1. Enhance the activity of benzodiazepines (e.g. Cimetidine or erythromycin)
  17. Drug Abuse Dependence and Withdrawal:
    1. Withdrawal symptoms: convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia
    2. Gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks.
    3. The recommendation for tapering is particularly important in patients with a history of seizures.
    4. The risk of dependence increased in: patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders.
  18. Influence on sleep:
    1. Flurazepam decreases sleep latency and number of awakenings for a consequent increase in total sleep time.
  19. Rebound Insomnia:
    1. A transient syndrome whereby the symptoms that led to treatment with a benzodiazepines recur in an enhanced form, may occur on withdrawal of hypnotic treatment.
  20. Caution in patients with Specific Conditions:
    1. Impaired hepatic and renal function
    2. Compromised respiratory function.
  21. Caution in patients Requiring Mental Alertness:
    1. Because of Flurazepam’s (flurazepam hydrochloride) CNS depressant effect, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
  22. Use in Children: should not be used in children below the age of 15
  23. Laboratory Tests in the case of repeated usage:
    1. periodic blood counts,
    2. liver, and kidney function tests
  24. Overdosage:
    1. Manifestations overdosage include: somnolence, confusion and coma.
    2. Treatment is supportive.
    3. The benzodiazepine antagonist: flumazenil (‘Anexate’), is a specific antidote.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Midazolam, VERSED®

Brand name

  • VERSED®

Drug Class

  • Benzodiazepines (Premedicant-Sedative-Anesthetic Agent )

Preparations

Midazolam Injection: 5 mg/mL, 15 mg/3 mL, 5 mg/5mL, 50 mg/10 mL.

Indications

Adults:

1. As intramuscular premedication prior to surgical or diagnostic procedures.

2. As an intravenous agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or short diagnostic procedures and direct-current cardioversion.

3. As an alternative intravenous agent for the induction of anesthesia.

4. Continuous intravenous infusion in intubated, mechanically ventilated patients requiring sedation in the Intensive Care Unit (ICU)


Pediatrics:

1. As intramuscular premedication prior to surgical or diagnostic procedures.

2. As an intravenous agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or short diagnostic procedures and direct-current cardioversion.

3. As an alternative intravenous agent for the induction of anesthesia.

4. Continuous intravenous infusion in intubated, mechanically ventilated patients requiring sedation in the Intensive Care Unit (ICU)

Pharmacology

  • Mechanism of action: Enhances GABAergi (gamma-Aminobutyric acid) inhibition, Midazolam decreases the cyclic GMP level in the cerebellum.

Metabolism

  • Absorption: Intramuscular, Intravenous. Onset of sedative effect: about 15 minutes. Peak sedation occurring: 30-60 minutes following injection. Peak plasma concentration >>> 90 ng/ML (intramuscular)
  • Metabolism: predominantly mediated by cytochrome P-450 3A4 (CYP3A4) isozyme in liver.
  • Distribution: 97% binds to plasma proteins
  • Excretion:Half life: 2-6 hours, 90% Urine, 10% Feces

Dosing

Midazolam is compatible with:

  1. 5% Dextrose Injection and
  2. 9% Sodium Chloride Injection.
  3. Both the 1 mg/mL and 5 mg/mL formulations may be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

Recommended Adult Dosage:

1. Intramuscular Premedication for preoperative sedation and to impair memory of perioperative events >>> 0.07 to 0.08 mg/kg IM administered 30 to 60 minutes preoperatively >>> Decrease the dose of Midazolam in concomitant use with Opioids.


2. Intravenous Sedation:

For short endoscopic or short diagnostic procedures and direct current cardioversion >>> Injection 1 mg/mL IV slowly injection! (When used for intravenous sedation, midazolam should not be administered by rapid or single bolus intravenous administration>>> Midazolam can be used alone or concomitantly with opioids!

Patients <55 y/o:

Initial dose: No more than 2 to 2.5 mg

Max dose: 5 mg (Do not exceed 0.1 mg/kg)

 

 

Patients >=55y/o:

Initial dose: No more than 1 to 1.5 mg

Max dose: 3.5 mg (Do not exceed 0.07 mg/kg

 

 

Dosage for Intravenous Induction:

A: Unpremedicated Patients:

Patient < 55 y/o:

Initial dose: 0.3-0.35 mg/kg

Increments: If needed to complete induction, increments of approximately 25%of the initial dose may be used.

 

 

 

Patient >= 55y/o:

Initial dose: 0.3 mg/kg

Increments: If needed to complete induction, increments of approximately 25%of the initial dose may be used.

 

 

Patient with severe systemic disease or debilitation:

Initial dose: 0.2-0.25 mg/kg (In some casesas little as 0.15mg/kg will suffice)

Increments: The need forincrement doses tocomplete inductionmust be evaluated bythe anesthesiologist

 

 

 

B: Premedicated Patients: (Opioids or CNS Depressants)

Patients < 55 y/o:

Initial dose: 0.15-0.35 mg/kg /0.25 mg/kg will usually suffice

Increments: If needed to complete induction, increments of approximately 25% Of the initial dose may be used.

 

 

Patients >=55 y/o:

Initial dose: 0.2 mg/kg

Increment dose: If needed to complete induction, increments of approximately 25% of the initial dose may be used.

 

 

Patient with severe systemic disease or debilitation:

Initial dose: 0.15-0,2 mg/kg in some cases as little as 0.15 mg/kg will suffice

Increments: The need for increment doses to complete induction must be evaluated by the

anesthesiologist

(Method of Administration doses are administered over 20 to 30 seconds, allowing 2 minutes for effect)


3.  ICU Sedation: For initiation and maintenance of ICU sedation in intubated, mechanically ventilated patients

 


4. Recommended Pediatric Dosage:

Generally require higher doses of midazolam than do adults.

In obese individuals, the dose should be calculated based on ideal body weight.

 

 

Intramuscularly

Usual Pediatric Dose >>> 0.1-0.15 mg/kg

For more anxious pediatric patients >>> doses up to 0.5 mg/kg

 

 

Intravenously by Intermittent Injection

Usual Pediatric Dose:

6 months-5 years => Initial dose: 0.015-0.1 mg/kg / Total dose: 0.6 mg/kg

6-12 years => Initial dose: 0.025-0.05 mg/kg / Total dose: 0.4 mg/kg

12-17 years => Initial dose and Total dose => As adults

Attention: The initial dose should be administered over 2-3 minutes, wait for an additional 2-3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments, until the appropriate level of sedation is achieved.

 

 

Continuous Intravenous Infusion (For Sedation in Critical Care Settings)

Usual Pediatric Dose:

Initial dose: => 0.05 to 0.2 mg/kg over at least2 to 3 minutes

Continuous intravenous infusion dose: 0.001-0.002 mg/kg/min (1-2 mcg/kg/min).

Neonates: Midazolam Intravenous loading doses should not be used in neonates (Preterm and term) => continuous intravenous infusion of Midazolam Injection should be initiated at a rate of 0.0005-0.001 mg/kg/min (0.5-1 mcg/kg/min).

Drug Interactions

1. Enzyme inhibitor medications >>> Concomitant use of Midazolam with these medications will increase the plasma dose level of Midazolam:

 

  • Itraconazol: In case of administering with high dose Midazolam
  • Fluconazol: In case of administering with high dose Midazolam
  • Erythromycin
  • Saquinavir

2. Enzyme inducer medication: Concomitant use of Midazolam with these medications will increase the plasma dose level of Midazolam:

  • Sodium Valporate: May increase the need for Midazolam. Adjust the dose in epileptic patients.

Adverse Effects

More than 10%:

  • Decreased respiratory rate >>> more than 20%
  • Apnea

Less than 10%:

  • Drowsiness
  • Excessive Sedation
  • Dizziness
  • Hallucination
  • Emesis/Vomiting

Less than 1%:

  • Cardiovascular: Premature ventricular contractions, bigeminy, vasovagal episode, bradycardia, tachycardia, and nodal rhythm.
  • Respiratory: Laryngospasm, bronchospasm, dyspnea, shallow respiration, hyperventilation and wheezing.
  • CNS/Neuromuscular: Nervousness, restlessness, anxiety, argumentativeness, aggression, insomnia, nightmares; deep sedation, prolonged sedation, oversedation, disorientation, slurred speech, emergence delirium, agitation during emergence, prolonged emergence from anesthesia, dreaming during emergence; dysphoria, euphoria, anterograde amnesia, lightheadedness, feeling faint; tremors, muscle contractions, twitches and abnormal spontaneous muscular activity, tonic/clonic movements, athetoid movements; ataxia.
  • Gastrointestinal: Acid taste, excessive salivation and retching.
  • Special Senses: Blurred vision, diplopia, nystagmus, visual disturbance, difficulty focusing eyes, pinpoint pupils, cyclic movement of eyelids, ears blocked and loss of balance.
  • Dermatological: Erythema, rash, pruritus and hives.

Hypersensitivity: Allergic reactions, including anaphylactic shock.

Contraindications

  • Known hypersensitivity to benzodiazepines
  • Acute pulmonary insufficiency
  • Severe chronic obstructive pulmonary disease (COPD)
  • Acute narrow angle glaucoma
  • Some medications: Boceprevir, Cobicistat, Itraconazol, Nelfinavir, Ritonavir, Paritaprevir, Ombitasvir, Sodium oxybate, Telaprevir.

Pregnancy and Breastfeeding

Pregnancy: Category D

Lactation: Not recommended in nursing mother

Precautions

1.  Midazolam Injection must never be used without individualization of dose. The immediate availability of oxygen and other appropriate medication, and the equipment necessary for resuscitation, the maintenance of a patent airway, support of ventilation and cardiac function, should be ensured prior to the use of intravenous midazolam in any dose.


2. Continuously monitor patients for early signs of hypoventilation or apnea >>> Caution for hypoxia/cardiac arrest. Vital signs should continue to be monitored during the recovery period. Opioid agonists and other sedatives add to the respiratory depression produced by midazolam.


3. Caution: Midazolam should only be administered intramuscularly or


4. Concomitant use of barbiturates, alcohol, opioids or other CNS depressants increases the risk of apnea and may contribute to excessive and/or prolonged drug effect.


5. Midazolam should not be given with an opioid as an intramuscular combination for premedication due to the risk of apnea >>> If opioid premedication is given, Decrease the subsequent dose of midazolam.


6. Patients MUST NOT engage in hazardous activities requiring complete mental alertness >>> operating machinery / driving a motor vehicle


7. During bronchoscopies, in patients with high Co2 retention, use of opioid premedication is recommended.


8. Physical and psychological dependence may occur during benzodiazepine treatment >>> Especially in patients with long-term/ High dose treatment >>> alcoholism, drug abuse or marked psychiatric disorders.

 

  • Withdrawal: symptoms may occur from a few hours to over a week after discontinuing treatment >>> tremor, restlessness, insomnia, anxiety, headache and inability to concentrate to sweating, muscular/abdominal spasms and perceptual changes. Do not do abrupt dose reduction! Do it gradually.

9. Geriatrics and debilitated patients: Decrease Midazolam dose


10. Pediatrics: pediatric patients generally require higher doses of midazolam than adults


11. When given immediately before Cæsarean section, midazolam can cause depression of the infant.


12. Extremely caution in patients with: congestive heart failure, chronic renal failure, severe alcoholic cirrhosis >>> exhibit changes in Midazolam elimination half-life.


13. hypnotic effect of intravenous midazolam and the risk of apnea is accentuated by premedication, particularly opioids (e.g. morphine, meperidine and fentanyl), secobarbital, and the droperidol-fentanyl

14. Single bolus intravenous administration >>> When used for intravenous sedation, midazolam should not be administered by rapid or single bolus intravenous administration.


15. Decrease the dose of Midazolam in concomitant use with Opioids.


16. The onset of effect of midazolam is rapid and its duration of action short.


17. Overdosage:

Symptoms:

  • Sedation, somnolence, confusion, impaired, coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest.

Treatment:

  • Continuous monitoring of vital signs including EKG immediately.
  • Immediate attention should be given to the maintenance of an adequate airway and support of ventilation.
  • Cardiopulmonary resuscitation may be required
  • Flumazenil (Benzodiazepine antagonist –Specific antidote) >>> 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr (contact your regional Poison Control Centre for more information)

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Protriptyline, Vivactil®

Brand name

  • Vivactil®

Drug Class

  • Tricyclic Anti-depressant (TCA)

Preparations

  • Tablets: 5 mg and 10 mg

Indications

  • Major Depressive Disorders (MDDs)
  • Migraine
  • Neuropathic pain
  • Obesity (to lose weight)

Pharmacology

Mechanism of action & Pharmacodynamics:

  • It is effect in the case of depression by decreasing the reuptake of norepinephrine and serotonin in the central nervous system.
  • Slow therapeutic effects with significant effects after 14 days imitation.

 

Metabolism

Pharmacokinetics:

  • Absorption: gastrointestinal tract
  • Distribution: penetrates the brain rapidly
  • Metabolism: hepatic (Metabolized by Cytochrome P450 2D6)with 8-12 hours peak plasma time and 55-92 hours half-life
  • Excretion: urine

Dosing

1. Adults:

  • Initial: start at low dose 15 to 40 mg/day divided q6-8hr
  • Maximum dose: 60 mg/day

2. Adolescent and Elderly Patients:

  • Initial: 15 mg/day divided into 3 doses

Drug Interactions

  1. Cimetadine
  2. Antidepressants: MAOI, SSRI, and TCA
  3. Alcohol
  4. Ephedrine or pseudoephedrine
  5. Cisapride
  6. Tramadol
  7. Quinidine
  8. Phenothiazines
  9. Propafenone
  10. Flecainide

Adverse Effects

1%- 10% :

  1. Nausea
  2. Vomiting
  3. Fatigue
  4. Headache
  5. Agitation
  6. Lethargy
  7. Anxiety
  8. Dry mouth
  9. Insomnia
  10. Muscle rigidity
  11. Disturbed concentration

Less than 1% :

  1. Cardiovascular: Myocardial infarction , stroke, hypotension
  2. Psychiatric: anxiety, restlessness, agitation, disorientation, delusions
  3. Neurological: Seizures, incoordination, ataxia, tremors, peripheral neuropathy
  4. Anticholinergic: Paralytic ileus, hyperpyrexia, urinary retention, delayed micturition
  5. Allergic: Drug fever, petechiae, skin rash, urticaria, itching
  6. Hematologic: Agranulocytosis, bone marrow depression, leukopenia
  7. Endocrine: Impotence, increased or decreased libido, gynecomastia in the male; breast enlargement and galactorrhea in the female
  • Manifestation of protriptyline toxicity: cardiac arrhythmias, significant hypotension, seizures, and coma. Changes in the electrocardiogram, particularly in QRS axis or width.

Contraindications

  1. Hypersensitivity to this drug
  2. Avoid prescribe with monoamine oxidase inhibitors(risk of hyperpyretic crises, severe convulsions, and death)
  3. In the setting of substitute protripyline for monoamine oxidase inhibitors (MAOi), it should be a period of 14 days after discontinuation MAOi to initiate this drug.
  4. Severe cardiovascular disorders: It is contraindicated to prescribe protriptyline in patient who is consuming cisaprideà QT prolongation, cardiac arrhythmias, and conduction system disturbances.
  5. Narrow angle glaucoma

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Excretes in milk => Not Recommended in nursing women

Precautions

1. If it is prescribed to treat the depressive component of schizophrenia, psychotic symptoms may be seen.


2. Paranoid delusions with or without hostility may be aggravated.


3. In agitated or overactive cases anxiety or agitation are possible.


4. The probability of suicide in depressed cases exists until dramatic remission.


5. Be cautious in administration of protriptyline and electro-convulsive shock therapy (ECT) simultaneously.


6. Discontinue this medication several days before surgery If possible.


7. Chance of lowering and elevation of blood sugar


8. Risk of manic episodes in bipolar disorders


9. Not recommended in pediatrics < 18 y/o.


10. Use with caution in elderlies! >>> Monitor cardiovascular system if dose goes beyond 20 mg/day >>> When relief of symptoms are observed, reduce to lowest dosage in which no symptoms return

Important Notice

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

References:

  1. http://www.fda.gov/downloads/drugs/drugsafety/ucm089820.pdf

Oxazepam, SERAX®

Brand name

  • SERAX®

Drug Class

Benzodiazepines

Preparations

  • Capsule 10, 20 and 30 mg

Indications

1. Alcohol withdrawal syndrome


2. Anxiety disorders (Social phobia, Post-traumatic stress disorder, Premenstrual syndrome, Insomnia Acute Panic Attack)

Pharmacology

  • The exact mechanism of action of benzodiazepines has not yet been elucidated.
  • Mechanism of action: May has effect on Gamma-Aminobutyric acid (GABA) >>> Increases the inhibitory effect of GABA (Increases the permeability of neuron membrane to Chloride ions) >>> Stabilization of neuronal membrane.

Metabolism

  • Distribution: Peak plasma time >>> 2.8- 5.7 hours. Peak plasma concentration >>> 3 hours
  • Metabolism: Glucoronic acid conjugation. No active metabolite. The cytochrome P450 system has not been shown to be involved in the disposition of oxazepam and, unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with Oxazepam
  • Absorption: 95-98% binds with plasma proteins
  • Excretion: Urine

Dosing

1. Mild to moderate anxiety:

  • 5-15 mg, 3 or 4 times daily

2. Severe anxiety agitation or anxiety associated with depression:

  • 15-30 mg, 3 or 4 times daily

3. Elderly patients with anxiety, tension, irritability and agitation:

  • Initial dose is 7.5 mg, 2-3 times daily.
  • Increase cautiously to 15 mg, 3 or 4 times daily.

4. Alcoholics with tremulousness or anxiety on withdrawal:

  • Dose is 15-30 mg, 3 or 4 times daily
  • Oxazepam should not be administered to alcoholics with acute inebriation.

Drug Interactions

  1. Barbiturates
  2. Alcohol
  3. Sedatives
  4. Tricyclic antidepressants
  5. Non selective MAO inhibitors
  6. Phenothiazine and other antipsychotics
  7. Skeletal muscle relaxants
  8. Antihistamines
  9. Narcotic analgesics
  10. Anaesthetics
  11. Anticonvulsants

Adverse Effects

1. More common:

  • Mild drowsiness

2. Less common:

  • Transient Amnesia Or Memory Impairment
  • Oedema
  • Hypotension
  • Skin Rashes (Morbilliform, Urticarial And Maculopapular)
  • Nausea
  • Hepatic Dysfunction, And Abdominal Pain
  • Hypersensitivity
  • Lethargy
  • Altered Libido
  • Slurred Speech
  • Blurred Vision
  • Disorientation
  • Fever
  • Leucopenia
  • Tremor
  • Paraesthesia
  • Dizziness
  • Vertigo
  • Headache
  • Syncope
  • Ataxia,
  • Confusion
  • Hallucination
  • Aggression
  • Unpleasant dreams
  • Paradoxical Reactions

Contraindications

1. Known hypersensitivity to benzodiazepines


2. Chronic obstructive airways disease with incipient respiratory failure


3. Sleep apnea

Pregnancy and Breastfeeding

Pregnancy: Category C


Lactation: Avoid using in nursing mother

Precautions

1. The pharmacokinetics of Oxazepam remain unaltered in older patients, however the elderly generally show increased central nervous system sensitivity to benzodiazepines, >>> may require a reduced dosage.


2. Pediatric: Not recommended in children less than 16 years of age.


3. Caution in patients with Hepatic diseases! >>> May require a reduced dosage.


4. Caution in patients with renal dysfunction! >>> May require a reduced dosage.


5. Caution in concomitant use with CNS-depressant medications! May cause synergistic effect >>> may increase sedation!


6. Avoid driving while taking Oxazepam!


7. Avoid using dangerous machinery vehicles while taking Oxazepam!


8. Impaired Respiratory Function: Caution in the use of Oxazepam is recommended in-patients with respiratory depression. In-patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.


9. In general, benzodiazepines should be prescribed for short periods only (e.g. 2-4 weeks). Continuous long-term use of Oxazepam is not recommended.


10. Following the prolonged use of Oxazepam at therapeutic dose, withdrawal from the medication should be gradual >>> an individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected. (Periods from four weeks to four months) >>> abrupt withdrawal of benzodiazepines in-patients with convulsive disorders.


11. Abuse: Caution in administering Oxazepam to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative.


12. Dependence: The use of benzodiazepines may lead to dependence as defined by the presence of a withdrawal syndrome on discontinuation of the drug.


13. Tolerance: As defined by a need to increase the dose in order to achieve the same therapeutic effect seldom occurs in-patients receiving recommended doses under medical supervision >>> Caution for Tolerance to sedation may occur with benzodiazepines especially in those with drug seeking behaviour.


14. Caution for hypotension after taking Oxazepam >>> especially in elderlies!


15. Caution in patients with Myasthenia Gravis >>> could increase the muscle weakness


16. Caution should be used in the treatment of patients with narrow-angle glaucoma >>> because of atropine-like side effects.


17. Oxazepam may cause Blood Dyscrasias >>> Do periodic Complete Blood Test.


18. Oxazepam is not recommended as primary therapy in-patients with depression and psychosis >>> psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Caution for Suicidal tendencies may be present.


19. Paradoxical reactions such as acute rage, stimulation or excitement may occur; should such reactions occur, Oxazepam should be discontinued >>> Rebound phenomena.


20. Caution: Oxazepam may have Interference With Clinical, Laboratory And Other Tests:

  • Oxazepam may decrease values of leukocytes in testing for leukopoiesis.
  • Oxazepam may give high blood glucose level utilising the Somogyi procedure but not the glucose oxidase procedure.

21. Over-dosage:

  • Clinical manifestations has wide ranges, from drowsiness to coma

22. Treatment:

  • Activated charcoal should be given to reduce absorption.
  • Do supportive treatments for any possible respiratory depression or hypotension
  • Flumazenil (Benzodiazepine antagonist –Specific antidote) 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Clomipramine Hydrochloride , ANAFRANIL®

Brand name

  • ANAFRANIL®

Drug Class

1. Tricyclic anti-depressant

2. Anti-Obsessional

Preparations

  • Tablets 10 mg, 25 mg and 50 mg

Indications

  • Obsessive Compulsive Disorder
  • Major Depressive Disorder

Pharmacology

  • Inhibits norepinephrine and serotonin uptake into central nerve terminals >>> blocking the membrane-pump of neurons
  • Weak antihistamine
  • Potentiates the effect of norepinephrine and other drugs acting on the central nervous system

Metabolism

  • Absorption: Completely orally >>> Peak plasma levels >>> 2 hours >>> Plasma half-life ~ 21 hours.
  • Distribution: binding to serum proteins is very high -96 to 97%-
  • Metabolism: Hydroxylation, Demethylation and N-oxidation.
  • Excretion: 2/3 Urine, 1/3 Feces.

Dosing

1. Depression:

Adults:

  • Initial Dosage: 25mg/day >>> 150 mg by the end of two weeks (Gradual increase) >>> over a period of several weeks to 200 mg (Gradual Increase)
  • Maintenance dose: lowest effective level
  • Max Dose: 300 mg/day

 

Elderly And Debilitated Patients:

  • Initial Dosage: 20 to 30 mg daily (Divided suggested) >>> very gradual increments, depending on tolerance and response
  • Maintenance dose: lowest effective level

2. Obsessive Compulsive Disorders:

Adults:

  • Initial Dosage: 25 mg/day >>> 100 or 150 mg by the end of 2 weeks (Gradual Increase) >>> over a period of several weeks to 200 mg (Gradual Increase)
  • Maintenance dose: lowest effective level
  • Max Dose: 250 mg/day

Children And Adolescents:

  • Aged 10 to 17 years>>> Initial Dose: 25 mg per day >>> Increase within 3 to 4 day intervals >>> in 2 weeks, titrate up to 100-150 mg per day or 3 mg/kg
  • Maintenance dose: Lowest effective dose
  • Max Dose: 200 mg/day

Elderly And Debilitated Patients:

  • Initial Dose: 20-30 mg/day >>> very gradual increments, depending on tolerance and response
  • Maintenance dose: Lowest effective dose

Drug Interactions

1. Major Depressive Disorder: (MDD)

2. Obsessive Compulsive Disorder: (OCD)

3. Alcoholic beverages

4. CNS depressants, eg:

  • Barbiturates
  • Benzodiazepines
  • General anaesthetics

5. Guanethidine

6. Bethanidine

7. Clonidine

8. Reserpine

9. Alpha-methyldopa

10. Isoprinosine

11. Ephedrine

12. Phenylephrine

13. Noradrenaline

14. Adrenaline

15. Amphetamine (methylphenidate)

16. Selective serotonin reuptake inhibitors (SSRIs)

17. Enzyme inhibitor medications such as: Cimetidine

18. Enzyme inducer Medications: Barbiturates, Carbamazepine, Phenytoin, Nicotine & Oral contraceptives.

19. Neuroleptic agents: (e.g., phenothiazines and butyrophenones, thioridazine )

20. Alprazolam

21. Disulfiram

Adverse Effects

Frequent: (> 10 %)

  • Mild sedation
  • Mania
  • Somnolence
  • Tremor
  • Sexual Dysfunction: (Libido change, Impotence, Ejaculation Failure)
  • Urinary Retention
  • Blurred Vision
  • Dyspepsia
  • Dry Mouth, Nausea, Vomiting, Constipation

< 10%:

  • Orthostatic Hypotension
  • Suicidal thoughts/ Ideation
  • Myocardial Infarction
  • Thrombocytopenia & Agranulocytosis: (Bone Marrow Failure)

Contraindications

  • Hypersensitivity to medication.
  • Monoamine oxidase inhibitor (MAOIs).
  • Acute recovery phase following myocardial infarction.
  • Acute congestive heart failure.
  • Liver or kidney
  • Blood dyscrasias.
  • Narrow angle Glaucoma
  • Paralytic ileus
  • Pheochromocytoma
  • Neuroblastoma

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Do not use in nursing mother

Precautions

1. Mild sedative effect >>> Alleviating the anxiety accompanying depression >>> difficulty in concentrating and thinking >>> Avoid Driving! Using complex machineries, swimming, climbing.


2. Persistent increase in the frequency of shifts into stage I sleep >>> produces marked reduction or suppression of rapid eye movement sleep


3. Elderly patients require lower doses of ANAFRANIL.


4. Practically concentration-independent within the therapeutic range. (Low Therapeutic index)


5. Should not be given in conjunction with monoamine oxidase inhibitor >>> Caution for Serotonin Syndrome: Hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions / coma / death >>> Wait for least 14 days!


6. Anti- Cholinergic effects : Do not use in Glaucoma & urinary retention (prostatic hypertrophy) >>> aggravated condition >>> atropine-like effects.


7. Seizures: extreme caution in patients with a history of convulsive disorders/ predisposing factors: brain damage, alcoholism, drugs lower the seizure threshold.


8. Cardiovascular: particularly in high doses, sinus tachycardia, changes in conduction time (AV block 1-2-3) + arrhythmias (premature ventricular contractions, ST-T wave changes = Most common) >>> Use with caution!

  •  Check the patient’s blood pressure before stating Clomipramine
  • Do regular ECGs & Blood pressure. (Postural Hypotension > Diminish the dose)
  • QTc prolongation & Torsades de points at supra-therapeutic doses
  • Hyperthyroid patients/ patients receiving thyroid medication: Transient cardiac arrhythmias.
  • Caution in concomitant use with: Guanethidine, Bethanidine, Clonidine, Reserpine /alpha-methyldopa.
  • Potentiate the cardiovascular effects of noradrenaline / adrenaline, amphetamine, nasal drops & sympathomimetic, local anaestheticsg. >>> Isoprenaline, Ephedrine, Phenylephrine.

9.  Paralytic ileus: Ederly & hospitalized patients >>> Use with caution!


10. Tumors of the adrenal medulla: Pheochromocytoma, Neuroblastoma >>> Use with caution!


11. Suicidal abuse risk: Prescribe ANAFRANIL for the smallest possible quantity of the drug consistent with good patient management.


12. Psychosis, Mania-Hypomania:

Patients treated with TCAs >>> May Occur:

  • Activation of latent schizophrenia/
  • Aggravation of existing psychotic manifestations
  • Over-stimulation of agitated patients
  • In predisposed & elderly patients >>> Provoke delirium. (Especially with night use)

13. Hepatic Changes: elevations in SGOT and SGPT >>> Caution is considered!


14. Hematologic Changes: bone marrow depression with agranulocytosis >>> Use with caution in hematologic disorder patients!


15. Withdrawal Symptoms: Do not do abrupt discontinuation! >>> Taper gradually


16. Metabolic Effects: Tricyclic antidepressants have been associated with porphyrinogenicity in susceptible patients.


17. Renal Function: monitor renal function during long-term therapy (BUN, Cr)


18. Dental Effects: Lengthy treatment >>> increased incidence of dental caries.


19. Decreased lacrimation: may cause damage to the corneal epithelium in patients with contact lenses.


20. Endocrine Effects: ANAFRANIL elevates prolactin levels


21. ANAFRANIL has not been studied in patients under 10 y/o


22. Diuretics: Concomitant use may lead to hypokalemia


23. Co-medication with Selective serotonin reuptake inhibitors (SSRIs) may lead to additive effects on the serotonergic system. >>> Caution!


24. ANAFRANIL should be discontinued prior to elective surgery.


25. Concomitant treatment with neuroleptic agents: (e.g., phenothiazines and butyrophenones) >>> Enzyme inhibitor effect >>> increased plasma concentrations of ANAFRANIL >>> lowered convulsion threshold.


26. Lower the dosage of ANAFRANIL if administered concomitantly with Alprazolam or Disulfiram.


27. Tricyclic antidepressants may potentiate the anticoagulant effect of Coumarin drugs (eg: Warfarin) by inhibiting hepatic metabolism of these drugs. Careful monitoring of Protrombine time + INR.


28. Over-dosage: (General treatment overview):

  • Symptoms: drowsiness, stupor, ataxia, vomiting, cyanosis, restlessness, muscle rigidity, athetoid and choreiform movements, & convulsions, Cardiac Shock, Coma.
  • Admit to hospital without delay > Gastric lavage up to 12 hours> Heart Monitoring > activated charcoal > peritoneal dialysis and hemodialysis.
  • Goal: insure maintenance of the vital functions

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Amoxapine , AMOXAPINE® , ASENDIN®

Brand name

  • Amoxapine®: only generic formulations are available in the US
  • Asendin®: previously marketed in CA, US

Drug Class

  • Tricyclic anti-depressants (TCAs)

Preparations

  • Tablets 25mg/50mg/100mg/150mg

Indications

1- Major Depressive Disorder (MDD)

2- Neurotic or reactive depressive disorders

3- Endogenous depression

4- Depression accompanied by anxiety or agitation

Pharmacology

  • Mechanisem of action: Exact mechanism of action unknown; inhibits norepinephrine and serotonin reuptake

Metabolism

  • Metabolism: liver; CYP450
  • Absorption: almost complete absorption
  • Distribution: Half-life: 8h (amoxapine), 30h (8-hydroxyamoxapine). Plasma peak >>> 90 min. 90% binds to plasma proteins
  • Excretion: urine 60%, feces 18%

Dosing

Depression: (Adult only!)

  • Initial dose: 25 mg every 8 -12 hour >>> gradual increase every 5-7 days to 200-300 mg/day qHS ( incase neede more tham 300mg, divide the doses)
  • Max Outpatient dose: 400mg/day
  • Max Inpatient dose: 600 mg/day divided q12hr

Drug Interactions

  • Monoamine oxidase inhibitors
  • Aripiprazole
  • Amphetamine / Dextroamphetamine
  • Aspirin
  • Lorazepam
  • Calcium 600 D (Calcium / Vitamin D)
  • Duloxetine
  • Fluconazole
  • Cyclobenzaprine
  • Lurasidone
  • Promethazine
  • Lansoprazole
  • Omeprazole
  • Albuterol
  • Fluoxetine
  • Nabumetone
  • Vortioxetine
  • Diazepam
  • Vilazodone
  • Bupropion

Adverse Effects

Very common (>10% incidence) adverse effects:

  • Constipation
  • Dry mouth
  • Sedation

 


Common (1-10% incidence) adverse effects:

  • Anxiety
  • Ataxia
  • Blurred Vision
  • Confusion
  • Dizziness
  • Headache
  • Fatigue
  • Nausea
  • Nervousness
  • Restlessness
  • Rash
  • Tremor
  • Palpitation
  • Nightmares
  • ECG changes
  • Edema
  • Increased sweating
  • Increased Prolactin

Contraindications

1-Known hypersensitivity to Amoxapine or other dibenzoxazepine-derivative like TCAs

2- Monoamine oxidase inhibitors

3- Uncorrected narrow angle glaucoma

4- Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation)

Pregnancy and Breastfeeding

Pregnancy: Category C

Lactation: Not recommended in nursing mothers

Precautions

1. Caution in concomitant use with Monoamine oxidase inhibitors >>> at least 2 weeks should be elapsed.


2. Caution for worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment


3. Caution for Angle-Closure Glaucoma


4. Tardive Dyskinesia: Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity >>> caution especially in elderlies!


5. Caution!! Amoxapine may cause Neuroleptic Malignant Syndrome (NMS) >>> Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity >>> caution especially in elderlies!


6. Safety and effectiveness in the pediatric population have not been established.


7. Caution in patients with hepatic or renal impairment


8. Over-dosage Signs and Symptoms: Amoxapine overdosage differ significantly from those of other tricyclic antidepressants:

  • Serious cardiovascular effects are seldom if ever observed. However, CNS effects – particularly grand mal convulsions – occur frequently, and treatment should be directed primarily toward prevention or control of seizures.
  • No universal antidote, >>> Do symptomatic and supportive treatment

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Chlordiazepoxide Hydrochloride – Librax® – Libriumv® – Limbitrol®

Brand name

  • Librax®, Librium®, Limbitrol®

Drug Class

  • Benzodiazepines
  • Anxiolytic
  • Sedative

Preparations

Chlordiazepoxide Hydrochloride Capsules:

  • 5 mg, 10 mg, 25 mg

Chlordiazepoxide and Amitriptyline Hydrochloride film-coated Tablets:

  • 5 mg Chlordiazepoxide and 12.5 mg Amitriptyline Hydrochloride
  • 10 mg Chlordiazepoxide and 25 mg Amitriptyline Hydrochloride

Chlordiazepoxide Hydrochloride and Clidinium Bromide Capsules:

  • 5 mg Chlordiazepoxide Hydrochloride and 2.5 mg Clidinium Bromide

Indications

1. Alcohol Withdrawal:

  • Relief of agitation and tremor and prevention or symptomatic relief of delirium tremens and hallucinations associated with acute alcohol withdrawal.

2. Anxiety and Depressive Disorders:

3. Preoperative Anxiolytics:

4. Peptic Ulcer Disease, Irritable Bowel Syndrome, and Acute Enterocolitis

Pharmacology

  • Inhibition of GABA neurotransmitter action in CNS
  • Site and mechanism of action within the CNS: Appear to involve a macromolecular complex that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.

Metabolism

Absorption

  • Bioavailability: GI tract

Distribution

  • Extent:
    • Widely distributed into body tissues & cross the blood-brain barrier
    • Excrete into milk and crosses the placenta
  • Plasma Protein Binding: highly bound to plasma proteins

Elimination

  • Metabolism: Mainly in the liver
  • Elimination Route: principally in urine
  • Half-life: 5–30 hours

Special Populations

  • Half-lives of chlordiazepoxide is prolonged in:
    • Geriatric patients
    • Patients with liver disease
    • Patients on hemodialysis

Dosing

Pediatric Patients

1. Anxiety Disorders in children ≥6 years of age:

  • Usual dosage: 5 mg 2–4 times daily or 0.5 mg/kg daily or 15 mg/m2 daily in 3 or 4 divided doses.
  • Maximum initial dosage: 10 mg daily

Adults

1. Alcohol Withdrawal:

  • Initial dose: 50-100 mg dose (repeat dose until agitation is controlled)
  • Max dose: 300 mg daily

2. Anxiety and Depressive Disorders:

  • Monotherapy:
    • Maximum initial dose: 10 mg daily
    • Mild to moderate anxiety: 5–10 mg 3 or 4 times daily
    • Severe anxiety: 20–25 mg 3 or 4 times daily
  • Chlordiazepoxide/Amitriptyline Combination Therapy:
    • Initial dose: 30 or 40 mg/75 or 100 mg daily in divided doses.

3. Preoperative Anxiolytic:

  • 5–10 mg 3 or 4 times daily (for several days preceding surgery.)

4. Peptic Ulcer Disease, Irritable Bowel Syndrome, and Acute Enterocolitis:

  • Maintenance dosage: 5 or 10 mg 3 or 4 times daily

Special Populations

  • Hepatic Impairment: Reduce dosage to the smallest effective dosage
  • Renal Impairment: No specific dosage recommendations
  • Geriatric or Debilitated Patients: Reduce initial dosage and use the smallest effective dosage

Drug Interactions

  1. Antacids (aluminum- and magnesium-containing): Possible decrease in rate chlordiazepoxide absorption
  2. Anticoagulants
  3. Cimetidine: Decreased clearance and increased plasma concentrations of chlordiazepoxide
  4. CNS depressants (e.g., alcohol, anticonvulsants, psychotropic drugs, sedatives)
  5. Psychotropic agents: Concomitant use is not recommended.
  6. Disulfiram: Reduce chlordiazepoxide dosage
  7. Levodopa: decreased control of parkinsonian symptoms
  8. Test for pregnancy (Gravindex test): Possible false-positive reaction
  9. Tests for urinary alkaloids: falsely elevated readings
  10. Tests for urinary 17-ketosteroids: falsely elevated or decreased concentrations

Adverse Effects

>10%:

  • Ataxia, drowsiness, memory impairment, sedation, muscle weakness, rash, decreased libido, menstrual disorders, xerostomia, salivation decreased, increased/decreased appetite, weight gain/loss, micturition difficulties

1-10%:

  • Confusion, dizziness, disinhibition, akathisia, dermatitis, hypotension, increased salivation, sexual dysfunction, incontinence, rigidity, tremor, muscle cramps, tinnitus, nasal congestion

Contraindications

  1. Hypersensitivity to chlordiazepoxide, other benzodiazepines, or any ingredient in the formulation.
  2. Acute angle-closure glaucoma

Pregnancy and Breastfeeding

  • Pregnancy: Category D
  • Lactation: not recommended in nursing mothers.

Precautions

1. CNS Effects:

  • Performance of activities requiring mental alertness and physical coordination may be impaired.
  • Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.
  • Paradoxical reactions (e.g., excitement, stimulation, acute rage) reported in psychiatric patients and in hyperactive aggressive children.

2. Fetal/Neonatal Morbidity: Increase risk of congenital malformations in infants of mothers receiving chlordiazepoxide during the first trimester of pregnancy >>> Usage during the first trimester almost always should be avoided.

3. Usage in patients with Psychiatric problems: should not be used in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.

4. Abuse Potential:

  • Tolerance, psychologic dependence, and physical dependence might occur following prolonged use
  • Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence

5. Withdrawal Syndrome:

  • Abrupt discontinuance may result in symptoms of withdrawal
  • Symptoms may be relieved by tapering the dosage.

6. Suicide possibility: Use with caution in depressed patients; potential for suicidal tendencies.

7. Use of Fixed Combinations: When used in fixed combination with clidinium bromide or amitriptyline hydrochloride, consider the cautions, precautions, and contraindications associated with the concomitant agent.

8. Usage in Porphyria: because of exacerbation of porphyria use with caution

9. Laboratory Testing: Blood dyscrasias (including agranulocytosis), jaundice, and hepatic dysfunction might occur occasionally >>> Monitor blood counts and liver function tests periodically during prolonged therapy.

10. Caution in Pediatric Usage:

  • Not recommended in children <6 years
  • Response of children to CNS drugs is unpredictable >>>initiate therapy at low dosage and increase as required.
  • Monitor hyperactive, aggressive children for paradoxical reactions (e.g., excitement, stimulation, acute rage)

11. Caution in Geriatric Usage: Prolonged elimination of chlordiazepoxide and its metabolites >>> possibility of increased risk of drowsiness, ataxia, and confusion; generally preventable by proper dosage adjustment

12. Hepatic Impairment: Prolonged elimination of chlordiazepoxide and its metabolites >>> Use with caution.

13. Renal Impairment: Use with caution.

14. Alcohol usage: Advice to patients about importance of not consuming alcoholic beverages.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

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