All posts by Poori Ghadiri

Fluphenazine decanoate, Fluphenazine hydrochloride, Prolixin®, Fluphenazine Omega®

Brand name

  • Prolixin®
  • Fluphenazine Omega®

Drug Class

  • First-generation anti-psychotics (Typical)
  • Phenothiazines

Preparations

  • Fluphenazine hydrochloride => orally or IM
  • Fluphenazine decanoate => Slow Release => IV Injection form

Indications

1. Shizophrenia: Fluphenazine decanoate injections is a long-acting parenteral preparation


2. Maintenance treatment of non-agitated, chronic schizophrenia.


3. Not indicated for:

  • Severely agitated psychotic patients, psychoneurotic patients or geriatric patients with confusion and/or agitation
  • Children under 12 years of age.

Pharmacology

Pharmacodynmics:

  • Mechanism Of Action: Blocking dopamine and other catecholamine receptor sites.

Metabolism

Pharmacokinetics:

Absorption:

  • Onset of action => 24 to 72 hours. Initial effects= > within 48 to 96 hours
  • Onset of action: 24 and 72 hours after injection

Distribution:

Not fully elucidated; reportedly crosses blood-brain barrier.  Phenothiazines cross the placenta and are distributed into milk.

Metabolism:

  • Highly protein-bound (greater than 90%) in plasma. Peak plasma concentration : 24-hours after intramuscular injection

Excretion:

  • Serum half-life=> 7-10 days. Feces and Urine.

Dosing

1. Adults Patients:

 

  • Initial dose: 5 mg to 12.5 mg of fluphenazine decanoate (12.5 mg is usually well tolerated)/ 10 mg daily of fluphenazine hydrochlorid.
  • Use fluphenazine hydrochloride dosages more than10 mg daily with caution! Safety of prolonged administration of dosages up to 40 mg daily not
  • In particularly sensitive patients, a second dose of 12.5 mg or 25 mg can be given 4 to 10 days after the initial injection.
  • Controlled with 25 mg or less, every two to three weeks.
  • Max dose: 100mg only in some patients!
  • Response to a single injection lasts usually two to three weeks; it may last for four weeks or more.
  • Fluphenazine Omega 100 mg/mL may be administered in preference to Fluphenazine Omega 25 mg/mL in patients who complain of discomfort with a large injection volume or when a smaller injection volume is wanted.

2. Elderlies:

  • The suggested initial test dose is 2.5 mg, gradually adjusted according to the response of the patient. Maintenance doses in the lower range (1/4 to 1/3 of those in younger adults) may be sufficient for most elderly patients.
  • Fluphenazine Omega (fluphenazine decanoate injection) is usually given as an intramuscular injection gluteus Maximus and sometimes subcutaneously. Fluphenazine Omega is not for intravenous.

Drug Interactions

  • CNS Depressants
  • Alcohol
  • Analgesics
  • Tricyclic Antidepressants
  • Lithium
  • ACE inhibitors
  • Thiazide Diuretics
  • Guanethidine, clonidine and other adrenegic-blocking antihypertensive agents may be blocked. Clonidine may decrease the antipsychotic activity of phenothiazines.
  • Beta Blockers: Plasma levels of both drugs may be increased.
  • Metrizamide: Phenothiazines may predispose patients to metrizamide-induces seizures => Discontinue for 48 hours prior to (at least 24 hours ) myelography.
  • Epinephrine and other sympathomimetics: Phenothiazines may antagonize the action of adrenaline and other sympathomimetics and may cause severe hypotension.
  • Levodopa: Phenothiazines may impair the anti-Parkinson effect of L-Dopa
  • Anticholinergics / Antimuscarinics: Cholinergic r muscarinergic blockade may be exaggerated when Fluphenazine is administered with anticholinergic agents, especially in older patients/ Atropine
  • Anticonvulsants: Anticonvulsant action may be impaired by Fluphenazine.
  • Anticoagulants: Phenothiazines may alter the effects of anticoagulants.
  • Cimetidine: Cimetidine may reduce plasma concentrations (Enzyme inducer effect) of phenothiazines.
  • Antacids / Antidiarrheal Agents: Concurrent administration may interfere with absorption. Administration of antacids should be spaced at least 1 hour before or 2-3 hours after fluphenazine dose.
  • Amphetamine / Anorectic Agents: Concurrent administration may produce antagonistic pharmacologic effects.

Adverse Effects

More Frequent:

  • Orthostatic Hypotension
  • Fluctuations in blood pressure
  • Extra Pyramid Side effects => Especially in Fluphenazine Omega (fluphenazine decanoate injection) = > Acute Dystonia, Akatasia, Parkinsonism, Rigidity, Tremor, tardive Dyskinasia
  • Drowsiness or lethargy
  • Neuroleptic malignant syndrome (NMS)

Less Frequent:

  • Loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation.
  • Blurred vision
  • Glaucoma,
  • Bladder paralysis
  • Fecal impaction
  • Paralytic ileus
  • Tachycardia
  • Nasal congestion
  • Weight change,
  • Peripheral edema
  • Hyponatremia
  • Syndrome of inappropriate antidiuretic hormone secretion
  • Abnormal lactation
  • Gynecomastia
  • Menstrual irregularities
  • False results on pregnancy tests
  • Impotency in men and libido changes in women have all been known to occur in some patients on phenothiazine therapy
  • Allergic Reactions
  • Leukopenia,
  • Agranulocytosis,
  • Thrombocytopenic or non-thrombocytopenic purpura
  • Eosinophilia and pancytopenia
  • Cholestatic jaundice

Contraindications

  • Known hypersensitivity to Fluphenazine and other Phenothiazines.
  • Marked cerebral athero-sclerosis
  • Suspected or established subcortical brain damage, +/- hypothalamic damage, since a hyperthermic reaction with temperatures above 40C may occur, sometimes not until 14-16 hours after drug administration.
  • Patients receiving large doses of CNS depressants => Alcohol, barbiturates, narcotics, hypnotics, etc => possibility of potentiation.
  • Comatose or severity depressed states
  • Blood dyscrasias
  • Liver damage
  • Renal insufficiency
  • Pheochromocytoma
  • Severe cardiovascular disorders

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not recommended in nursing mother

Precautions

1. Fluphenazine exerts activity at various levels of the central nervous system as well as on peripheral organ systems:

  • Less potentiating effect on central nervous system depressants and anesthetics than do some of the phenothiazines and appears to be less sedating => Be cautious for side effects!

2. Fluphenazine (Phenothiazines) cross the blood-brain barrier, placenta easily => cannot be removed by dialysis


3. Severe adverse reactions requiring immediate medical attention may occur and are difficult to predict => Monitor the patient closely!


4. Caution for sedative effect of Fluphenazine! Avoid driving or using dangerous machineries need full alertness.


5. The safety and efficacy of fluphenazine decanoate in children have not been established.


6. Neuroleptic Malignant Syndrome: potentially fatal syndrome in association with antipsychotic drugs => Symptoms: Muscular rigidity, fever, hyperthermia, altered consciousness and autonomic:

  • Management: Immediate discontinuation of anti-psychotic drugs, intensive monitoring + treatment of symptoms, and treatment of any associated medical problems

7. Tardive dyskinesia: repetitive involuntary movements of the tongue, face, mouth or jaw => protrusion of the tongue, puffing the cheeks, puckering of the mouth, chewing movements. The trunk and limbs are less frequently involved. Risk is greater in elderly patients, especially females:

  • Relatively irreversible
  • Caused by cumulative dose of the drug increases
  • In case of Tardive dyskinesia: Discontinue the medication
  • There is no known effective treatment for tardive dyskinesia. Start Clozapin if indicated! (Has moderated effect in relieving symptoms)

8. Cerebrovascular Events: Increase the risk of cerebrovascular events especially in elderly patients. Caution is advised!


9. Possibility of cross-sensitivity => Fluphenazine decanoate injection should be used with caution in patients with cholestatic jaundice, and dermatoses, or other allergic reactions to phenothiazine derivatives.


10. Hypotensive phenomena may develop in phenothiazine-treated patients who are undergoing surgery => Careful observation is necessary


11. Caution for Anticholinergics effects of Fluphenazine => Paralytic ileus, even resulting in death, may occur especially in the elderly.


12. Fluphenazine decanoate should be used cautiously in patients exposed to extreme heat or phosphorus insecticides.


13. Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration.


14. Test for phenylketonuria (PKU): False Positive test may occur.


15. Tests for pregnancy: False Positive test may occur.


16. Tests for urobilinogen, amylase, uroporphyrins, porphobilinogens, 5-hydroxyindolacetic acid: Urinary metabolites of phenothiazines may cause urine to darken and result in false-positive test results


17. Abrupt Withdrawl: Generally phenothiazines do not produce psychic dependence; however:

  • Symptoms: gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt discontinuation of high-dose therapy => concomitant antiparkinson agents therapy can diminish the withdrawal symptoms if administrated several weeks after phenothiazine is withdrawn.

18. Use in the Elderly:

  • Used with care in elderly patients (>60 years old)
  • Doses 1/4 to 1/3 of those in younger adults

19. Caution in patients with: pheochromocytoma, cerebral vascular or renal insufficiency, or a severe cardiac reserve deficiency => prone to hypotensive reactions with phenothiazine compounds.


20. Over-dosage:

  • Symptoms: CNS depression progressing from drowsiness to coma with areflexia. Restlessness, confusion and excitement. Hypotension, tachycardia, hypothermia, pupillary constriction, restlessness, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing or breathing, cyanosis, and respiratory and/or vasomotor collapse, possibly with sudden
  • Treatment: Emesis should not be induce, Generally is supportive therapy
  • In case of acute dystonic reactionsIntramuscular benztropine (or another antiparkinsonian agent- Dopamin agonist or Anticholinergics) should be given immediately (adults: 1 to 2 mg i.m, children: 0.2 mg i.m. initially with increments if necessary).

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.

Prochlorperazine, Prochlorperazine edisylate, Prochlorperazine mesylate, Compzine®, Stemzine® , Buccastem®, Stemetil®, Phenotil®

Brand name

  • Compzine®
  • Stemzine®
  • Buccastem®
  • Stemetil®
  • Phenotil®

Drug Class

  • First-generation anti-psychotics (Typical)
  • Phenothiazines

Preparations

  • Tablets: 5 mg, 10 mg
  • Suppository: 25 mg
  • Injectable Solution: 5mg/mL

Indications

  • Migraine
  • Vertigo due to Meniere’s syndrome
  • Labyrinthitis
  • Others

Pharmacology

Pharmacodynamics:

Mechanism of action:

  • Anti-dopamine action
  • Adrenoreceptor antagonism => cardiovascular side effects such as orthostatic hypotension and reflex tachycardia.
  • Potentiation of noradrenaline by blocking its reuptake into nerve terminals.
  • Weak anticholinergic action.
  • Weak antihistamine action.
  • Weak serotonin antagonism.
  • Has an effect on temperature control and blocks conditioned avoidance responses.

Metabolism

Pharmacokinetics:

  •  Absorption: GI tract (Orally –Po)
  • Distribution: widely distributed to tissues including the brain, fat, kidney, heart and skin and is stored in reticuloendothelial tissues.
  • Metabolism: Enterohepatic circulation
  • Excretion: Very small amount (0.1%) of prochlorperazine and its metabolites (N-desmethyl Prochlorperazine => active metabolite) are excreted in the first 24 hours in the urine and the drug may continue to be excreted in the urine for up to 3 weeks after cessation of long term therapy. half-life is approximately 24 hours.

Dosing

1. Nausea and Vomiting (Adults):

  • Acute attack: 20 mg at once, followed, if necessary by 10 mg two hours later Maintenance dose: 5 or 10 mg two or three times daily.

 

  • Attention: If oral administration is not practical, a deep intramuscular injection of 1 mL (12.5 mg) or a 25 mg suppository should be used, followed if required, by normal oral medication six hours later.
  • Do not use a darkened solution for injection (more than pale yellow).
  • Adjust the dose to the lowest clinically effective possible.

2. Nausea and Vomiting (Children):

  • Preferebly do not use prochlorperazine for children. However if it is considered unavoidable => the dosage is 250 micrograms/kg
  • Bodyweight two or three times a day.
  • After a cumulative dosage of 500 micrograms/kg=> Watch out for dystonic reactions has been associated with Prochlorperazine => It should therefore be used cautiously in children.
  • Not recommended for children weighing less than 10 kg and should not be given to children by the rectal or intramuscular route.
  • When treating children, it is recommended that the 5 mg tablets be used.

3. Vertigo and Meniere’s Disease:

Adults:

  • Oral: 5 to 10 mg three or four times daily. Dosage may be reduced gradually after several weeks to a maintenance dosage of 5 to 10 mg daily.

Children:

  • Oral: Dose, same as for nausea and vomiting.

Geriatric:

  • Dosages in the lower range are sufficient for most elderly patients. Dosage should be increased more gradually in elderly patients.

4. Impaired Liver Function:

 Prochlorperazine is extensively metabolised by the liver. Thus, dosage reduction may be necessary.

Drug Interactions

 

  • Class Ia antiarrhythmics: Quinidine and Disopyramide
  • Class III antiarrhythmics: Amiodarone and Sotalol
  • Bepridil
  • Cisapride
  • Sultopride
  • Thioridazine
  • Methadone
  • Intravenous erythromycin
  • Intravenous vincamine
  • Halofantrine
  • Pentamidine
  • Sparfloxacin
  • Medicines which induce bradycardia: bradycardia-inducing calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, digitalis
  • Medicines which can cause hypokalaemia: such as diuretics, stimulant laxatives intravenous amphotericin B, glucocorticoids, tetracosactides
  • Other antipsychotics.
  • Alcohol (Ethanol)
  • Desferrioxamine

Adverse Effects

More frequent:

  • Gastrointestinal
  • Constipation
  • Dry mouth
  • Nervous System
  • Drowsiness
  • Akathisia
  • Parkinsonism (dyskinesia, tremor and rigidity)
  • Blurred vision

Less frequent:

  • Biochemical abnormalities: Elevated serum levels of bilirubin and hepatic enzymes may occur if the patient develops cholestatic jaundice.
  • Hypotension
  • Peripheral oedema
  • Cardiac arrhythmias
  • QT interval prolongation
  • Sudden cardiac death
  • Venous thromboembolism
  • Pulmonary embolism
  • Dermatitis or contact dermatitis
  • Maculopapular eruptions
  • Erythema multiforme
  • Urticarial
  • Photosensitivity
  • Abnormal pigmentation
  • Elevated prolactin levels
  • hyperglycaemia
  • Hypoglycemia
  • Menstrual irregularities
  • Galactorrhoea
  • Gynaecomastia
  • Paralytic ileus
  • Agranulocytosis
  • Atypical lymphocytes
  • Thrombocytopenia
  • Leucopenia
  • Aplastic anaemia
  • Acute dystonic reactions
  • Seizures
  • EEG changes
  • Headache
  • Insomnia
  • Catatonia
  • Hyperpyrexia
  • Pigmentary rentinopathy
  • Activation of psychotic symptoms
  • Respiratory depression

Contraindications

  • Circulatory collapse
  • Central nervous system depression (coma or drug intoxication)
  • Previous history of a hypersensitivity reaction
  • Bone marrow depression
  • Renal dysfunction
  • Parkinson’s disease
  • Hypothyroidism
  • Pheochromocytoma
  • Myasthenia gravis
  • Prostate hypertrophy

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not recommended in nursing mothers

Precautions

1. Should be avoided in patients with renal dysfunction, Parkinson’s disease, hypothyroidism, phaeochromocytoma, myasthenia gravis and prostate hypertrophy.


2. Patients with hypotension: The autonomic side effects of the piperazine derivatives are less troublesome than those of other phenothiazines, however care should be taken if prochlorperazine is used in the elderly or in patients undergoing surgery with spinal anaesthesia.


3. Epileptic patients: Piperazine derivatives are also less epileptogenic than other phenothiazines, but care should still be exercised in epileptic patients.

  • Phenothiazines may lower the convulsive threshold; dosage adjustments of anticonvulsants may be necessary

4. Anticholinergic side- effects: Prochlorperazine can cause problems due to anticholinergic effects, especially in the elderly (urinary difficulties, constipation and precipitation of acute narrow angle glaucoma), but to a lesser extent than with other phenothiazines.


5. Hypocalcaemia: Patients with hypoparathyroidism => prone to acute dystonic reactions with prochlorperazine.


6. Sedative effect: Prochlorperazine may impair mental and physical activity especially during the first few days of therapy:

  • Avoid driving while taking prochlorperazine.
  • Avoid working with dangerous machineries need concentration and full alertness.

7. Antiemetic effects: The antiemetic effects of prochlorperazine may mask signs of over dosage of toxic drugs or obscure the diagnosis of conditions such as intestinal obstruction, brain tumour. Caution along with close follow ups is advised!


8. Reye’s Syndrome and hepatic-encephalopatic patients: The use of prochlorperazine and other potential hepatotoxins should be avoided in children and adolescents whose signs and symptoms suggest Reye’s Syndrome and hepatic-encephalopathy.


9. Hypothermia: Severe hypothermia may occur during swimming in cold water or in patients receiving antipyretic therapy concomitantly with Prochlorperazine.


10. Liver disease: Caution should be used in patients with existing liver disease due to the extensive hepatic metabolism of prochlorperazine.


11. Tardive dyskinesia: repetitive involuntary movements of the tongue, face, mouth or jaw => protrusion of the tongue, puffing the cheeks, puckering of the mouth, chewing movements. The trunk and limbs are less frequently involved. Risk is greater in elderly patients, especially females:

  • Relatively irreversible
  • Caused by cumulative dose of the drug increases
  • In case of Tardive dyskinesia : Discontinue the medication
  • There is no known effective treatment for tardive dyskinesia. Start Clozapin if indicated! (Has moderatet effect in relieving sympotoms)

12. Neuroleptic Malignant Syndrome: potentially fatal syndrome in association with antipsychotic drugs => Symptoms: Muscular rigidity, fever, hyperthermia, altered consciousness and autonomic:

  • Management: immediate discontinuation of anti-psychotic drugs, intensive monitoring + treatment of symptoms, and treatment of any associated medical problems

 13. QT Interval: QT interval prolongation => torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalemia, and congenital or acquired (i.e., drug induced) QT prolongation. If the clinical situation permits, medical and laboratory evaluations should be performed to rule out possible risk factors before initiating treatment.


14. Cerebrovascular Events: Increase the risk of cerebrovascular events especially in elderly patients. Caution is advised!


15. Thromboembolism: Increased the risk of venous thromboembolism. Caution is advised!


16. Elderly Patients with Dementia: Elderly patients with dementia-related psychosis =>increased risk of death.


17. Hyperglycaemia: Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on prochlorperazine, should get appropriate glycaemic monitoring during treatment.


18. Prochlorperazine is not recommended for use in children under 10 kg in weight or less than 2 years of age => acute extrapyramidal reactions may occur.

  • Attention: Prochlorperazine should not be given to children by the rectal or intramuscular route.

19. Do not consume Alcohol while taking Prochlorperazine: May enhance the CNS depressant effects of alcohol and other depressant drugs + potentiate the anticholinergic effects of atropinic agents + tricyclic antidepressants.


20. In patients taking Desferrioxamine: Simultaneous administration may cause transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours.


21. Patients taking Thiazide diuretics: May accentuate the orthostatic hypotension that may occur with phenothiazines.


22. Caution in patients on anti-coagulants: Phenothiazines can decrease the effect of oral anticoagulants.


23. Concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs.


24. Over-dosage:

  • Symptoms: CNS depression progressing from drowsiness to coma with areflexia. Restlessness, confusion and excitement. Hypotension, tachycardia, hypothermia, pupillary constriction, restlessness, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing or breathing, cyanosis, and respiratory and/or vasomotor collapse, possibly with sudden
  • Treatment: Emesis should not be induce, Generally is supportive therapy
  • In case of Acute dystonic reactionsIntramuscular benztropine (or another antiparkinsonian agent- [Dopamin agonist / Anticholinergics]) should be given immediately (adults: 1 to 2 mg i.m., children: 0.2 mg i.m. initially with increments if necessary).

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.

Penfluridol, Semap®, Micefal®, Asemap®, Nhwa®

Brand name

  • Semap®
  • Micefal®
  • Asemap®
  • Nhwa®

Drug Class

  • 1th generation (Typical) anti-psychotics
  • Diphenylbutylpiperidine
  • Dopamin Antagonist

Preparations

  • Tablet: 20 mg

Indications

  • Chronic schizophrenia

Pharmacology

Pharmacodynamics:

  • Mechanisem of action: blocks the postsynaptic dopamine receptor in the mesolimbic dopaminergic system and inhibits the release of hypothalamic and hypophyseal hormones.

Metabolism

Pharmacokinetics:

 Absorption:

  • Orally. Peak plasma concentrations after 2 hours.

Distribution:

 

 Metabolism:

  • Enterohepatic

Excretion:

  • Urine and faeces (as N-dealkylated metabolite). Elimination half-life: 36 hours (initial), 120 hours (terminal).

Dosing

Psychoses (Adult):

  • Initial dose: 20-60 mg Po (orally) weekly
  • Maximum dose: 250 mg Po (orally) once a week in severe or resistant conditions.

Drug Interactions

  • Orthostatic hypotension with MAOIs
  • Increase sedation with alcohol, hypnotics, antihistamines, opiates
  • Antacids containing aluminum salts may decrease absorption of Penfluridol
  • Additive antimuscarinic effects with TCAs
  • Reduce bromocriptine‘s ability to reduce serum prolactin
  • Amphetamines may increase psychosis
  • Inhibit antiparkinsonian effects of levodopa
  • Increase risk of extrapyrimidal symptoms with Metoclopramide
  • Increase phenytoin levels (phenytoin may reduce penfluridol levels)
  • Possible additive effects on QT interval with type 1a antiarrhythmics, TCAs, some quinolone antibiotics (e.g. Moxifloxacin)
  • Have additive hypotensive effects with Trazodone
  • May increase levels of valproic acid (Enzyme inhibitor effect of Penfluridol).
  • Potentially Fatal: May produce neurotoxicity with lithium.
  • Food interactions: Avoid valerian, St John’s wort, kava kava, gotu kola => increased risk of CNS depression.

Adverse Effects

More Frequent:

  • Slightly sedative
  • Extrapyramidal symptoms: Parkinsonism, rigidity, tremor Akathisia, Tardive Dyskinesiae and pseudo-Parkinsonism.

Less Frequent:

  •  Lower threshold for seizures 
  • Blurring of vision
  • Dry mouth  
  • Retention of urine
  • Constipation
  • Orthostatic hypotension
  • Weight gain
  • Impaired glucose tolerance
  • Allergic skin rashes
  • cholestatic jaundice
  • Delirium
  • Agitation
  • Anxiety
  • Depression
  • Euphoria
  • Anorexia
  • Constipation
  • Diarrhea
  • Alopecia
  • Amenorrhoea
  • Hyperprolactinemia (Leaking milk from breast)
  • Hypoglycaemia
  • hyponatraemia
  • hypersalivation
  • Nausea, vomiting
  • Bronchospasm
  • Venous blood clots, particularly in the legs (the symptoms include swelling, pain and redness in the legs)
  • Potentially Fatal side effects: Blood dyscrasias; neuroleptic malignant syndrome; alteration of heart conduction leading to QT prolongation and life threatening arrhythmias.

Contraindications

  • MAOIs
  • Alcohol, hypnotics, antihistamines, opiates
  • Antacids containing aluminum salts
  • TCAs
  • Hyperprolactinemia due to any cause
  • Amphetamines
  • Levodopa
  • Metoclopramide
  • Phenytoin
  • Medications cause long Q-T interval: 1a antiarrhythmics, TCAs, some quinolone antibiotics (e.g. Moxifloxacin)
  • Trazodone
  • valproic acid
  • Lithium.
  • Valerian, St John’s wort, kava kava, gotu kola

Pregnancy and Breastfeeding

Pregnancy: Category C

Lactation: Not recommended in nursing mother

Precautions

1. Extremely long elimination half-life and its effects last for many days after single oral dose.


2. Slightly sedative, but often causes extrapyramidal side effects, such as akathisia, dyskinesiae and pseudo-Parkinsonism.


3. Caution in elderlies! do a dose adjustment with close monitoring.


4. Caution in patients with epilepsy!


5. Caution in preexisting cardiac conduction problems; hypokalaemia, hypomagnesemia; hypothyroidism.


6. Use with caution in patients with => liver, heart, kidney diseases


7. Avoid driving and using of machinery while taking Penfuridol => it reduces awareness, sleepiness, dizziness and visual problems associated with the use of this medicine.


8. Caution for Neuroleptic Malignant Syndrome (NMS): hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure), elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal, requires intensive symptomatic treatment and immediate discontinuation of neuroleptic treatment.


9. Over-dosage:

  • Severe extrapyramidal reactions
  • Hypotension (can produce shock like state)
  • Sedation
  • Treatment: No specific antidote, do a supportive therapy, Heart monitoring, ECG (QT Prolongation), Pulse-Oxymetery, Observe Airway, Breathing, circulation.

10. Caution for Tardive Dyskinesia:

  • Rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements) Irreversible in some patients in patients treated with neuroleptics with antipsychotic properties and other drugs with substantial neuroleptic activity. The risk of developing tardive dyskinesia may minimize by reducing the dose of the neuroleptic drug used and its duration of administration => anti-Parkinson agents usually do not alleviate the symptoms of this syndrome.

11. Caution in administration of Penfuridol in patients with bone marrow suppression disorders, failures due to any cause => close observation (Complete blood count with differential and absolute neutrophil count in mandatory)

Note:

This document is prepared by the “Mental Health for All” team. The general information provided on the Website is for informational purposes only and is not professional medical advice, diagnosis, treatment, or care, nor is it intended to be a substitute therefore. Always seek the advice of your physician or other qualified health provider properly licensed to practise medicine or general healthcare in your jurisdiction concerning any questions you may have regarding any information obtained from this Website and any medical condition you believe may be relevant to you or to someone else. Never disregard professional medical advice or delay in seeking it because of something you have read on this Website. Always consult with your physician or other qualified healthcare provider before embarking on a new treatment, diet, or fitness program. Information obtained on the Website is not exhaustive and does not cover all diseases, ailments, physical conditions, or their treatment.

Haloperidol, Haloperidol Decanoate , Haloperidol Lactate, Haldo®

Brand name

  • Haldo®
  • Haldol Decanoate®
  • Haloperidol La®
  • Peridol®
  • Aloperidin®
  • Bioperidolo®
  • Brotopon®
  • Dozic®
  • Duraperidol (Germany)®
  • Einalon S®
  • Eukystol®
  • Haldol (common tradename in the US and UK)®
  • Halosten®
  • Keselan®
  • Linton®
  • Peluces®
  • Serenace®
  • Sigaperidol®

Drug Class

1th generation (Typical) anti-psychotics

Butyrophenones

Dopamin Antagonist

Preparations

  • Tablet: 0.5mg, 1mg, 2 mg, 5 mg, 10 mg, 20 mg
  • Oral Concentrate: 2 mg/mL
  • Injectable solution: 50 mg/mL, 100 mg/mL, Ampoule 5 mg/mL, 1 mL

Indications

Haloperidol:

Adults: Gilles de la Tourette’s syndrome (Tic disorder), , Schizophrenia

  • Bipolar Manic disorder
  • Intractable hiccups
  • Alcohol induced psychosis (Alcohol induced hallucinations) as adjunctive therapy.
  • Acute psychosis: Drug-induced psychosis => LSD, psilocybin, amphetamines, ketamine and phencyclidine.
  • Opioid withdrawal symptom management
  • Borderline personality disorder (Therapeutic trial)
  • Severe Nausea/Vomiting: post operative patients, patients receiving chemotherapy or radiotherapy.
  • Chorea form disorders
  • Agitation and confusion associated with cerebral sclerosis
  • Delirious state: controlling agitation.

Pediatrics Older than 3 years of age: Gilles de la Tourette’s syndrome (Tic disorder), Psychotic disorder, Schizophrenia, Hyperactive disorder (Short-term use)

 


Haloperidol Lactate:

  • Adults:
  • Gilles de la Tourette’s Syndrome (Tic disorder)
  • Psychotic disorder
  • Schizophrenia
  • Bipolar Manic disorder
  • Intractable hiccups
  • Alcohol induced psychosis (Alcohol induced hallucinations) as adjunctive therapy.
  • Acute psychosis: Drug-induced psychosis => LSD, psilocybin, amphetamines, ketamine and phencyclidine.
  • Opioid withdrawal symptom management
  • Borderline personality disorder (Therapeutic trial)
  • Severe Nausea/Vomiting: post operative patients, patients receiving chemotherapy or radiotherapy.
  • Chorea form disorders
  • Agitation and confusion associated with cerebral sclerosis
  • Delirious state: controlling agitation.
  • Pediatrics: Not FDA approval

Pediatrics: Not FDA approval


Haloperidol Decanoate:

Adults:

  • Chronic Schizophrenia
  • Bipolar Manic disorder
  • Intractable hiccups
  • Alcohol induced psychosis (Alcohol induced hallucinations) as adjunctive therapy.
  • Acute psychosis: Drug-induced psychosis => LSD, psilocybin, amphetamines, ketamine and phencyclidine.
  • Opioid withdrawal symptom management
  • Borderline personality disorder (Therapeutic trial)
  • Severe Nausea/Vomiting: post operative patients, patients receiving chemotherapy or radiotherapy.
  • Chorea form disorders
  • Agitation and confusion associated with cerebral sclerosis
  • Delirious state: controlling agitation.

Pharmacology

Pharmacodynamics:

 

  • Mechanism of action: typical butyrophenone => D2 blocker, Alfa1 Blocker, Antagonist of 5-HT2 receptor, Muscarinic 1 receptor affinity (Anti-cholinergic effect), Histaminic 1 receptor affinity( Anti-histaminic effect)

 

 

 

 

Metabolism

Pharmacokinetics:

 

1. Absorption:

  • Oral: Bioavailability is 60%-70%. 30-60 minutes in intramuscular- intravenous injection.
  • Intramuscular injections: rapidly absorbed – high bioavailability almost 20 minutes.
  • Intravenous injections: Bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds.

2. Distribution: 90% binds to plasma proteins.

3. Metabolism: Cytochrome p450 in liver (CYP3A4).

4. Excretion: 30% Urine + 15% feces

Dosing

 Haloperidol (Adult Dose):

  • Gilles de la Tourette’s syndrome: Moderate symptoms => 0.5 to 2 mg/ Severe symptoms => 3 to 5 mg (Po) orally2 to 3 times per day (Bid-Tid).
  • Psychotic disorder: moderate symptoms => 0.5 to 2 mg / severe symptoms => 3 to 5 mg (Po) orally 2 to 3 times per day (Bid-Tid).
  • Schizophrenia: moderate symptoms => 0.5 to 2 mg / severe symptoms 3 to 5 mg (Po) orally 2 to 3 times per day (Bid-Tid).

Haloperidol (Pediatrics dose – Do not use in children less than 3 years of age):

 

1. Gilles de la Tourette’s syndrome:

Age 3 to 12 years (Weight: 15 to 40 kg):

  • Initial dose: lowest possible dose (0.5 mg per day) or weight-based dose (0.05 to 0.075 mg/kg/day) Orally (Po) in 2 to 3 divided doses, whichever is less.
  • Incremental dose:5 mg at 5 to 7 day intervals to therapeutic effect.

 Over age 12 years:

  • Moderate Symptoms => 0.5- 2 mg Orally (Po) 2 to 3 times per day (Bid-Tid)
  • Severe Symptoms => 3-5 mg Orally (Po) 2 to 3 times per day (Bid-Tid).

 

2. Hyperactive behaviour: (Short term administration- If patient is not responded to non-antipsychotic medications and psychotherapy)

3 to 12 years (weight 15 to 40 kg):

  • Initial dose:05 to 0.075 mg/kg/day Orally (Po) in 2 to 3 divided doses (Bid-Tid)
  • Incremental dose:5 mg at 5 to 7 day intervals to therapeutic effect
  • MAX daily dose: 0.075 mg/kg/day

Over age 12 years:

  • Moderate symptoms: 0.5 to 2 mg
  • Severe symptoms: 3 to 5 mg orally 2 to 3 times per day (Bid-Tid)

 

3. Psychotic disorder:

3 to 12 years (weight 15 to 40 kg)=>

  • Initial dose:05 mg/kg/day Orally (Po) in 2 to 3 divided doses (Bid-Tid),
  • Incremental dose5 mg/day at 5 to 7 day intervals to therapeutic effect
  • MAX daily dose15 mg/kg/day

12 years and older =>

  • Moderate symptoms:5 to 2 mg
  • Severe symptoms: 3 to 5 mg Orally (Po) 2 to 3 times (Bid-Tid)

 

4. Schizophrenia:

3 to 12 years (weight 15 to 40 kg) =>

  • Initial dose:05 mg/kg/day Orally (Po) in 2 to 3 divided doses (Bid-Tid)
  • Incremental dose:5 mg/day at 5 to 7 day intervals to therapeutic effect
  • MAX daily dose15 mg/kg/day

12 years and older:

  • Moderate symptoms:5 to 2 mg 3 to 5 mg
  • Severe symptoms: Orally (Po) 2 to 3 times daily (Bid-Tid)

 


Geriatric and debilitated patients:

  • May require higher doses (0.5 to 2 mg 2 to 3 times/day (Bid-Tid)
  • Chronic refractory schizophrenia: Initial dose:5 to 1.5 mg/day orally (Po) => Gradually increased to maintenance dose of 2 to 8 mg/day
  • Mentally retarded with hyperkinesia: Initial dose:5 to 6 mg/day orally (Po) in divided doses. Gradually increased to maintenance (minimally effective maintenance dose).
  • Maximum dose: 15 max/day to achieve control => Decrease to minimally clinically effective dose.

Haloperidol Decanoate:

Adult Dose:

Chronic Schizophrenia: (Two methods recommended)

  • Initial dose: stabilized on low daily oral doses (up to 10 mg/day), 10 to 15 times previous daily oral dose IM monthly or every 4 weeks.
  • Initial dose: stabilized on high daily oral doses, 20 times previous daily oral dose IM for the first month, then 10 to 15 times previous daily oral dose IM monthly or every 4 weeks,
  • MAX initial dose 100 mg

Pediatrics Dose: Not safe in this group


Haloperidol Lactate:

1. Adult Dose:

Gilles de la Tourette’s syndrome:

  • Initial dose: 2 to 5 mg IM, may repeat every 4 to 8 hours depending on patient response
  • Incremental dose: every 1 hour if needed

 

Schizophrenia:

  • Initial dose: 2 to 5 mg IM, may repeat every 4 to 8 hours depending on patient response
  • Incremental dose: every 1 hour if needed

 

2. Pediatrics Dose: Not safe in this group

Drug Interactions

  • Tricyclic antidepressants (Haloperidol is enzyme Enzyme inhibitor)
  • Carbamazepine (Carbamazepine is Enzyme inducer)
  • Anti-parkinsonism agents:e.g Levodopa
  • Amiodarone
  • Cizapride
  • Terfenadine
  • Sotalol
  • Quinidine
  • Pimozide
  • Pentamidine
  • Procainamide

Adverse Effects

More frequent:

  • Acute dystonia
  • Extra pyramidal symptoms – Rigidity (Parkinsonism)
  • Akathisia
  • Tardive dyskinesia (long term administration)

Less frequent:

  • Paralytic ileus
  • Priapism
  • Seizure
  • Sudden cardiac death
  • Tardive dyskinesia
  • Torsades de pointes
  • Prolonged QT interval
  • Jaundice
  • Hepatitis
  • Cholestasis
  • Acute hepatic failure
  • Liver function test abnormal
  • Hypoglycemia
  • Hyperglycemia
  • Hyponatremia
  • Anaphylactic reaction
  • Hypersensitivity
  • Neutropenia
  • Leukopenia
  • Thrombocytopania
  • Pancytopenia
  • Confusional state
  • Depression
  • Insomnia
  • Seizure
  • Ventricular fibrillation
  • Ventricular tachycardia
  • Extrasystoles
  • Bronchospasm
  • Laryngospasm
  • Laryngeal edema
  • Dyspnea
  • Nausea
  • Vomiting
  • Leukocytoclastic vasculitis
  • Dermatitis exfoliative
  • Urticaria
  • Photosensitivity reaction
  • Rash
  • Itchiness
  • Increased sweating
  • Urinary retention
  • Gynecomastia
  • Sudden death
  • Face edema
  • Edema
  • Hypothermia
  • Hyperthermia
  • Injection site abscess
  • Anorexia
  • Pulmonary embolism
  • Tardive dyskinesia
  • Cataracts
  • Retinopathy
  • Neuroleptic malignant syndrome

Contraindications

  • Comatose state from any cause
  • Known Hypersensitivity to Haloperidol
  • Parkinson’s disease
  • Central nervous system depression
  • Patients with dementia-related psychosis
  • Narrow angle glaucoma
  • Bone marrow suppression/failure patients
  • Leukopenic / Neutropenic patients due to any cause

Pregnancy and Breastfeeding

Pregnancy: Category C

Lactation: Not recommended in nursing mother

Precautions

1. Haloperidol Decanoate is in a sesame seed oil base and must not be given intravenously (Absolute contraindication). => Only deep intramuscular injection (21G needle) into the gluteal region. Maximum recommended volume is 3 milliliters per injection site.


2. Do NOT administer Haloperidol Lactate intravenously (Relative contraindication). Although it is recommended not to inject intravenously (Not FDA approval- off label), some centers (Coronary care unites) administer it:

  • Initial infusion doses of 2 to 25 milligrams per hour (Initial bolus dose of 10 milligrams followed by continuous infusion beginning as 10 milligrams per hour is recommended.)
  • Maximum infusion rate: 40mg/hr
  • Caution: administer Haloperidol Lactate intravenous continuous dose in patients not effectively managed by first line sedatives and in those attempted reversal of the cause of agitation has been unsuccessful.

3. Switching from injectable to oral haloperidol:

the first oral dose should be administered within 12- 24 hours following the last parenteral dose.


4. Caution is advised in patients with phaeochromocytoma and conditions predisposing to epilepsy such as alcohol withdrawal and brain damage. Haloperidol may lower the convulsive threshold.


5. Caution in administration of Haloperidol in patients with bone marrow suppression disorders, failures due to any cause => close observation (Complete blood count with differential and absolute neutrophil count in mandatory)


6. Caution in patients with Cognitive diseases => Alzheimer disease. May prone the patient to pneumonia.


7. Caution for Tardive Dyskinesia: 

  • Rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements)  Irreversible in some patients in patients treated with neuroleptics with antipsychotic properties and other drugs with substantial neuroleptic activity. The risk of developing tardive dyskinesia may minimize by reducing the dose of the neuroleptic drug used and its duration of administration => anti-Parkinson agents usually do not alleviate the symptoms of this syndrome.

8. Do not do abrupt discontinuation => gradual withdrawal of antipsychotic drugs will decrease the incidence of withdrawal emergent neurological signs.


9. Administer cautiously to patients with severe impairment of liver or kidney


10. Haloperidol may interfere with the anticoagulant properties of phenindione. Possibility should be kept in mind of a similar effect occurring when Haloperidol is used with other anticoagulants.


11. Haloperidol may antagonize the action of adrenaline and other sympathomimetic agents and reverse the blood-pressure-lowering effects of adrenergic-blocking agents such as guanethidine.


 12. Caution in concomitant use with methyldopa: Enhanced CNS effects have seen.


13. Caution in concomitant use with Tricyclic antidepressants: Haloperidol inhibits the metabolization of Tricyclic antidepressants => increasing plasma levels of these drugs => increased tricyclic antidepressant toxicity (anticholinergic effects, cardiovascular toxicity, lowering of seizure threshold).


14. Caution in concomitant use with Carbamazepine (Carbamazepine has enzyme inducer effect) => May cause significant reduction of plasma level of Haloperidol => do a dose adjustment.


15. Caution in concomitant use with Levodopa (Anti-parkinsonism agent) => it may have a synergistic effect! (Increase extrapyramidal symptoms: akathisia, Tardive dyskinesia, dystonia, hyperreflexia, rigidity, opisthotonos, and occasionally, oculogyric crisis):

  • Administration of an anti-Parkinson agent is usually, but not always effective in preventing or reversing neuromuscular reactions associated with Haloperidol Decanoate.

16. Watch out for Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also taking antipsychotic medications: Haloperidol.


17. Neuroleptic drugs (Anti-psychotics including Haloperidol) elevate prolactin levels; the elevation persists during chronic administration. => galactorrhea, amenorrhea, gynecomastia and impotence may occur.


18. Caution for Neuroleptic Malignant Syndrome (NMS): hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure), elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal, requires intensive symptomatic treatment and immediate discontinuation of neuroleptic treatment:

  • Hyperpyrexia and heat stroke, not associated with the above symptom complex, has also been reported.

19. Over-dosage:

  • Symptoms: Severe extrapyramidal reactions, Hypotension (can produce shock like state), Sedation
  • Treatment: No specific antidote, do a supportive therapy, Heart monitoring, ECG (QT Prolongation), Pulse-Oxymetery, Observe Airway, Breathing, circulation.

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.

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.

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.

error: Content is protected !!