Depof

Uses

Chlordiazepoxide is a benzodiazepine used to treat the withdrawal symptoms of acute alcoholism, to treat preoperative anxiety, and to treat anxiety over a short term period.

For the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety.

Depression: For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.

Childhood Enuresis: May be useful as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older, after possible organic causes have been excluded by appropriate tests. In patients having daytime symptoms of frequency and urgency, examination should include voiding cystourethrography and cystoscopy, as necessary. The effectiveness of treatment may decrease with continued drug administration.

Anxiety states: It controls excessive anxiety, tension, and agitation seen in neuroses or associated with somatic conditions. The treatment or prevention of nausea and vomiting of various causes. The management of psychotic disorders, such as acute or chronic catatonic, hebephrenic and paranoid schizophrenia; psychosis due to organic brain damage, toxic psychosis, and the manic phase of manic-depressive illness.

Depof is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Depression, Peptic Ulcer Disease, Acute Anxiety, Pyschosomatic diseaseAttention Deficit Hyperactivity Disorder (ADHD), Bulimia Nervosa, Enuresis, Major Depressive Disorder (MDD), Neuropathic Pain, Panic Disorder, Post Traumatic Stress Disorder (PTSD)Agitation, Psychosis, Schizophrenia, Acute non-psychotic Anxiety

How Depof works

Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor. BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties.

Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin . It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin . Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression .

Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Dosage

Depof dosage

Depression: Initially up to 75 mg daily in divided doses increased gradually to 150-200 mg (up to 300 mg in hospital); up to 150 mg may be given as a single dose at bed time; elderly, initially 10 mg daily, increased gradually to 30-50 mg daily; child not recommended for depression.

Panic attack: Initially 10-25 mg/day, depending on how the medication is tolerated, raise the dose until the desired response is obtained. The daily doses required vary greatly from patient to patient, between 75-150 mg, if necessary it can be increased to 200 mg.Nocturnal enuresis(Child):

• 7 years: 25 mg
• 8 to 11 years: 20-50 mg
• Over 11 years: 50-75 mg at bedtime; max. period of treatment (Including gradual withdrawal) is 3 months; full physical examination is required before further course.

Schizophrenia and other psychoses:

• Adults and child over 12 years: Recommended starting dose is 2-5 mg b.i.d, increased by 5 mg daily after 1 week then at interval of 3 days, according to response.
• Children (6-12 years): Dosage should be adjusted to the weight of the child and severity of the symptoms. The starting dosage is 1 mg b.i.d. Dosage may be increased gradually until symptoms are controlled or until side effects become troublesome. While it is usually not necessary to exceed dosages of 15 mg daily.
• Elderly: Reduce initial dose by at least half

Short-term management of severe anxiety:

• Adult and child over 12 years: 1-2 mg b.i.d, increased if necessary to 6 mg daily.
• Child (3-5 years): 1 mg daily
• Child (6-12 years): Up to 4 mg daily in divided dose.
• Elderly: Reduce initial dose by at least half

Antiemetic:

• Adult: 2-4 mg daily in divided doses; max. 6 mg daily;
• Child 3-5 years: up to 1 mg daily, 6-12 years up to 4 mg daily.

Side Effects

Dry mouth, less sedation, blurred vision (disturbances of accommodation, increased intraocular pressure), constipation, nausea, difficulty with micturation; cardiovascular side-effects, sweating, tremors, rashes and hypersensitivity reaction (including urticaria & photosensitivity), behavioral disturbances (particularly in children) hypomania or mania (particularly in elderly), interference with sexual function; blood sugar changes, increased appetite, weight gain (occasionally weight loss).

Common side effects are transient restlessness, dystonias or may resemble parkinsonism. Other CNS Reactions are drowsiness, dizziness, fatigue, blurred vision, seizures. Without these Peripheral oedema, blood dyscrasias, jaundice may occasionally occur. Tachycardia, constipation, urinary hesitancy and retention and hyperpyrexia have been reported very rarely.

Toxicity

LD₅₀=537 mg/kg (Orally in rats). Signs of overdose include respiratory depression, muscle weakness, somnolence (general depressed activity).

The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract .

Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations.

Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue.

Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured.

Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention.

Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs.

LD₅₀/> Values

Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg

Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg

Human range of toxicity is considered to include single dosages greater than 5 mg/kg.

Symptoms of overdose include agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and restlessness.

Precaution

Cardiac diseases (particularly with arrhythmias), history with epilepsy, pregnancy and breast feeding, elderly, hepatic impairment (avoid if severe), thyroid disease, psychoses, angle-closure glaucoma, history of urinary retention, concurrent electro-convulsive therapy. Drowsiness may affect performances of skilled tasks (e.g. driving), alcohol induced Imipramine effect.

Care should be taken when treating elderly patients, and initial dosage should be reduced. Such patients can be specially sensitive, particularly to extra pyramidal and hypotensive effects. Patients with cardiovascular disease including arrhythmias should also be treated with caution. Care should be taken in patients with angina pectoris.

Interaction

Imipramine should not be used in combination with Monoamine oxidase inhibitors (MAO), anticholinergic agents, antihypertensive agents, methylphenidate, levodopa, antipsychotic drug, cimetidine, barbiturates, and oral contraceptives.

Trifluoperazine may diminish the effect of oral anticoagulants. Concomitant administration of propranolol with trifluoperazine results in increased plasma levels of both drugs. Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concurrently. Potentiation may occur if antipsychotic drugs are combined with CNS depressants such as alcohol. hypnotics and anticonvulsant.

Volume of Distribution

Imipramine has a high apparent volume of distribution of 10-20 L/kg . The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation.

Elimination Route

Rapidly and well absorbed (>95%) after oral administration . The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food.

Half Life

24-48 hours

Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h .

10-20 hours

Clearance

Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg .

Elimination Route

Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.

Imipramine is primarily excreted in the urine with less than 5% present as the parent compound

Pregnancy & Breastfeeding use

Pregnancy category D. Limited data suggest that imipramine is likely to be excreted in human breast milk. Known risk of damage to fetus.

Pregnancy: Safety for the use of trifluoperazine during pregnancy has not been established. Therefore, it is not recommended that the drug be given to pregnant patients except when, in the judgement of the physician, it is essential. The potential benefits should clearly outweigh possible hazards. There are reported instances of prolonged jaundices, extrapyramidal signs, hyperreflexia or hypoflexia in newborn infants whose mother received phenothiazines.

Lactation: Adequate human data are not available in case of lactation.

Contraindication

Recent myocardial infarction, arrhythmias (particularly heart block), not indicated in manic phase, severe liver disease.

Do not use Trifluoperazine in comatose patients, or in those with existing blood dyscrasias or known liver damage, or in those hypersensitive to the active ingredient or related compounds.

Acute Overdose

Children have been reported to be more sensitive than adults to an acute overdosage of imipramine. An acute overdose in infants or young children must be considered serious and potentially fatal.

Signs and symptoms will be predominantly extrapyramidal; hypotension may occur. Treatment consists of gastric lavage together with supportive and symptomatic measures. Do not induce vomiting. Extra pyramidal symptoms may be treated with an anticholinergic, antiparkinsonism drug. Treat hypotension with fluid replacement; if severe or persistent. nor adrenaline may be considered. Adrenaline is contraindicated.

Storage Condition

Store in a cool & dry place, protected from light and moisture. Keep all medicines out of the reach of children.

It should be store at room temperature between 15-30° C away from light and moisture.

Innovators Monograph

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