Doxepin

Pharmacological properties

doxepin belongs to the group of tricyclic antidepressants. antidepressant effect is combined with anxiolytic and sedative.

Doxepin inhibits the reuptake of biogenic amines (norepinephrine and serotonin) in synaptic structures. Also has antihistamine, anticholinergic and α₁-adrenergic blocking effect. It does not cause euphoria, psychomotor agitation.

Pharmacokinetics Doxepin is well absorbed in the digestive tract, quickly (2-4 hours after administration) reaches C_max in blood plasma. A stable therapeutic concentration in the blood is achieved 2 weeks after the start of treatment.

Doxepin is metabolized in the liver mainly by demethylation with the formation of the main metabolite - desmethyldoxepine (Nordoxepine). The binding of doxepin and its metabolites to plasma proteins is about 76%. Distribution volume - about 20 l / kg of body weight. T_½ doxepin is 8-24 hours, the main active metabolite is 33-80 hours. Doxepin passes through the placenta and the BBB and passes into breast milk.

Indications

Neurotic disorders with symptoms of depression or anxiety. organic neurosis associated with insomnia. Depressive and anxiety in alcoholism. depression and anxiety associated with somatic disorders and diseases.

Depression accompanied by fear and anxiety on the background of psychosis, including involutional depression and the depressive phase of bipolar disorder.

Application

Take inside. the dose of the drug is selected individually depending on the severity of the symptoms and therapeutic effect.

The dose of doxepin is 30-300 mg / day. A dose of up to 100 mg can be used both once and divided. Doses in excess of 100 mg should be used in 3 divided doses. The maximum single dose is 100 mg (apply before bedtime). For moderate or severe symptoms, the usual starting dose is 75 mg / day. In most patients, this dose is effective. In severe forms of the disease, the dose is increased to 300 mg (in 3 divided doses) per day.

In patients with insomnia, the total dose should be distributed so that a higher dose is applied in the evening. In the event that insomnia is reported as an adverse reaction, this regimen can also be used or the dose should be reduced.

After achieving a satisfactory therapeutic effect, the dose should be adjusted to the minimum maintenance.

Reducing the severity of anxiety symptoms when taking Doxepin is achieved earlier than the antidepressant effect. The antidepressant effect manifests itself after 2-3 weeks of treatment.

Elderly patients with moderate symptoms of the disease are recommended half the usual recommended dose of doxepin hydrochloride (10-50 mg daily). Satisfactory clinical effects were obtained after the use of doxepin at a dose of 30-50 mg / day. The dose of the drug should be adjusted individually depending on the clinical response of the patient.

Patients with impaired liver function should reduce the dose.

Contraindications

Hypersensitivity to the drug, cross-sensitivity to other dibenzoxepins. manic syndrome; severe liver dysfunction; glaucoma; urinary retention; simultaneous use with MAO inhibitors or their use 2 weeks before treatment with doxepin. hypersensitivity to tricyclic antidepressants. urinary retention tendency.

Side effects

Doxepin is usually well tolerated. most moderate side effects occur at the beginning of treatment and disappear after drug withdrawal or dose reduction. some of the adverse reactions listed below are not specific to doxepin, however, the possibility of these reactions due to the similarity of its pharmacological properties with other tricyclic agents should be considered.

Adverse reactions are distributed according to the frequency of manifestations: very often (1/10), often (1/100, 1/10), infrequently (1/1000, 1/100), rarely (1/10 000, 1/1000), very rarely (1/10 000), unknown (frequency cannot be determined according to available information).

From the side of the nervous system and mental disorders: very often - drowsiness; infrequently - headache, dizziness, insomnia, nightmares, confusion, disorientation, anxiety, numbness or paresthesia, tremors (usually moderate). When using the drug in high doses (especially in elderly patients), extrapyramidal symptoms may occur, including tardive dyskinesia; rarely - hallucinations, ataxia (in general, if several drugs acting on the central nervous system are used), convulsions (in patients prone to seizures, which may be caused by brain damage or the use of alcohol and substance abuse); unknown - suicidal thoughts and behavior. Cases of the occurrence of suicidal thoughts and behavior were reported during treatment with doxepin or immediately after its withdrawal.

Mental manifestations, including mania and paranoid hallucinations, may be exacerbated by treatment with tricyclic antidepressants. Tinnitus has been reported occasionally.

From the side of the organ of vision: very rarely - impaired vision (blurred).

From the vascular system: rarely - orthostatic hypotension, flushing.

From the side of the heart: very rarely - tachycardia, ECG disorders (expansion of the QRS complex, lengthening of the P – R interval).

From the immune system: infrequently - allergic reactions, including rash, facial edema, increased photosensitivity, itching, urticaria. During treatment with tricyclic antidepressants, an exacerbation of AD is possible.

On the part of the skin and subcutaneous tissue: rarely - increased sweating, the above skin allergic reactions; very rarely - alopecia.

On the part of the blood system and lymphatic system: rarely - eosinophilia and bone marrow dysfunction with symptoms such as agranulocytosis, leukopenia, thrombocytopenia, purpura and hemolytic anemia.

From the digestive system: very often - dryness of the mucous membrane of the mouth and nose, constipation; rarely - nausea, vomiting, dyspepsia, taste disturbance, diarrhea, anorexia, stomatitis.

From the endocrine system: rarely - violation of the secretion of antidiuretic hormone, gynecomastia, breast enlargement, galactorrhea in women; isolated cases - a change in libido, swelling of the testicles, an increase or decrease in blood glucose.

From the kidneys and urinary system: rarely - urinary retention (in men with prostatic hypertrophy, complaints may intensify).

From the hepatobiliary system: rarely - jaundice.

General disorders: very often - fatigue, weakness, weight gain, chills, hyperpyrexia (in patients taking chlorpromazine at the same time).

Cancel doxepin. With the abrupt cancellation of tricyclic antidepressants, withdrawal symptoms can occur, including insomnia, irritability, and excessive sweating. Withdrawal symptoms in newborns whose mothers took tricyclic antidepressants in the third trimester include respiratory depression, convulsions and hyperreflexia.

special instructions

Patients with concomitant diseases or those taking other drugs should use a single dosage regimen. this also applies to patients using anticholinergic drugs.

Elderly people should also use this dosage regimen and with caution correct it. These patients are prone to developing adverse reactions such as anxiety, confusion, and orthostatic hypotension. Therefore, the initial dose should be prescribed with caution and under close monitoring of the patients condition and his reaction to the drug. Half the dose of doxepin may be sufficient for an appropriate clinical effect.

Patients should be cautioned that drowsiness may occur during treatment and alcohol intake may enhance the effect of the drug.

In case of worsening symptoms of psychosis or manic episodes during treatment with doxepin, a dose reduction of the drug or the addition of a group of tranquilizers (antipsychotics) to the treatment regimen may be required.

Although doxepin has less effect on the vascular system than other tricyclic antidepressants, it should be used with caution in patients with severe cardiovascular diseases (heart block, cardiac arrhythmia and recent myocardial infarction).

Caution is required when using doxepin in patients with impaired renal, hepatic, and persons with a history of epileptic seizures.

Suicide / suicidal thoughts or clinical impairment. In patients with severe depression, there is a risk of suicidal thoughts and actions that may persist until remission is achieved. In the case when improvement does not occur during the first few weeks of treatment or even more, patients need careful monitoring until the condition improves. It is known from general clinical practice that the risk of suicidal thoughts or actions may increase in the early stages of treatment.

In other psychiatric conditions for which doxepin is prescribed, there is also an increased risk of suicide. Therefore, for such patients, special precautions must be observed.

Careful monitoring is needed throughout the treatment of patients with a suicidal ideation or a history of suicide attempts.

Careful monitoring of patients, especially high-risk groups, should be combined with the use of appropriate drugs, especially in the early stages, followed by a change in dosage if necessary. It is required to inform patients (and those who are observing them) about the need to monitor if any clinical impairment, suicidal behavior, thoughts or unusual behavior changes occur and immediately seek medical help if these symptoms occur.

A meta-analysis of placebo-controlled studies using antidepressants in adult patients with mental disorders showed an increased risk of developing suicidal behavior in patients under the age of 25 years compared with placebo.

In patients with moderate prostate hypertrophy, urinary retention may increase.

Doxepin contains lactose monohydrate, therefore, patients with rare hereditary forms of galactose intolerance, glucose and galactose malabsorption syndrome, Lapp lactase deficiency are not recommended.

Patients with hypersensitivity or intolerance to gluten should not use this drug, since starch is included in its excipients.

Use during pregnancy or lactation. A study of reproductive function in animals did not reveal an adverse effect on the fetus; adequate and clear controlled studies in pregnant women have not been conducted. Thus, during pregnancy, the drug is used only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Doxepin passes into breast milk, so you should stop breast-feeding during treatment.

Children. Safety and efficacy of doxepin in children have not been established.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms.During treatment with doxepin, it is forbidden to drive vehicles or work with complex mechanisms that require concentration, since the drug can lead to drowsiness and other negative reactions from the central nervous system.

Interactions

With the simultaneous use of ethanol, antidepressants, barbiturates, benzodiazepines and general anesthetics, a significant increase in the inhibitory effect on the central nervous system, respiratory depression and hypotensive effect is possible. doxepin increases the anticholinergic effect of amantadine. phenothiazines, antiparkinsonian drugs, atropine, biperiden, antihistamines increase the risk of side effects from the central nervous system, vision, intestines, and bladder. with simultaneous use with antihistamines, clonidine, the inhibitory effect on the central nervous system increases, with atropine, the risk of paralytic intestinal obstruction increases, with drugs that cause extrapyramidal reactions, the body weight and the frequency of extrapyramidal effects increase. with the simultaneous use of doxepin with indirect anticoagulants (coumarin or indadione derivatives), an increase in the anticoagulant activity of the latter is possible. doxepin may increase depression caused by corticosteroids. when combined with anticonvulsants, it is possible to increase the inhibitory effect on the central nervous system, lower the threshold for convulsive readiness (when used in high doses) and reduce the effectiveness of the latter. drugs for the treatment of thyrotoxicosis increase the risk of agranulocytosis. doxepin reduces the effectiveness of phenytoin and α-blockers. microsomal oxidation inhibitors (cimetidine) lengthen t½, increase the risk of toxic effects of doxepin (may require a dose reduction of doxepin by 20-30%), inducers of microsomal liver enzymes (barbiturates, carbamazepine, phenytoin, nicotine and oral contraceptives) reduce plasma concentrations and the effectiveness of doxepin. fluoxetine and fluvoxamine increase the concentration of doxepin in the blood plasma (a dose reduction of doxepin by 50% may be required). with simultaneous use with anticholinergics, phenothiazines and benzodiazepines - mutual enhancement of the sedative and central anticholinergic effects and an increased risk of epileptic seizures (lowering the threshold for convulsive readiness); phenothiazines, in addition, may increase the risk of neuroleptic malignant syndrome. with the simultaneous use of doxepin with clonidine, guanethidine, betanidine, reserpine and methyldopa - a decrease in the hypotensive effect of the latter; with cocaine - the risk of developing cardiac arrhythmias. estrogen-containing oral contraceptives and estrogens may increase the bioavailability of doxepin; antiarrhythmic drugs (quinidine) increase the risk of rhythm disturbances (possibly slowing down the metabolism of doxepin). simultaneous use with disulfiram and acetaldehydrogenase inhibitors provoke delirium. incompatible with MAO inhibitors (an increase in the frequency of periods of hyperpyrexia, severe convulsions, a hypertensive crisis, and patient death is possible). pimozide and probucol can increase cardiac arrhythmia, which is manifested by lengthening the q – t interval by ecg. the effect on the cardiovascular system of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine increases (including when these agents are part of local anesthetics) and the risk of developing heart rhythm disturbances, tachycardia, and severe ag. the simultaneous use of α-adrenoreceptor blockers for intranasal administration or for use in ophthalmology (with significant systemic absorption) can enhance the vasoconstrictor effect of the latter.when combined with thyroid hormones, a mutual enhancement of the therapeutic effect and toxic effects (including cardiac arrhythmia and stimulating effect on the central nervous system). m-anticholinergics and antipsychotics increase the risk of hyperpyrexia (especially in hot weather).

Overdose

Symptoms: drowsiness, restlessness, dry mouth, stupor, impaired vision, arrhythmia. if such symptoms occur, the drug should be discontinued and the patient examined.

In severe overdose, there may be a decrease / increase in blood pressure, dilated pupils, tachycardia, urinary retention (atony of the bladder), ileus, hyperthermia / hypothermia, respiratory depression, increased sweating, convulsions, coma.

Treatment: stopping the drug, gastric lavage, mechanical ventilation, monitoring of the cardiovascular system, the use of sleeping pills. If necessary, the introduction of physostigmine salicylate 1-3 mg. Therapy is symptomatic. Hemodialysis and forced diuresis are ineffective.

Storage conditions

At a temperature not exceeding 25 ° c in a dark place.