Doxepin

INSTRUCTIONS for medical use of the medicinal product DOXEPIN (Doxepin)

Composition:

Active substance: doxepin;

1 capsule contains doxepin 10 mg or 25 mg as doxepin hydrochloride;

Excipients: maize starch, lactose monohydrate, magnesium stearate, sodium lauryl sulfate;

Capsule shell: indigocarmine (E 132), titanium dioxide (E 171), gelatin, erythrosine (E 127); for 10 mg capsules, patented blue V (E 131) is additionally included.

Pharmaceutical form. Capsules.

Main physicochemical properties:

for 10 mg capsules: body – blue, cap – cherry red;

for 25 mg capsules: body – pink, cap – cherry red;

white powder in cylindrical-shaped capsules with rounded ends, size № 4.

Pharmacotherapeutic group. Antidepressants. Non-selective inhibitors of neuronal monoamine reuptake. ATC code N06A A12.

Pharmacological properties.

Pharmacodynamics. Doxepin belongs to the group of tricyclic antidepressants. Its antidepressant effect is combined with anxiolytic and sedative actions.

Doxepin reversibly inhibits the reuptake of biogenic amines (noradrenaline and serotonin) in synaptic structures and also exerts antihistaminic, anticholinergic, and α1-adrenergic blocking effects. It does not cause euphoria or psychomotor stimulation.

Pharmacokinetics.

Doxepin is well absorbed from the gastrointestinal tract and rapidly reaches maximum plasma concentration within 2–4 hours after administration. A stable therapeutic blood concentration is achieved approximately 2 weeks after the start of treatment.

Doxepin is metabolized in the liver, primarily via demethylation, forming the main active metabolite—desmethyldoxepin (nordoxepin). Protein binding of doxepin and its metabolites is approximately 76%. Volume of distribution is about 20 L/kg. The elimination half-life of doxepin ranges from 8 to 24 hours, while that of the primary active metabolite is 33 to 80 hours. Doxepin crosses the placenta and the blood-brain barrier and penetrates into breast milk.

Clinical characteristics.

Indications.

• Neurotic disorders with symptoms of depression or anxiety.
• Organic neuroses associated with insomnia.
• Depressive and anxiety states in alcoholism.
• Depression and anxiety states associated with somatic disorders and diseases.
• Depression accompanied by fear and anxiety in the context of psychoses, including involutional depression and the depressive phase of bipolar disorders.

Contraindications.

• Hypersensitivity to doxepin, tricyclic antidepressants, or to any of the excipients of the medicinal product;
• Manic state;
• Severe hepatic impairment;
• Breastfeeding period;
• Glaucoma;
• Predisposition to urinary retention;
• Concomitant use with monoamine oxidase inhibitors (MAOIs), or use of MAOIs within two weeks prior to initiation of doxepin therapy.

Interaction with other medicinal products and other forms of interactions.

Metabolism of doxepin, as with other tricyclic antidepressants, is mediated by cytochrome P450 isoenzymes (CYP2D6). Concomitant use of inhibitors or substrates of these isoenzymes (e.g., quinidine, selective serotonin reuptake inhibitors) with doxepin may lead to increased plasma concentrations of tricyclic antidepressants.

Increased pharmacological effects of doxepin should be considered when it is used concomitantly with other antidepressants, alcohol, or anxiolytic agents. Since MAO inhibitors are known to potentiate the effects and adverse reactions of other medicinal products, doxepin must not be used concomitantly with MAO inhibitors or within two weeks after discontinuation of such therapy.

Serotonergic medicinal products, such as buprenorphine, may increase the risk of serotonin syndrome—a potentially life-threatening condition—when used concomitantly with doxepin (see section "Special precautions").

Cimetidine causes significant fluctuations in the steady-state concentration of doxepin.

Doxepin must not be used concomitantly with sympathomimetics such as ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine.

Analgesic agents for systemic or local use containing sympathomimetics, when used during antidepressant therapy, may increase the risk of arrhythmias and arterial hypotension or hypertension. If surgery is required, the anesthesiologist must be informed about the patient's ongoing therapy.

Doxepin may reduce the effect of antihypertensive agents such as debrisoquine, betanidine, guanethidine, and clonidine. To prevent the influence of doxepin on the effect of guanethidine, the dose of doxepin should not exceed 150 mg. Monitoring of the patient is recommended when any antihypertensive agents are used concomitantly with tricyclic antidepressants.

Barbiturates may accelerate the metabolism of doxepin.

Doxepin may reduce the effectiveness of sublingual nitrate formulations.

Concomitant use of doxepin may require a reduction in the dose of thyroid hormones.

Special precautions for use.

Patients with concomitant diseases or those taking other medicinal products are recommended to follow a single dose regimen. This also applies to patients using drugs with anticholinergic effects.

Elderly patients should also follow this dosing regimen and dosage adjustments should be made cautiously. These patients are prone to developing adverse reactions such as anxiety, confusion, and orthostatic hypotension. Therefore, initial doses should be prescribed cautiously and under close monitoring of the patient's condition and response to the drug. For adequate clinical effect, half the dose of doxepin may be sufficient.

Patients should be warned that drowsiness may occur during treatment. Alcohol consumption may enhance the effect of the medicinal product.

If symptoms of psychosis or manic episodes worsen during treatment with doxepin, dose reduction of doxepin or addition of neuroleptic agents 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 disorders (heart block, cardiac arrhythmia, and recent myocardial infarction).

Doxepin should be used cautiously in patients with impaired renal or hepatic function and in patients with a history of epileptic seizures.

Serotonin syndrome

Concomitant use of doxepin and other serotonergic agents, such as buprenorphine, may lead to serotonin syndrome, a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

Suicide/suicidal thoughts or clinical worsening

In patients with marked depression, there is a risk of suicidal thoughts and behaviors, which may persist until significant remission is achieved. Since improvement may not occur during the first few weeks of treatment or even longer, careful monitoring of patients is required until their condition improves. Clinical experience shows that the risk of suicidal thoughts or behaviors may increase in the early stages of treatment.

Other psychiatric conditions for which doxepin is prescribed are also associated with an increased risk of suicide. Moreover, these conditions may be comorbid with major depressive disorder. Therefore, the same precautions applied in treating major depressive disorder should also be observed when treating patients with other psychiatric disorders.

Careful monitoring throughout the treatment period is essential for patients with a history of suicidal thoughts or suicide attempts, or with significant levels of suicidal ideation prior to starting treatment. Close monitoring of patients, especially those at high risk, should be combined with appropriate drug prescription, particularly in the early stages, with subsequent dose adjustments as necessary. Patients (and caregivers) should be advised to closely monitor any clinical worsening, suicidal behavior or thoughts, or unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

A meta-analysis of placebo-controlled trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age compared to placebo.

Urinary retention may be exacerbated in patients with moderate severity benign prostatic hyperplasia.

Doxepin contains lactose monohydrate and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Patients with gluten sensitivity or intolerance should not use Doxepin, as corn starch, an excipient in the formulation, may contain gluten.

Use during pregnancy or breastfeeding.

Reproductive studies in animals have not shown any adverse effects on the fetus. Adequate and well-controlled studies in pregnant women have not been conducted; therefore, the drug should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Doxepin is excreted in breast milk; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Driving vehicles or operating complex machinery requiring concentration of attention is not permitted during treatment with doxepin, as doxepin may cause drowsiness and prolong reaction time.

Method of Administration and Dosage

Administered orally. The dosage is individually adjusted by a physician depending on the severity of symptoms and therapeutic response.

The dose of Doxepin ranges from 30 to 300 mg per day. A dose up to 100 mg may be administered as a single dose or divided. Doses exceeding 100 mg should be divided into three doses. The maximum single dose is 100 mg (usually taken at bedtime).

For moderate or severe symptoms, the usual initial dose is 75 mg daily.

This dose is adequate for most patients. In severe cases, the daily dose may be increased up to 300 mg (in three divided doses).

In patients with insomnia, the total daily dose should be distributed so that the highest dose is taken in the evening. If insomnia occurs as a side effect, the drug may be administered according to this regimen or the dose should be reduced.

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

Anxiety symptom relief occurs earlier with Doxepin than the antidepressant effect. The antidepressant effect becomes apparent after 2–3 weeks of treatment.

For elderly patients with moderate symptoms, half the usual recommended dose of doxepin is recommended (10–50 mg daily). Satisfactory clinical effects have been achieved with doxepin doses of 30–50 mg daily. The dose should be individually adjusted based on the patient's clinical response.

Dosage should be reduced in patients with impaired liver function.

Children

The safety and efficacy of doxepin in children have not been established.

Overdose

Symptoms: drowsiness, stupor, visual disturbances, dry mouth.

If such symptoms occur, the drug should be discontinued and the patient examined.

Supportive therapy should be administered as needed.

In cases of severe overdose, possible symptoms include: drowsiness, respiratory depression, hypotension or hypertension, coma, seizures, arrhythmia, tachycardia, urinary retention (bladder atony), decreased peristalsis (functional intestinal obstruction), hyperthermia (or hypothermia), mydriasis, hyperactive reflexes. Fatal outcomes have been reported following doxepin overdose, both as monotherapy and in combination with other drugs or alcohol.

Treatment: Discontinue the drug, perform gastric lavage, provide artificial ventilation of the lungs, monitor cardiovascular function, administer sedatives as needed. If necessary, intravenous administration of 1–3 mg physostigmine salicylate may be considered. In cases of seizures, standard anticonvulsant therapy may be required; however, barbiturates may potentiate respiratory depression. Hemodialysis and forced diuresis are ineffective.

Adverse Reactions

Doxepin is generally well tolerated. Most adverse reactions are mild in severity. They usually occur at the beginning of treatment and resolve with continued use of the medication or upon dose reduction (if necessary). Some of the adverse reactions listed below are not specific to doxepin; however, the possibility of their occurrence should be considered due to similarities in its pharmacological properties with other tricyclic agents.

Adverse reactions are categorized by frequency of occurrence: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000); unknown (frequency cannot be estimated from available data).

Central nervous system and psychiatric disorders

Very common: drowsiness.

Uncommon: headache, dizziness, insomnia, nightmares, confusion, disorientation, agitation, numbness or paresthesia, tremor (usually mild to moderate). Extrapyramidal symptoms, including tardive dyskinesia, may occur during treatment with high doses (especially in elderly patients).

Rare: hallucinations, ataxia (generally when multiple CNS-acting drugs are used), seizures (in patients predisposed to seizures due to brain injury or use of alcohol and psychoactive substances).

Unknown: suicidal thoughts and behavior*.

Eye disorders

Very rare: visual disturbances (blurred vision).

Ear and labyrinth disorders

Rare: tinnitus.

Vascular disorders

Rare: orthostatic hypotension, facial flushing.

Cardiac disorders

Very rare: tachycardia, ECG abnormalities (QRS complex widening, PR interval prolongation).

Immune system disorders

Uncommon: allergic reactions, including skin rash, facial swelling, increased photosensitivity, itching, urticaria.

Exacerbation of bronchial asthma may occur during treatment with tricyclic antidepressants.

Skin and subcutaneous tissue disorders

Rare: increased sweating, skin allergic reactions as mentioned above.

Very rare: alopecia.

Blood and lymphatic system disorders

Rare: eosinophilia and bone marrow dysfunction with symptoms such as agranulocytosis, leukopenia, thrombocytopenia, purpura, and hemolytic anemia.

Gastrointestinal disorders

Very common: dryness of mucous membranes of mouth and nose, constipation.

Rare: nausea, vomiting, dyspepsia, taste disturbances, diarrhea, anorexia, aphthous stomatitis.

Endocrine disorders

Rare: disturbances in antidiuretic hormone secretion, gynecomastia, breast enlargement, galactorrhea in women.

Isolated cases: increased or decreased libido, testicular swelling, increased or decreased blood glucose levels.

Renal and urinary disorders

Rare: urinary retention (in men whose condition is due to prostatic hyperplasia, symptoms may worsen).

Hepatobiliary disorders

Rare: jaundice.

General disorders

Very common: fatigue, weakness, weight gain, chills, hyperpyrexia (in patients concurrently taking chlorpromazine).

* Cases of suicidal thoughts and suicidal behavior have been reported during doxepin therapy or shortly after discontinuation (see section "Special precautions").

Psychotic symptoms, including mania and paranoid delusions, may be exacerbated during treatment with tricyclic antidepressants.

Discontinuation of doxepin

Symptoms of withdrawal may occur following abrupt discontinuation of tricyclic antidepressants, including insomnia, irritability, and excessive sweating. Withdrawal symptoms in newborns whose mothers took tricyclic antidepressants during the third trimester include respiratory depression, convulsions, and hyperreflexia.

Class-specific effects of SSRIs

Epidemiological studies, mainly involving patients aged 50 years and older, have shown an increased risk of bone fractures in patients treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. The mechanism of this risk is unknown.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Packaging.

10 capsules per blister; 3 blisters per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

TEVA OPERATIONS POLAND SP. Z O.O.

Manufacturer's address and place of business.

80 Mogilska Street, 31-546 Kraków, Poland.