PRESARTAN-50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXEPIN-ZN (DOXEPIN-ZN)

Composition

active substance: doxepin hydrochloride; 1 hard capsule contains doxepin hydrochloride in terms of doxepin 25 mg; excipients: pre-gelatinized starch (granulated), magnesium stearate, sodium lauryl sulfate, gelatin, quinoline yellow (E 104), erythrosine (E 127), titanium dioxide (E 171).

Pharmaceutical Form

Hard capsules.

Main Physico-Chemical Properties

Hard gelatin capsules No. 3 with a white body and a yellow cap with hemispherical ends. The contents of the capsules are a powder of almost white color.

Pharmacotherapeutic Group

Antidepressants. Non-selective inhibitors of neuronal monoamine reuptake.

ATC Code N06A A12.

Pharmacological Properties

Pharmacodynamics

Doxepin hydrochloride belongs to the group of tricyclic antidepressants (TCAs). The antidepressant effect is combined with anxiolytic and sedative effects.

Doxepin hydrochloride inhibits the reuptake of biogenic amines (norepinephrine and serotonin) in synaptic structures. It also has antihistamine, anticholinergic, and alpha-1 adrenergic blocking effects. It does not cause euphoria or psychomotor stimulation.

Pharmacokinetics

Doxepin hydrochloride is well absorbed from the gastrointestinal tract, quickly (within 2-4 hours after administration) reaching maximum concentration in serum. A stable therapeutic concentration in the blood is achieved approximately 2 weeks after the start of treatment.

Doxepin hydrochloride is metabolized in the liver, mainly by demethylation with the formation of the main active metabolite - desmethyldoxepin (nordoxepin). The binding of doxepin and its metabolites to plasma proteins is about 76%. The volume of distribution is approximately 20 L/kg. The half-life of doxepin is 8-24 hours, and the main active metabolite is 33-80 hours. Doxepin hydrochloride passes through the placenta and the blood-brain barrier and enters 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 background of psychoses, including involutional depression and the depressive phase of bipolar disorders.

Contraindications

• Increased sensitivity to doxepin, TCA, or any of the excipients;
• manic state;
• severe liver dysfunction;
• breastfeeding period;
• glaucoma;
• tendency to urine retention;
• concomitant use with monoamine oxidase inhibitors (MAOIs) or use of the latter within two weeks before starting doxepin therapy.

Interaction with Other Medicinal Products and Other Types of Interactions

Drugs metabolized by CYP2D6: the biochemical activity of the metabolizing enzyme isoform of cytochrome P450 (CYP) 2D6 (debrisoquine hydroxylase) is reduced in a subgroup of the Caucasian population (approximately 7-10% of Caucasians are so-called "slow metabolizers"); there is no reliable assessment of the prevalence of reduced activity of the CYP2D6 isoform among Asian, African, and other populations. "Slow metabolizers" have a higher than expected plasma concentration of TCA when using standard doses. Depending on the fraction of the drug metabolized by CYP2D6, the increase in plasma concentration may be small or quite significant (8-fold increase in TCA AUC in plasma).

In addition, certain drugs inhibit the activity of this isoform and make "normal metabolizers" similar to "slow metabolizers". A stable dose of TCA for a patient may become suddenly toxic when using one of these inhibiting drugs as concomitant therapy. Drugs that inhibit CYP2D6 include those that are not metabolized by the enzyme (quinidine, cimetidine) and many that are substrates for CYP2D6 (many other antidepressants, phenothiazines, and antiarrhythmic drugs of type 1C propafenone and flecainide). Although all selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit CYP2D6, they may differ in the degree of inhibition. The degree of SSRI-TCA interaction may cause clinical problems and will depend on the degree of inhibition and the pharmacokinetics of the involved SSRIs. Nevertheless, caution should be exercised when concomitantly using TCA with any of the SSRIs, as well as when switching from one class to another. It is especially important that before starting TCA treatment in a patient who is stopping fluoxetine, sufficient time should pass, taking into account the long half-life of the active substance and its active metabolite (at least 5 weeks may be required).

Concomitant use of TCA with drugs that may inhibit CYP2D6 may require lower doses than those usually prescribed for TCA or another drug. In addition, whenever one of these other drugs is withdrawn from combination therapy, it may be necessary to increase the dose of TCA. It is desirable to monitor TCA levels in plasma blood whenever TCA is planned to be used in combination with another drug that is known to be a CYP2D6 inhibitor.

Doxepin is primarily metabolized by CYP2D6 (and CYP1A2 and CYP3A4 as secondary isoforms). Inhibitors or substrates of CYP2D6 (i.e., quinidine, SSRIs) may increase the plasma concentration of doxepin when used concomitantly. The degree of interaction depends on the variability of the effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated.

MAOIs: serious side effects and even death have been reported after concomitant use of certain drugs with MAOIs. Therefore, the use of MAOIs should be stopped at least two weeks before the cautious start of therapy with the medicinal product. The exact duration may vary and depends on the specific MAOI used, the duration of its administration, and the dose.

Serotoninergic drugs, such as buprenorphine, when used concomitantly with doxepin, may increase the risk of developing serotonin syndrome, a potentially life-threatening condition (see the "Special Instructions" section).

Cimetidine: it has been reported that cimetidine causes clinically significant fluctuations in steady-state concentrations of various TCAs in serum. Serious anticholinergic symptoms (i.e., severe dry mouth, urine retention, and blurred vision) have been associated with increased TCA levels in serum at the start of cimetidine therapy. In addition, higher than expected TCA levels have been observed in patients already taking cimetidine. In patients who have been reported to respond well to TCA therapy and are receiving concomitant cimetidine therapy, it has been reported that stopping cimetidine decreases established steady-state TCA levels in serum and worsens their therapeutic effect.

Alcohol: it should be noted that alcohol consumption may increase the risk associated with any intentional or unintentional overdose of the medicinal product. This is especially important for patients who may abuse alcohol.

Tolazamide: a case of severe hypoglycemia has been reported in a patient with type II diabetes who received tolazamide (1 g/day) 11 days after adding doxepin (75 mg/day).

Special Instructions

Patients with concomitant diseases or patients taking other medicinal products should be given a single-dose regimen. This also applies to patients who are taking drugs with anticholinergic effects.

Elderly patients should also be given this dosing regimen and with caution, adjusting it. These patients are prone to developing side effects such as anxiety, confusion, and orthostatic hypotension. Therefore, the initial dose should be prescribed with caution and under close monitoring of the patient's condition and their response to the drug. For the corresponding clinical effect, half the dose of doxepin may be sufficient.

Patients should be warned that during treatment, drowsiness may occur, and alcohol consumption may enhance the effect of the drug.

In the event of worsening symptoms of psychosis or manic episodes during treatment with doxepin, it may be necessary to reduce the dose of doxepin or add drugs from the group of tranquilizers (neuroleptics) to the treatment regimen.

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

Doxepin should be used with caution in patients with liver, kidney dysfunction, and patients with a history of epileptic seizures.

Serotonin Syndrome

Concomitant use of doxepin and other serotoninergic agents, such as buprenorphine, may lead to serotonin syndrome, a potentially life-threatening condition (see the "Interaction with Other Medicinal Products and Other Types of Interactions" section).

Suicidal/Suicidal Thoughts or Clinical Worsening

In patients with pronounced depression, there is a risk of suicidal thoughts and actions, which may persist until significant remission is achieved. Since improvement may not occur within the first few weeks of treatment or even more, patients require close monitoring until their condition improves. It is known from general clinical practice that the risk of suicidal thoughts or actions may increase at the early stages of treatment.

In other psychiatric conditions for which doxepin is prescribed, there is also an increased risk of suicidal events. In addition, these conditions may be comorbid with major depressive disorder. Therefore, the precautions taken when treating major depressive disorder should be taken when treating patients with other mental disorders.

Close monitoring is necessary throughout treatment for patients with suicidal thoughts or attempts in their history or with a significant level of suicidal thinking before starting treatment.

Close monitoring of patients, especially high-risk groups, should be combined with the appointment of appropriate medicinal products, especially at the early stages, with subsequent dose adjustment if necessary. Patients (and those caring for them) should be informed about the need to monitor for the occurrence of any clinical worsening, suicidal behavior, thoughts, or unusual changes in behavior and to seek medical help immediately if these symptoms occur.

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

In patients with moderate prostatic hyperplasia, urinary retention may worsen.

Use During Pregnancy or Breastfeeding

Reproductive function studies in animals have not revealed adverse effects on the fetus; adequate and well-controlled studies in pregnant women have not been conducted. Therefore, the medicinal product can be used in pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus.

Doxepin-ZN passes into breast milk, so breastfeeding should be stopped during treatment with the medicinal product.

Ability to Affect Reaction Speed When Driving or Operating Other Mechanisms

During treatment with doxepin, it is not allowed to drive vehicles or work with complex mechanisms that require concentration of attention, as doxepin may cause drowsiness and increase the reaction time.

Method of Administration and Dosage

Administer orally. The dose of the medicinal product should be selected individually, depending on the severity of symptoms and the therapeutic effect.

The dose of doxepin is 30-300 mg per day. A dose of up to 100 mg can be administered as a single dose or divided. Doses exceeding 100 mg should be administered in 3 doses. The maximum single dose is 100 mg (usually administered before bedtime).

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

In most patients, this dose is satisfactory. For severe forms of the disease, the daily dose can be increased to 300 mg (in 3 doses).

In patients with insomnia, the total dose should be distributed so that the highest dose is administered in the evening. In cases where insomnia is reported as a side effect, this dosing regimen can also be used, or the dose should be reduced.

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

Relief of anxiety symptoms when taking doxepin is achieved earlier than the antidepressant effect. The antidepressant effect manifests within 2-3 weeks of treatment.

Elderly patients with moderate symptoms of the disease are recommended to take half the usual recommended dose of doxepin (10-50 mg per day). Satisfactory clinical effects were achieved after administration of doxepin at a dose of 30-50 mg per day. The dose of the medicinal product should be adjusted individually, depending on the patient's clinical response.

Patients with liver dysfunction should have their doses reduced.

Children

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

Overdose

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

If such symptoms occur, the administration of the medicinal product should be stopped, and the patient should be examined.

If necessary, supportive therapy should be prescribed.

In cases of severe overdose, the following may be possible: drowsiness, respiratory depression, decreased/increased blood pressure, coma, seizures, arrhythmia, tachycardia, urine retention (urinary bladder atony), decreased peristalsis (functional intestinal obstruction), hyperthermia (or hypothermia), dilated pupils, hyperactive reflexes.

There have been reports of fatal cases of doxepin overdose when used alone or in combination with other medicinal products or alcohol.

Treatment: discontinuation of the medicinal product, gastric lavage, artificial ventilation of the lungs, monitoring of the cardiovascular system, administration of sedatives. If necessary, intravenous administration of physostigmine salicylate 1-3 mg. In cases of seizures, standard anticonvulsant therapy may be necessary. However, barbiturates may enhance respiratory depression. Hemodialysis and forced diuresis are ineffective.

Side Effects

Doxepin-ZN is generally well tolerated. Most side effects are mild, they are observed at the beginning of treatment, and they disappear during further administration of the medicinal product or when reducing its dose if necessary. Some side effects listed below are not specific to doxepin but should be considered due to the similarity of its pharmacological properties with other tricyclic agents.

From the Nervous System and Mental Disorders

Very often: drowsiness.

Rarely: headache, dizziness, insomnia, nightmares, confusion, disorientation, agitation, numbness or paresthesia, tremor (usually of moderate severity). When using high doses (especially in elderly patients), extrapyramidal symptoms, including late dyskinesia, may occur.

Rarely: hallucinations, ataxia (usually if several central nervous system-acting drugs are used), convulsions (in patients prone to seizures, which may be caused by brain damage or alcohol and drug use).

Unknown: suicidal thoughts and behavior.

From the Organs of Vision

Very rarely: vision disturbances (blurred vision).

From the Organs of Hearing

Rarely: tinnitus.

From the Vascular System

Rarely: orthostatic hypotension, facial hyperemia.

From the Cardiovascular System

Very rarely: tachycardia, ECG disturbances (QRS complex prolongation, PR interval prolongation).

From the Immune System

Rarely: allergic reactions, including skin rashes, facial edema, increased photosensitivity, itching, urticaria.

During treatment with TCAs, exacerbation of bronchial asthma is possible.

From the Skin and Subcutaneous Tissue

Rarely: increased sweating, skin allergic reactions mentioned above.

Very rarely: alopecia.

From the Blood and Lymphatic System

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

From the Gastrointestinal Tract

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

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

From the Endocrine System

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

Very rarely: increased or decreased libido, testicular edema, increased or decreased blood glucose levels.

From the Kidneys and Urinary System

Rarely: urinary retention (in men, where this disturbance is a consequence of prostatic hyperplasia, complaints may worsen).

From the Hepatobiliary System

Rarely: jaundice.

General Disorders

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

Withdrawal of Doxepin

When suddenly stopping TCA, withdrawal symptoms may occur in newborns whose mothers took TCA during the third trimester, including respiratory depression, convulsions, and hyperreflexia.

Reporting of Side Effects

Reporting side effects after the registration of the medicinal product is important. This allows monitoring the benefit/risk ratio of using this medicinal product. Medical and pharmaceutical workers, as well as patients or their authorized representatives, should report all cases of suspected side effects and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf Life

2 years.

Storage Conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Store in a place inaccessible to children.

Packaging

10 capsules in a blister pack; 3 blister packs in a cardboard box.

Release Category

By prescription.

Manufacturer

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu"."

Location of the Manufacturer and Address of the Place of Its Activities

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kulykivska street, building 41.