Duloxenta 60mg capsules №28

Mechanism of action

Antidepressant, serotonin reuptake inhibitor and norepinephrine (norepinephrine). Weakly inhibits dopamine uptake, does not have significant affinity for histamine, dopamine, cholinergic and adrenergic receptors. The mechanism of action of duloxetine is to suppress the reuptake of serotonin and norepinephrine (norepinephrine). Duloxetine has a central mechanism for the suppression of pain, which is primarily manifested by an increase in the pain sensitivity threshold in pain syndrome of neuropathic etiology.

Pharmacokinetics

After ingestion, duloxetine is well absorbed from the gastrointestinal tract, absorption begins 2 hours after ingestion, C_max reached 6 hours after administration. Reception simultaneously with food increases the time to reach C_max up to 10 h, which reduces the degree of absorption (approximately 10%), but does not affect the value of C_max.

Plasma protein binding is high (more than 90%), mainly with albumin and α₁-globulin. Violations of the liver or kidneys do not affect the degree of protein binding. Duloxetine is actively biotransformed with the participation of CYP2D6 and CYP1A2 isoenzymes, which catalyze the formation of two major metabolites (the glucuronic conjugate of 4-hydroxiduloxetine,sulfate conjugate 5-hydroxy, 6-methoxydioxetine). Circulating metabolites do not possess pharmacological activity. T_1/2 is 12 h. The average clearance of duloxetine is 101 l / h. Excreted in the urine as metabolites.

In patients with end-stage chronic renal failure on hemodialysis, C values_max and AUC of duloxetine increased by 2 times. In this regard, it is necessary to consider the feasibility of reducing the dose of the drug in patients with clinically expressed impaired renal function.

Patients with clinical signs of liver failure may experience slower metabolism and duloxetine elimination. After a single dose of duloxetine in a dose of 20 mg in 6 patients with cirrhosis of the liver and moderate liver dysfunction (Child-Pugh class B) duration T_1/2 duloxetine was approximately 15% higher than that of healthy people of the corresponding sex and age with a fivefold increase in the average AUC. Although C_max patients with cirrhosis were the same as in healthy people, T_1/2 about 3 times more.

Indications drug Duloxetine

Depression, painful form of diabetic neuropathy.

Dosage and administration

The recommended initial dose is 60 mg 1 time / day.

If necessary, you can increase the daily dose from 60 mg to a maximum dose of 120 mg / day in 2 divided doses.

In patients with severe impaired renal function (CC <30 ml / min), the initial dose should be 30 mg 1 time / day.In patients with impaired liver function, reduce the initial dose of the drug or reduce the frequency of administration.

Side effect

From the side of the central nervous system: often - dizziness (except vertigo), sleep disturbances (drowsiness or insomnia), headache (headache was less common than in the placebo); sometimes - tremor, weakness, blurred vision, lethargy, anxiety, yawning; very rarely - glaucoma, mydriasis, visual impairment, agitation, disorientation.

Gastrointestinal: often - dry mouth, nausea, constipation; sometimes - diarrhea, vomiting, loss of appetite, change in taste, impaired liver function indicators; very rarely - hepatitis, jaundice, increased activity of alkaline phosphatase, ALT, AST and bilirubin level; belching, gastroenteritis, stomatitis.

Musculoskeletal system: sometimes muscle tension and / or twitching; very rarely - bruxism.

Cardiovascular: sometimes palpitations; very rarely - orthostatic hypotension, syncope (especially at the beginning of therapy), tachycardia, increased blood pressure, cooling of the extremities.

From the reproductive system: sometimes - anorgasmia, decreased libido, delayed and impaired ejaculation, erectile dysfunction.

Urogenital: sometimes - difficulty urinating; very rarely - nocturia.

Other: sometimes - weight loss, increased sweating, hot flashes, night sweats; very rarely - Anaphylactic reactions, thirst, hyponatremia, chills,angioedema, rash, Stevens-Johnson syndrome, urticaria, feeling unwell, feeling hot and / or cold, weight gain, dehydration, photosensitization. When canceled, dizziness, nausea, and headache were often noted. In patients with the painful form of diabetic neuropathy, a slight increase in fasting blood glucose can be observed.

Contraindications

Uncompensated angle-closure glaucoma, simultaneous use with MAO inhibitors, hypersensitivity to duloxetine.

Use during pregnancy and lactation

Use of the drug during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus, because Clinical experience with duloxetine during pregnancy is not enough.

If necessary, the use of the drug during lactation should decide on the termination of breastfeeding (due to lack of experience with the application).

Patients should be warned that in the event of the onset or planning of pregnancy during the period of use of duloxetine, they should be informed about this by their attending physician.

Application for violations of the liver

With caution used in violation of the liver. In patients with impaired liver function, reduce the initial dose of the drug or reduce the frequency of administration.

Application for violations of kidney function

With caution used in violation of the kidneys.In patients with severe impaired renal function (CC <30 ml / min), the initial dose should be 30 mg 1 time / day.

Special notes

It is used with caution in exacerbation of manic / hypomania state, epileptic seizures, mydriasis, impaired liver or kidney function, in patients with suicidal tendencies.

When prescribing serotonin reuptake inhibitors in combination with MAO inhibitors, there have been cases of serious reactions, sometimes fatal (hyperthermia, rigidity, myoclonus, various disorders with possible drastic fluctuations in the vital functions of the body and changes in mental status, including pronounced agitation with going into delirium and to whom). Such reactions are also possible in cases where the serotonin reuptake inhibitor was canceled shortly before administration of MAO inhibitors (symptoms may develop, including those characteristic of a malignant neuroleptic syndrome).

The effects of the combined use of duloxetine and MAO inhibitors have not been evaluated in humans or animals. The use of duloxetine simultaneously with MAO inhibitors or for up to 14 days after their cancellation is not recommended, since duloxetine is a serotonin reuptake inhibitor, and norepinephrine (norepinephrine). MAO inhibitors should not be prescribed for at least 5 days after discontinuation of duloxetine.

Use with caution in patients with a history of manic episodes, as well as with epileptic seizures in history.

Depressive states are accompanied by a high risk of suicidal behavior.As a consequence, patients with a diagnosis of depression taking duloxetine should inform the physician of any disturbing thoughts and feelings.

With the use of the drug may develop mydriasis, caution should be exercised in the appointment of duloxetine in patients with elevated intraocular pressure or in individuals at risk of developing acute angle-closure glaucoma.

In patients with arterial hypertension and / or other diseases of the cardiovascular system, it is recommended to monitor blood pressure.

Influence on ability to drive motor transport and control mechanisms

Patients taking duloxetine should use caution when engaging in potentially hazardous activities (due to possible drowsiness).

Drug interaction

The simultaneous use of duloxetine (at a dose of 60 mg 2 times / day) did not have a significant effect on the pharmacokinetics of theophylline, metabolized by CYP1A2. Duloxetine is unlikely to have a clinically significant effect on the metabolism of other drugs - CYP1A2 substrates.

Simultaneous administration of duloxetine with potential inhibitors of CYP1A2 (for example, fluoroquinolones) may lead to an increase in the concentration of duloxetine, since CYP1A2 is involved in the metabolism of duloxetine (the appointment of such a combination requires caution and lower doses of duloxetine).

The potent CYP1A2 inhibitor fluvoxamine (when taken at a dose of 100 mg 1 time per day) reduced the average plasma clearance of duloxetine by about 77%.

When prescribing duloxetine with drugs metabolized by CYP2D6 and having a narrow therapeutic index, caution should be exercised (since duloxetine is a moderate CYP2D6 inhibitor). With simultaneous use with duloxetine at a dose of 60 mg 2 times / day, the AUC of desipramine (CYP2D6 substrate) increases 3-fold. Simultaneous use with duloxetine (at a dose of 40 mg 2 times / day) increased the stable part of the AUC of tolterodine (used at a dose of 2 mg 2 times / day) by 71%, but did not affect the pharmacokinetics of the 5-hydroxyl metabolite. The simultaneous use of duloxetine with potential inhibitors of CYP2D6 can lead to an increase in duloxetine concentrations. Paroxetine (when used in a dose of 20 mg 1 time / day) reduced the average clearance of duloxetine by approximately 37%. When using duloxetine with CYP2D6 inhibitors (for example, with selective serotonin reuptake inhibitors), caution should be exercised.

With the simultaneous use of duloxetine and other drugs that affect the central nervous system and have a similar mechanism of action (including ethanol and ethanol-containing drugs), mutual reinforcement of effects is possible (this combination requires caution).

Duloxetine binds to plasma proteins to a significant degree, therefore simultaneous use with other drugs that bind to plasma proteins to a high degree can lead to an increase in the concentration of free fractions of both drugs.