Depratal^® (Tablets) Instructions for Use

Marketing Authorization Holder

Adamed Pharma, S.A. (Poland)

ATC Code

N06AX21 (Duloxetine)

Active Substance

Duloxetine (Rec.INN registered by WHO)

Dosage Forms

	Depratal®	Enteric-coated film-coated tablets, 30 mg: 7, 14, or 28 pcs.
		Enteric-coated film-coated tablets, 60 mg: 7, 14, or 28 pcs.

Dosage Form, Packaging, and Composition

Enteric-coated film-coated tablets white or almost white, round, biconvex; on one side of the tablet there is an engraving in the form of a curved line ( ).

Excipients : compressible sugar (Compessus MS) – 100 mg, corn starch – 14.14 mg, magnesium stearate – 0.75 mg.

Enteric coating: methacrylic acid-ethyl acrylate copolymer (1:1) dispersion (30%) in terms of dry substance – 9 mg, triethyl citrate – 1.35 mg, micronized talc – 2.69 mg, titanium dioxide – 0.39 mg, simethicone emulsion – q.s.

7 pcs. – blisters (1) – cardboard packs with first opening control.
7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.

Enteric-coated film-coated tablets white or almost white, round, biconvex.

Excipients : compressible sugar (Compessus MS) – 200 mg, corn starch – 28.28 mg, magnesium stearate – 1.5 mg.

Enteric coating: methacrylic acid-ethyl acrylate copolymer (1:1) dispersion (30%) in terms of dry substance – 16 mg, triethyl citrate – 2.4 mg, micronized talc – 4.8 mg, titanium dioxide – 0.68 mg, simethicone emulsion – q.s.

7 pcs. – blisters (1) – cardboard packs with first opening control.
7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics, antidepressants, other antidepressants

Pharmacological Action

Antidepressant, serotonin and norepinephrine reuptake inhibitor. It weakly inhibits dopamine reuptake, does not have significant affinity for histamine, dopamine, cholinergic, and adrenergic receptors.

The mechanism of action of duloxetine involves the inhibition of serotonin and norepinephrine reuptake.

Duloxetine has a central mechanism of pain suppression, which is primarily manifested by an increase in the pain threshold in neuropathic pain syndrome.

Pharmacokinetics

After oral administration, Duloxetine is well absorbed from the gastrointestinal tract, absorption begins 2 hours after administration, C_max is reached 6 hours after administration.

Taking with food increases the time to reach C_max to 10 hours, which reduces the extent of absorption (by approximately 10%) but does not affect the C_max value.

Plasma protein binding is high (more than 90%), mainly with albumin and α₁-globulin.

Liver or kidney disorders 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 main metabolites (glucuronide conjugate of 4-hydroxyduloxetine, sulfate conjugate of 5-hydroxy,6-methoxyduloxetine).

Circulating metabolites do not possess pharmacological activity.

T_1/2 is 12 hours. The average clearance of duloxetine is 101 L/h. It is excreted in the urine as metabolites.

Indications

Depression, generalized anxiety disorder, painful peripheral diabetic neuropathy, chronic musculoskeletal pain syndrome.

ICD codes

Dosage Regimen

Initiate treatment at the recommended starting dose of 60 mg administered once daily.

Swallow the tablet whole; do not crush, chew, or open the enteric-coated tablet.

Administer the dose with or without food; taking with food may delay the time to peak concentration but does not significantly affect absorption.

For major depressive disorder and generalized anxiety disorder, the effective dose is 60 mg once daily.

For diabetic peripheral neuropathic pain and chronic musculoskeletal pain, the effective dose is 60 mg once daily.

If a dose increase is clinically necessary, titrate from 60 mg once daily to a maximum dose of 120 mg per day.

Divide the maximum daily dose of 120 mg into two administrations of 60 mg each.

Dose escalation above 60 mg/day requires careful assessment of therapeutic benefit against increased risk of adverse reactions.

In patients with mild to moderate renal impairment (CrCl 30-80 ml/min), consider a reduced initial dose or extended dosing interval.

Contraindicated in severe renal impairment (CrCl less than 30 ml/min).

Use with caution and consider dose reduction in patients with hepatic impairment; contraindicated in liver disease resulting in hepatic failure.

For discontinuation, taper the dose gradually to minimize potential withdrawal symptoms; do not abruptly stop therapy.

Monitor blood pressure periodically during treatment, particularly in patients with pre-existing hypertension.

Adverse Reactions

From the central nervous system often – dizziness (excluding vertigo), sleep disorders (drowsiness or insomnia), headache (headache was reported less frequently than with placebo); sometimes – tremor, weakness, blurred vision, lethargy, anxiety, yawning; very rarely – glaucoma, mydriasis, vision disorders, agitation, disorientation.

From the digestive system often – dry mouth, nausea, constipation; sometimes – diarrhea, vomiting, decreased appetite, taste change, impaired liver function tests; very rarely – hepatitis, jaundice, increased activity of ALP, ALT, AST and bilirubin level; belching, gastroenteritis, stomatitis.

From the musculoskeletal system sometimes – muscle tension and/or twitching; very rarely – bruxism.

From the cardiovascular system sometimes – palpitations; very rarely – orthostatic hypotension, syncope (especially at the beginning of therapy), tachycardia, increased blood pressure, cold extremities.

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

From the urinary system sometimes – difficult urination; very rarely – nocturia.

Other sometimes – weight loss, increased sweating, hot flushes, night sweats; very rarely – anaphylactic reactions, thirst, hyponatremia, chills, angioedema, rash, Stevens-Johnson syndrome, urticaria, malaise, feeling of heat and/or cold, weight gain, dehydration, photosensitivity. Upon discontinuation, dizziness, nausea, and headache were frequently reported. In patients with painful diabetic neuropathy, a slight increase in fasting blood glucose may be observed.

Contraindications

Uncontrolled narrow-angle glaucoma; liver disease accompanied by hepatic failure; severe renal failure (CrCl <30 ml/min); uncontrolled arterial hypertension; simultaneous use with MAO inhibitors, concurrent use of potent inhibitors of the CYP1A2 isoenzyme (fluvoxamine, ciprofloxacin, enoxacin); hypersensitivity to duloxetine.

Use in Pregnancy and Lactation

Use of duloxetine during pregnancy is only possible in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use duloxetine during lactation, the issue of discontinuing breastfeeding should be considered (due to lack of experience of use).

Patients should be warned that in case of pregnancy occurrence or planning during the use of duloxetine, they must inform their attending physician.

Use in Hepatic Impairment

Contraindicated in liver disease accompanied by hepatic failure.

Use with caution in impaired liver function. In patients with impaired liver function, the initial dose of the drug should be reduced or the frequency of administration should be reduced.

Use in Renal Impairment

Use with caution in impaired renal function.

Contraindicated in severe renal impairment (CrCl<30 ml/min).

Special Precautions

Use with caution in exacerbation of manic/hypomanic state, epileptic seizures, mydriasis, impaired liver or kidney function, in patients with a tendency to suicidal attempts.

When prescribing serotonin reuptake inhibitors in combination with MAO inhibitors, cases of serious reactions, sometimes fatal (hyperthermia, rigidity, myoclonus, various disorders with possible sharp fluctuations in vital signs and changes in mental status, including severe agitation progressing to delirium and coma), have been reported. Such reactions are also possible in cases where a serotonin reuptake inhibitor was discontinued shortly before prescribing MAO inhibitors (symptoms may develop, including those characteristic of neuroleptic malignant syndrome).

The effects of combined use of duloxetine and MAO inhibitors have not been evaluated in humans or animals. The use of duloxetine simultaneously with MAO inhibitors or within 14 days after their discontinuation is not recommended, because Duloxetine is an inhibitor of serotonin and norepinephrine reuptake. 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 a history of epileptic seizures.

Depressive states are associated with a high risk of suicidal behavior. Therefore, patients diagnosed with depression taking Duloxetine should inform the doctor about any disturbing thoughts and feelings.

During the use of duloxetine, mydriasis may develop; caution should be exercised when prescribing duloxetine to patients with increased intraocular pressure or to persons at risk of acute narrow-angle glaucoma.

In patients with arterial hypertension and/or other cardiovascular diseases, blood pressure monitoring is recommended.

Effect on ability to drive vehicles and operate machinery

Patients taking Duloxetine should exercise caution when engaging in potentially hazardous activities (due to the possible occurrence of drowsiness).

Drug Interactions

Concomitant use of duloxetine (at a dose of 60 mg twice daily) did not have a significant effect on the pharmacokinetics of theophylline, which is metabolized by CYP1A2. Duloxetine is unlikely to have a clinically significant effect on the metabolism of other drugs that are substrates of CYP1A2.

Concomitant administration of duloxetine with potential inhibitors of CYP1A2 (e.g., fluoroquinolones) may lead to an increase in duloxetine concentration, because CYP1A2 is involved in the metabolism of duloxetine (prescribing such a combination requires caution and reduction of duloxetine doses).

The potent CYP1A2 inhibitor fluvoxamine (when taken at a dose of 100 mg once daily) reduced the mean plasma clearance of duloxetine by approximately 77%.

Caution should be exercised when prescribing duloxetine with drugs metabolized by CYP2D6 and having a narrow therapeutic index (because Duloxetine is a moderate inhibitor of CYP2D6). When used concomitantly with duloxetine at a dose of 60 mg twice daily, the AUC of desipramine (a CYP2D6 substrate) increases 3-fold. Concomitant use with duloxetine (at a dose of 40 mg twice daily) increased the steady-state AUC of tolterodine (used at a dose of 2 mg twice daily) by 71%, but did not affect the pharmacokinetics of the 5-hydroxyl metabolite. Concomitant use of duloxetine with potential inhibitors of CYP2D6 may lead to increased duloxetine concentrations. Paroxetine (when used at a dose of 20 mg once daily) reduced the mean clearance of duloxetine by approximately 37%. Caution should be exercised when using duloxetine with CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors).

When duloxetine is used concomitantly with other drugs that affect the central nervous system and have a similar mechanism of action (including ethanol and ethanol-containing drugs), mutual enhancement of effects is possible (such a combination requires caution).

Duloxetine is highly bound to plasma proteins, therefore, concomitant use with other drugs that are highly bound to plasma proteins may lead to an increase in the concentration of free fractions of both drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.