Duloxenta enteric capsules 30mg, 14pcs

Composition

1 capsule enteric 30 mg / 60 mg contains pellets:

Active ingredient:

Duloxetine Hydrochloride 33.675 mg / 67.350 mg, equivalent to Duloxetine 30,000 mg/60,000 mg

Auxiliary substances:

Granulated sugar, hypromellose 6 cP, sucrose, hypromellose phthalate HP-50, talc, triethyl citrate

Solid gelatin Capsules No. 3/ No. 1

Housing:

Titanium dioxide (E171), indigo carmine (E 132) (for 60 mg capsules), iron oxide yellow dye (E 172) (for 60.00 mg capsules), gelatin

Cap:

Indigo carmine (E 132), Titanium dioxide (E171), gelatin

Ink composition:

Shellac (E904), ethanol (E1510), isopropanol, butanol, propylene glycol (E1520), water ammonia (E527), iron oxide black dye (E172), potassium hydroxide (E525), purified water

Pharmacological action

antidepressant

Clinical pharmacology

Pharmacodynamics

Duloxetine is an antidepressant, serotonin and norepinephrine reuptake inhibitor (SSRI) and weakly suppresses dopamine uptake, without significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. The mechanism of action of duloxetine in the treatment of depression is to suppress the reuptake of serotonin and norepinephrine, resulting in increased serotonergic and noradrenergic neurotransmission in the central nervous system (CNS).

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

Pharmacokinetics

Absorption

Duloxetine is well absorbed when taken orally. Absorption begins 2 hours after taking the drug. The maximum concentration (cmax) in the blood plasma of duloxetine is reached 6 hours after use.

Food intake does not affect the_cmax of duloxetine, but increases the time to reach_cmax from 6 to 10 hours, which slightly reduces the degree of absorption (by approximately 11%).

Distribution

The apparent volume of distribution is about 1640 liters. Duloxetine binds well to plasma proteins (> 90%), mainly albumin and α1-acid glycoprotein, but liver or kidney disorders do not affect the degree of binding to plasma proteins.

Metabolism

Duloxetine is extensively metabolized, and its metabolites are mainly excreted by the kidneys.

Both CYP2D6 and CYP1A2 catalyze the formation of two major metabolites (4-hydroxyduloxetine glucuronide,5-hydroxy, and 6-methoxyduloxetine sulfate).

Circulating metabolites have no pharmacological activity.

Deduction

The elimination half-life (T_1/2) of duloxetine is 12 hours. The average clearance of duloxetine is 101 l / h.

Special patient groups

Gender

Although there were differences in the pharmacokinetics of duloxetine in men and women (the average clearance of duloxetine is lower in women), these differences are not so large that it is necessary to adjust the dose depending on gender.

Age group

Although there were differences in the pharmacokinetics of duloxetine in middle-aged and elderly patients (the area under the concentration-time curve [AUC] is higher and the duration of T_1/2 of the drug is longer in elderly patients), these differences are not sufficient to change the dose depending on the patient’s age alone.

Impaired renal function

In patients with severe renal impairment (end-stage chronic renal failure) undergoing hemodialysis, the values of_cmax and mean exposure to duloxetine increased 2-fold. In this regard, it is necessary to consider the feasibility of reducing the dose of duloxetine in patients with clinically expressed renal impairment.

Impaired liver function

Patients with clinical signs of hepatic insufficiency may experience a slowdown in the metabolism and elimination of duloxetine. After a single dose of 20 mg of duloxetine in 6 patients with cirrhosis of the liver with moderate hepatic impairment (Child-Pugh class B), the duration of T_1/2of duloxetine was approximately 15% higher than in healthy people of the corresponding gender and age with a five-fold increase in average exposure. Despite the fact that_cmaxin patients with cirrhosis of the liver was the same as in healthy people, T_1/2 was about 3 times longer.

Indications

* Depression.

* Painful form of peripheral diabetic neuropathy.

* Generalized anxiety disorder.

* Chronic musculoskeletal pain (including fibromyalgia-related pain, chronic lower back pain, and knee osteoarthritis).

Use during pregnancy and lactation

Pregnancy

Due to insufficient experience with the use of duloxetine during pregnancy, Duloxetine should only be prescribed during pregnancy if the potential benefit to the mother significantly exceeds the potential risk to the fetus. Patients should be warned that if pregnancy occurs or is planned during treatment with duloxetine, they should inform their doctor about this.

Epidemiological data suggest that the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, especially in the late stages, may increase the risk of persistent pulmonary hypertension in newborns (PPHN). Despite the lack of studies on the relationship between PHN and SSRI use, a potential risk cannot be excluded, given the mechanism of action of duloxetine (serotonin reuptake inhibition).

As with the use of other serotonergic drugs, withdrawal syndrome can occur in newborns if the mother uses duloxetine in late pregnancy.

Withdrawal symptoms include the following: : low blood pressure, tremor, increased neuro-reflex excitability syndrome, feeding difficulties, respiratory distress syndrome, convulsions. Most of the symptoms were observed during labor or in the first few days after delivery.

Breast-feeding period

Due to the fact that duloxetine penetrates into breast milk (the concentration in the fetus at the rate of mg/kg of body weight is approximately 0.14% of the concentration in the mother), breast-feeding during therapy with Duloxetine®is not recommended.

Fertility

In animal studies, duloxetine had no effect on male fertility, and effects in females were observed only when administered at doses that were toxic to the mother’s body.

Contraindications

• Hypersensitivity to the drug.
• Concomitant use with monoamine oxidase inhibitors (see section “Special instructions”).
• Uncompensated angle-closure glaucoma.
• Under 18 years of age.
• Sucrose/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption syndrome (Duloxent® contains sucrose).
• Liver diseases accompanied by liver failure.
• Concomitant use of potent inhibitors of the CYP1A2 isoenzyme (fluvoxamine, ciprofloxacin, enoxacin).
• Severe chronic renal failure (creatinine clearance < 30 ml / min).
• Uncontrolled arterial hypertension.

Interaction

Monoamine oxidase inhibitors (MAOIs)

Due to the risk of serotonin syndrome, duloxetine should not be used in combination with MAOIs and for at least 14 days after discontinuation of MAOIs treatment. Based on the duration of T_1/2 of duloxetine, you should take a break for at least 5 days after the end of duloxetine before taking MAOI.

For selective reversible MAOIs, such as moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of reversible MAOIs and duloxetine is not recommended.

Inhibitors of the CYP1A2 isoenzyme

Due to the fact that the CYP1A2 isoenzyme is involved in the metabolism of duloxetine, simultaneous use of duloxetine with potential inhibitors of the CYP1A2 isoenzyme is likely to lead to an increase in the concentration of duloxetine. Powerful inhibitor of the CYP1A2 isoenzyme fluvoxamine (100 mg 1 time per day) reduced the mean plasma clearance of duloxetine by approximately 77%. Caution should be exercised when using duloxetine with inhibitors of the CYP1A2 isoenzyme (for example, some quinolone antibiotics) and lower doses of duloxetine should be used.

Drugs that affect the central nervous system

Caution should be exercised when using duloxetine concomitantly with other drugs and agents that affect the central nervous system, especially those that have a similar mechanism of action, including ethanol. Concomitant use with other drugs that have serotonergic effects (for example, SSRIs, SSRIs, triptans and tramadol) may lead to the development of serotonin syndrome.

Serotonin syndrome

In rare cases, concomitant use of SSRIs (e. g., paroxetine, fluoxetine) and serotonergic drugs has been associated with serotonin syndrome. Caution should be exercised when using duloxetine concomitantly with serotonergic antidepressants such as SSRIs, tricyclic antidepressants (clomipramine or amitriptyline), St. John’s wort preparations, venlafaxine or triptans, tramadol, pethidine and tryptophan.

Drugs that are metabolized by the CYP1A2 isoenzyme

Concomitant use of duloxetine (60 mg twice daily) did not significantly affect the pharmacokinetics of theophylline, which is metabolized by the CYP1A2 isoenzyme. Duloxetine is unlikely to have a clinically significant effect on the metabolism of substrates of the CYP1A2 isoenzyme.

Drugs that are metabolized by the CYP2D6 isoenzyme

Duloxetine is a moderate inhibitor of the CYP2D6 isoenzyme. When taking duloxetine at a dose of 60 mg 2 times a day simultaneously with a single dose of desipramine, a substrate of the CYP2D6 isoenzyme, the AUC of desipramine increases by 3 times. Concomitant use of duloxetine (40 mg twice daily) increased the steady-state concentration of tolterodine (2 mg twice daily) by 71%, but did not affect the pharmacokinetics of 5-hydroxymetabolite. Therefore, caution should be exercised when using duloxetine with drugs that are mainly metabolized by the CYP2D6 isoenzyme and have a narrow therapeutic index.

Inhibitors of the CYP2D6 isoenzyme

Since the CYP2D6 isoenzyme is involved in the metabolism of duloxetine, the simultaneous use of duloxetine with potential inhibitors of the CYP2D6 isoenzyme may lead to an increase in the concentration of duloxetine. Paroxetine (20 mg once daily) reduced the mean clearance of duloxetine by approximately 37%. Caution should be exercised when using duloxetine with inhibitors of the CYP2D6 isoenzyme (for example, SSRIs).

Oral contraceptives and other steroid medications

The results of invitro studies indicate that duloxetine does not induce the catalytic activity of the CYP3A isoenzyme. Specific studies of drug interactions in vivo have not been conducted.

Anticoagulants and antithrombotic drugs

Due to the potential increased risk of bleeding associated with pharmacodynamic interactions, caution should be exercised when using duloxetine concomitantly with anticoagulants or antithrombotic drugs. In addition, the concomitant use of duloxetine and warfarin increased the value of the international normalized ratio (INR). However, the concomitant use of duloxetine and warfarin under stable conditions in healthy volunteers in a clinical pharmacology study did not reveal a clinically significant change in INR from the average or a change in the pharmacokinetics of the right – or left-rotating isomer of warfarin.

Antacids and_H2-histamine receptor antagonists

Concomitant use of duloxetine and aluminum-and magnesium-containing antacids, or duloxetine and famotidine, did not significantly affect the degree of absorption of duloxetine at a dose of 40 mg.

Inducers of the CYP1A2 isoenzyme

Population pharmacokinetic analysis showed that compared with non-smokers, the plasma concentration of duloxetine was almost 50% lower in smoking patients.

Drugs that are highly bound to plasma proteins

Duloxetine is highly bound to plasma proteins (> 90%). Therefore, the use of duloxetine in a patient who is taking another drug that is highly bound to plasma proteins may lead to an increase in the concentration of free fractions of both drugs.

How to take, course of use and dosage

Inside. Capsules should be swallowed whole, without chewing or crushing.

Do not add Duloxent® to food or mix it with liquids, as this may damage the enteric coating of pellets.

Depression

The initial and recommended maintenance dose is 60 mg once a day, regardless of the meal time. In clinical studies, the safety of using doses from 60 mg to a maximum dose of 120 mg per day was evaluated. However, there was no clinical evidence that patients who did not respond to the initial recommended dose showed any improvement with increasing the dose.

Response to therapy is usually noted 2-4 weeks after the start of treatment.

In order to avoid relapse after achieving a response to antidepressant therapy, it is recommended to continue treatment for several months. In patients who respond positively to duloxetine therapy, with a history of recurrent depression, further long-term therapy at a dose of 60 mg/day to 120 mg/day is possible.

Generalized anxiety disorder

The recommended starting dose in patients with generalized anxiety disorder is 30 mg per day, regardless of the meal time. In patients with insufficient response to therapy, it is possible to increase the dose to 60 mg / day, the usual maintenance dose in most patients.

In patients with concomitant depression, the initial and maintenance dose is 60 mg / day (see also the recommendations above). Clinical trials have shown the efficacy of doses up to 120 mg / day, and safety considerations have also been evaluated for these dosages. Therefore, in patients with insufficient response to a dose of 60 mg/day, it may be advisable to increase the daily dose to 90 mg or 120 mg. Dose increases should be made based on clinical response and tolerability.

In order to avoid relapse after achieving a response to therapy, it is recommended to continue treatment for several months.

Painful form of peripheral diabetic neuropathy

The initial and recommended maintenance dose is 60 mg once a day, regardless of the meal time. During clinical trials, the safety of using doses from 60 mg/day to a maximum dose of 120 mg/day, divided into equal doses, was also evaluated. The concentration of duloxetine in blood plasma is characterized by significant individual variability. Therefore, some patients with insufficient response to the 60 mg/day dose may experience improvements with a higher dose.

Evaluation of the response to therapy should be carried out after 2 months. In patients with insufficient initial response, improvement in response after this time period is unlikely.

The therapeutic effect should be evaluated regularly (at least once every 3 months).

Chronic musculoskeletal pain (including fibromyalgia-related pain, chronic lower back pain, and knee osteoarthritis)

Initial treatment: the recommended dose of Duloxent® is 60 mg once a day. Therapy can be started with a dose of 30 mg for 1 week to allow patients to adapt to the drug before increasing the dose to 60 mg once a day. There is no evidence that higher doses provide an additional benefit, even in patients who do not respond to therapy with the drug at a dose of 60 mg / day. Higher doses are associated with a higher frequency of adverse reactions.

Continuation of treatment: The efficacy of duloxetine in the treatment of fibromyalgia has been demonstrated in placebo-controlled studies lasting up to 3 months. Efficacy has not been established in longer-term studies, but the decision to continue treatment should be based on the individual patient response.

Impaired renal function

With a creatinine clearance of 30-80 ml / min, no dose adjustment is required; with a creatinine clearance of less than 30 ml/min, the use of Duloxent® is contraindicated.

Impaired liver function

The drug Duloxent® should not be prescribed to patients with liver diseases accompanied by hepatic insufficiency.

Age group

In elderly patients, an initial dose of 30 mg/day is recommended for the treatment of generalized anxiety disorder for 2 weeks before starting the use of duloxetine at a target dose of 60 mg / day. In the future, it is possible to use the drug at a dose of more than 60 mg / day to achieve a good result. Systematic evaluation of the drug intake at a dose of more than 120 mg / day was not carried out. When using duloxetine for other indications, no dose adjustment is required depending on the patient’s age.

It is recommended to use the drug in patients ≥ 18 years of age. Duloxetine is not recommended for use in children

Discontinuation of therapy

Abrupt discontinuation of therapy should be avoided. When stopping treatment with duloxetine, the dose should be gradually reduced over 1-2 weeks in order to reduce the risk of developing withdrawal symptoms. If severe withdrawal symptoms occur after reducing the dose or after discontinuing treatment, then continuation of the previously prescribed dose may be considered. Subsequently, the doctor may continue to reduce the dose, but even more gradually.

Overdose

Overdose cases have been reported in clinical trials with simultaneous oral use of up to 3000 mg of duloxetine alone or in combination with other drugs. At the same time, one of these cases ended in a fatal outcome. However, spontaneous (post-marketing) reports contained descriptions of fatal acute overdoses, usually with a combined intake of several drugs, in which the dose of duloxetine was no more than 1000 mg.

Symptoms

Overdose of duloxetine (isolated or combined) may be accompanied by the following symptoms: drowsiness, coma, clonic seizures, serotonin syndrome, vomiting and tachycardia. In preclinical studies (in animals), the main signs of intoxication associated with overdose were related to disorders of the central nervous system and digestive system and included such manifestations as tremor, clonic seizures, ataxia, vomiting and decreased appetite.

Treatment

A specific antidote is not known, but if serotonin syndrome develops, correction treatment with ciproheptadine and the use of methods to normalize body temperature are possible. Adequate fresh air supply should be provided. It is recommended to monitor cardiac activity and monitor the main indicators of vital activity, along with symptomatic and supportive treatment. Gastric lavage may be indicated if little time has passed since taking the drug orally, or as part of symptomatic treatment. Activated carbon may be used to limit absorption. Duloxetine is characterized by a large volume of distribution, and therefore the effectiveness of forced diuresis, hemoperfusion, and exchange perfusion is questionable.

Description

30 mg Capsules:Solid gelatin capsules No. 3, white capsule body, dark blue capsule cap. The capsule body is marked 30 in black ink. The contents of the capsules are white or almost white pellets.

60 mg Capsules: Solid gelatin capsules No. 1, the capsule body is yellowish-green in color, the capsule cap is dark blue in color. The capsule body is marked 60 in black ink. The contents of the capsules are white or almost white pellets.

Special instructions

Mania and bipolar disorder (including in the anamnesis), seizures (including in the anamnesis), intraocular hypertension or risk of acute attack of angle-closure glaucoma, suicidal thoughts and attempts in the anamnesis, increased risk of hyponatremia (elderly patients, cirrhosis of the liver, dehydration, taking diuretics), impaired liver function and renal failure (creatinine clearance 30-60 ml/min).

Duloxetine is not recommended for use in children under 18 years of age due to insufficient data on its safety and efficacy in this age group of patients.

Impaired renal function

With a creatinine clearance of 30-80 ml / min, no dose adjustment is required; with a creatinine clearance of less than 30 ml/min, the use of Duloxent® is contraindicated.

Impaired liver function

The drug Duloxent® should not be prescribed to patients with liver diseases accompanied by hepatic insufficiency.

Age group

In elderly patients, an initial dose of 30 mg/day is recommended for the treatment of generalized anxiety disorder for 2 weeks before starting the use of duloxetine at a target dose of 60 mg / day. In the future, it is possible to use the drug at a dose of more than 60 mg / day to achieve a good result. Systematic evaluation of the drug intake at a dose of more than 120 mg / day was not carried out. When using duloxetine for other indications, no dose adjustment is required depending on the patient’s age.

Exacerbation of manic/hypomanic state

As with similar medications that affect the central nervous system, duloxetine should be used with caution in patients with a history of manic episodes.

Epileptic seizures

As with similar drugs that affect the central nervous system, duloxetine should be used with caution in patients with a history of epileptic seizures.

Mydriaz

Cases of mydriasis have been reported when taking duloxetine, so caution should be exercised when using duloxetine in patients with increased intraocular pressure or in those at risk of developing acute angle-closure glaucoma.

Increased blood pressure

In isolated cases, there was an increase in blood pressure during treatment with duloxetine. In patients with arterial hypertension and/or other cardiovascular diseases, it is recommended to measure blood pressure.

Impaired kidney and liver function

In patients with severe renal impairment (CC If the use of duloxetine is clinically justified in such patients, lower initial doses of the drug should be used.

Suicidal behavior

The risk of suicide exists in all patients with depression and some other mental disorders. This risk may persist until remission occurs. As a result, patients who have the highest risk of committing suicide should be under close medical supervision during pharmacotherapy. As well as taking other drugs that have a similar mechanism of pharmacological action to duloxetine (SSRIs, SSRIs), taking duloxetine during treatment, or when it was discontinued, in some cases was associated with the development of suicidal thoughts and suicidal behavior. The use of duloxetine in patients under 18 years of age has not been studied, so duloxetine is not intended for use in such patients. A causal relationship between the use of duloxetine and the occurrence of suicidal events in patients of this age group has not been established. At the same time, some analytical reviews of the results of a number of studies using antidepressants for the treatment of mental disorders indicate an increased risk of developing suicidal thoughts and/or suicidal behavior in children, adolescents, and adults under 25 years of age compared with placebo. Doctors should encourage patients to report any thoughts or feelings that are bothering them at any time.

Sexual dysfunction

SSRIs / SSRIs can cause symptoms of sexual dysfunction. There have been reports of long-term sexual dysfunction that persisted despite discontinuation of SSRIs/SSRIs.

Increased risk of bleeding

SSRIs and SSRIs, including duloxetine, may increase the risk of bleeding, including gastrointestinal bleeding (see section “Side effects”). Therefore, duloxetine should be used with caution in patients taking anticoagulants and / or medications that affect platelet function (for example, nonsteroidal anti-inflammatory drugs, including aspirin), and in patients with a history of bleeding.

Hyponatremia

Very rarely, hyponatremia has been reported (in some cases, serum sodium levels were lower than 110 mmol / l). Most of these cases occurred in elderly patients, especially in combination with a recent history of altered fluid balance or in the presence of conditions predisposing to a change in fluid balance.

Hyponatremia can manifest as non-specific symptoms (such as dizziness, weakness, nausea, vomiting, confusion, drowsiness, lethargy). Signs and symptoms that occurred in more severe cases included fainting, falls, and seizures.

IMAO

Patients taking a serotonin reuptake inhibitor concomitantly with a MAOI have experienced serious reactions, sometimes fatal, including hyperthermia, rigidity, myoclonus, peripheral disturbances with possible sharp fluctuations in vital signs, and changes in mental status, including severe agitation with the transition to delirium and coma. These reactions were also observed in patients who were discontinued a serotonin reuptake inhibitor shortly before the use of MAOI. In some cases, patients experienced symptoms characteristic of neuroleptic malignant syndrome. The effects of concomitant use of duloxetine and MAOI have not been evaluated in either humans or animals. Therefore, given the fact that duloxetine is an SSRI, it is not recommended to take duloxetine at the same time as MAOI or for at least 14 days after discontinuation of MAOI treatment. Based on the duration of T_1/2 of duloxetine, you should take a break for at least 5 days after the end of duloxetine before taking MAOI.

Increased liver enzyme activity in blood plasma

In some patients who took duloxetine in clinical trials, there was an increase in the activity of liver enzymes in blood plasma. The observed deviations were usually transient and disappeared spontaneously, or after discontinuation of duloxetine. A significant increase in the activity of liver enzymes (10 times or more exceeding the upper limit of normal) in blood plasma, as well as liver damage of cholestatic or mixed genesis, were rarely observed, and in some cases were associated with excessive alcohol consumption or previous liver disease. It is recommended to use duloxetine with caution in patients who consume alcohol in significant quantities, as well as with existing liver disease.

Special information on excipients

Duloxent® contains sucrose, so it should not be used in the following conditions: sucrose/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption syndrome.

While taking duloxetine, sedation, drowsiness and other side effects may occur. In this regard, patients taking Duloxent® should exercise caution when driving a car or using dangerous mechanical means.

Form of production

Enteric capsules,30 mg,60 mg.

7 or 10 capsules in a blister of combined OPA / Al material/PE + DES and aluminum foil.

1,2,4 or 12 blisters (a blister of 7 capsules) or 1,2,3 or 9 blisters (a blister of 10 capsules) together with the instructions for use are placed in a cardboard pack.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of reach of children.

Shelf

life is 2 years.

Do not use the drug after the expiration date.

Active ingredient

Duloxetine

Conditions of release from pharmacies

By prescription

Dosage form

Capsules