Simbalta - instructions for use, doses, side effects, contraindications

Active substanceDuloxetineDuloxetine

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Simbalta®

capsules inwards

Eli Lilly East SA Switzerland

Dosage form: & nbsp

Capsules, enteric, soluble

Composition:

Each capsule contains:

for a dosage of 30 mg:

active substance: duloxetine hydrochloride equivalent to 30 mg of duloxetine base;

Excipients:

contents of the capsule - hypromellose 11.2 mg, sucrose 18.1 mg, granulated sugar 40.6 mg, talc 23.6 mg, hypromellose acetate succinate 22.4 mg, triethyl citrate 4.5 mg, dye white (titanium dioxide, hypromellose) 14, 9 mg;

capsule shell - indigocarmine 0.11625 mg, titanium dioxide 1.77255 mg, sodium lauryl sulfate 0.06875 mg, gelatin ye.e. up to 50 mg;

overprint - green ink TekRrint ™ SВ-4028 trace amounts.

for dosage of 60 mg:

active substance: duloxetine hydrochloride equivalent to 60 mg of duloxetine base;

Excipients:

contents of the capsule - hypromellose 22.3 mg, sucrose 36.2 mg, granulated sugar 80.9 mg, talc 47.1 mg, hypromellose acetate succinate 44.6 mg, triethyl citrate 8.9 mg, dye white (titanium dioxide, hypromellose) 29, 6 mg;

capsule shell - indigocarmine 0.18006 mg, titanium dioxide 0.69848 mg, sodium lauryl sulfate 0.10763 mg, gelatin a.e.76 mg, iron dye yellow oxide 0.13449 mg;

overprint - white ink TekRrint ™ SB-0007P trace amounts.

Description:

Capsules 30 mg: opaque, hard gelatin capsules (# 3) consisting of a blue lid with green identification code "9543" and a white body with a green ink dose of "30 mg" applied in green ink.

Capsules 60 mg: opaque, hard gelatin capsules (No. 1), consisting of a blue lid with white inks marked with the identification code "9542" and a green colored enclosure with white ink dosed with "60 mg". The contents of the capsules are pellets from white to grayish white.

Pharmacotherapeutic group:antidepressant

ATX: & nbsp

N.06.A.X.21 Duloxetine

Pharmacodynamics:

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

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

Pharmacokinetics:Suction. Duloxetine well absorbed when taken orally. Suction starts 2 hours after taking the drug. The maximum concentration of the drug is reached after 6 hours after admission. Food intake does not affect the maximum concentration of the drug, but increases the time to reach the maximum concentration from 6 to 10 hours, which indirectly reduces the degree of absorption (approximately 11%).

Distribution. The apparent volume of distribution is about 1640 liters. Duloxetine binds well to plasma proteins (> 90%), mainly with albumin and αl-acid globulin, but violations of the liver or kidneys have no effect on the degree of binding to plasma proteins.

Metabolism. Duloxetine It is actively metabolized and its metabolites are mainly excreted in the urine.

Both the CYP2D6 isoenzyme and the CYP1A2 isoenzyme catalyze the formation of two major metabolites (4-hydroxyduloxetine glucuronide, 5-hydroxy, 6-methoxyduloxetine sulfate). Circulating metabolites do not have pharmacological activity.

Excretion. The duration of the half-life of duloxetine is 12 hours. The average clearance of duloxetine is 101 l / h.

Individual patient groups.

Floor: Although differences in pharmacokinetics between men and women have been identified (mean duloxetine clearance is lower in women), these differences are not so great that there is a need for dose adjustment depending on sex.

Age: although differences in pharmacokinetics between middle-aged and elderly patients (AUC-area under the "concentration-time" curve above and duration of the half-life of the drug more in the elderly) were revealed, these differences are not enough for changing the dose depending only on the age of the patients .

Impaired renal function: in patients with severe impairment of renal function (terminal stage of CRF-chronic renal failure) on hemodialysis, C max (maximum concentration) and average exposure (AUC) of duloxetine increased 2-fold. In this regard, it should be considered the expediency of reducing the dose of the drug in patients with clinically significant renal dysfunction.

Impaired liver function: in patients with clinical signs of hepatic insufficiency, metabolism and elimination of duloxetine can be observed. After a single dose of 20 mg of duloxetine in 6 patients with cirrhosis of the liver with moderate impaired hepatic function (Class B on the Child-Pugh scale), the duration of the half-life of duloxetine was approximately 15% higher than in healthy people of the corresponding sex and age with a fivefold increase in mean exposure . Despite the fact that Cmax in patients with cirrhosis was the same as in healthy people, the half-life was approximately 3 times longer.

Indications:

depression
painful form of peripheral diabetic neuropathy
generalized anxiety disorder
chronic pain syndrome of the musculoskeletal system (including due to fibromyalgia, chronic pain syndrome in the lower back and osteoarthrosis of the knee joint)

Contraindications:

Hypersensitivity to the drug;
Simultaneous use with monoamine oxidase inhibitors (MAOI) (see section "Special instructions");
Uncompensated angle-closure glaucoma;
Children under 18 years;
Deficiency of sugar / isomaltase, intolerance to fructose, glucose-galactose malabsorption;
Liver diseases accompanied by hepatic impairment;
Simultaneous administration of potent inhibitors of the isoenzyme CYP1A2 (fluvoxamine, ciprofloxacin, enoxacin);
Severe CRF (creatinine clearance (CK) is less than 30 ml / min);
Uncontrolled hypertension.

Carefully:

Mania and bipolar disorder (including history), convulsions (including in the anamnesis), intraocular hypertension or the risk of developing an acute attack of closed-angle glaucoma, suicidal thoughts and attempts in history, increased risk of hyponatremia (elderly patients, liver cirrhosis, dehydration, diuretics), liver dysfunction and kidney failure (KK 30-60 ml / min).

Pregnancy and lactation:

Due to the lack of experience with duloxetine during pregnancy, the drug should be administered during pregnancy only if the potential benefit to the patient significantly exceeds the potential risk to the fetus. Patients should be warned that in the event of the onset or planning of pregnancy during treatment with duloxetine, they need to inform their physician about it.

Epidemiological evidence suggests that the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, especially in later life, may increase the risk of persistent pulmonary hypertension in newborns. Despite the lack of research on the relationship between persistent pulmonary hypertension in newborns and the use of SSRIs, the potential risk can not be ruled out, given the mechanism of action of duloxetine (inhibition of serotonin reuptake).

As with the appointment of other serotonergic drugs, the "cancellation" syndrome can be observed in newborns if duloxetine is used by a mother at a late pregnancy.

The syndrome of "withdrawal" includes the following symptoms: low blood pressure, tremor, a syndrome of increased nervous reflex excitability, feeding difficulties, respiratory distress syndrome, convulsions. Most of the symptoms were observed during childbirth or in the first few days after childbirth.

Due to the fact that duloxetine penetrates into breast milk (concentration in the fetus is based on mg / kg body weight approximately 0.14% of the concentration in the mother), it is not recommended to breast-feed during duloxetine therapy.

Dosing and Administration:

Inside. Capsules should be swallowed whole, not chewing and crushing. Do not add the drug to food or mix it with liquids, as this can damage the enteric coating of pellets.

Depression. The initial and recommended maintenance dose is 60 mg once a day, regardless of food intake. In clinical trials, a safety assessment of doses from 60 mg to a maximum dose of 120 mg per day was performed. However, there was no clinical evidence that no improvement was seen in patients not responding to the initial recommended dose, with an increase in dose.

The response to therapy is usually noted in 2-4 weeks after the start of treatment.

To avoid recurrence after reaching the answer to antidepressant therapy, it is recommended to continue treatment for several months. In patients who are positively responding to duloxetine therapy, with repeated cases of depression in the anamnesis, further long-term therapy in a dose of 60 to 120 mg / day is possible.

Generalized anxiety disorder. The recommended initial dose in patients with generalized anxiety disorder is 30 mg per day, regardless of food intake. In patients with insufficient response to therapy, an increase in the dose to 60 mg, the usual maintenance dose in most patients, is possible.

In patients with concomitant depression, the initial and maintenance dose is 60 mg per day (see also the recommendations above). Clinical studies have shown the effectiveness of doses up to 120 mg / day, in addition, an assessment of these dosages in terms of safety. Therefore, in patients with an insufficient response to a dose of 60 mg, it may be advisable to increase the dose to 90 mg or 120 mg. The dose increase should be based on clinical response and tolerability.

To avoid relapse after reaching a response to therapy, it is recommended to continue treatment for several months.

Painful shape of peripheral diabetic neuropathy. The initial and recommended maintenance dose is 60 mg once a day, regardless of food intake.During clinical trials, a safety assessment of doses from 60 mg to a maximum dose of 120 mg per day divided into equal doses was also performed. The concentration of duloxetine in plasma is characterized by considerable individual variability. Therefore, in some patients with an insufficient response to a dose of 60 mg / day, improvements with a higher dose may be noted.

Evaluation of response to therapy should be conducted after 2 months. In patients with an insufficient initial response, an improvement in response after a given period of time is unlikely.

It is necessary to regularly evaluate the therapeutic effect (at least once every three months).

Chronic pain syndrome of the musculoskeletal system (including due to fibromyalgia, chronic pain syndrome in the lower back and osteoarthrosis of the knee joint). Initial treatment: The recommended dose of Simbalta® is 60 mg once daily. Therapy can be started with a dose of 30 mg for one week to allow patients to adapt to the drug before increasing the dose to 60 mg once daily.Evidence that higher doses provide an additional benefit are not available, even in patients who do not respond to drug therapy at a dose of 60 mg. Higher doses are associated with a high incidence of adverse reactions. Continuation of treatment: the effectiveness of Simbalta® in the treatment of fibromyalgia was demonstrated in placebo-controlled studies of up to 3 months. The efficacy of Simbalta® has not been established in longer-term studies, but the decision to continue treatment should be based on the individual response of the patient.

In patients with renal insufficiency: with creatinine clearance of 30-80 ml / min dose adjustment is not required, with creatinine clearance less than 30 ml / min, the drug is contraindicated.

In patients with impaired hepatic function: The drug can not be administered to patients with liver disease, leading to liver failure.

Age: elderly patients for the treatment of generalized anxiety disorder are recommended an initial dose of 30 mg for two weeks before starting duloxetine at a target dose of 60 mg.In the future, the use of the drug in a dose of more than 60 mg per day to achieve a good result. A systematic evaluation of the drug intake in a dose exceeding 120 mg was not performed. When duloxetine is used for other indications, dosage adjustment according to age is not required.

Recommended use of the drug in patients ≥ 18 years. Duloxetine it is not recommended to prescribe to children under 18 years, due to the lack of data on its safety and effectiveness of this age group of patients.

Abrupt treatment cancellation: should be avoided. If treatment with duloxetine is discontinued, the dose should be gradually reduced within one to two weeks in order to reduce the risk of withdrawal syndrome. If after the dose reduction or after the cessation of treatment the expressed symptoms of the "withdrawal" syndrome appear, then continuation of the administration of the previously prescribed dose can be considered. Subsequently, the doctor may continue to reduce the dose, but even more gradually.

Side effects:

The most common side effects in patients taking duloxetine, there was nausea, headache, dry mouth, drowsiness and dizziness.Nevertheless, most of these side effects were mild and moderate, occurred at the beginning of therapy, and subsequently their severity decreased.

Table 1 presents side effects and laboratory abnormalities noted in clinical research and / or post-marketing period:

Often (> 10 %)	Often (<10% and ≥1 %)		Infrequently (<1% and ≥ 0,1 %)	Rarely (<0.1% and ≥ 0,01 %)	Rarely (< 0,01 %)
Infectious and parasitic diseases
			Laryngitis
Immune system disorders
				Anaphylactic reaction Hypersensitivitythe
Disorders from the endocrine system
				Hypothyroidism
Disorders from the metabolism and nutrition
	Decrease appetite¹⁵		Hyperglycemia (especially often observed in patients with diabetes mellitus)	Dehydration Hyponatremia Syndrome inadequate secretion of antidiuretic hormone ⁶
Disorders of the psyche
	Agitation¹⁰ Insomnia¹¹ Anxiety Unusual dreaming² Decrease libido (including loss of libido) Violation orgasm (including anorgasmia)		Suicidal thoughts ^5,22 Sleep disorders Bruxism Disorientation¹⁹ Apathy	Suicidal behavior ^5,22 Mania Hallucinations Aggression and hostility⁴
Disturbances from the nervous system
Head pain Drowsiness¹²	Tremor Paresthesia¹⁸ Dizziness Lethargy		Myoclonus Akathisia²² Increased excitability Violation concentration Dysgeusia Dyskinesia Syndrome restless legs Decrease quality of sleep	Serotonin syndrome⁶ Convulsions¹ Psychomotor excitation⁶ Extrapyramidal disorders⁶
Disturbances on the part of the organ of sight
	Unclear view		Mydriasis Violation view Dry eyes	Glaucoma
Hearing disorders and labyrinthine disorders
	Noise in ears¹		Vertigo Ear pain
Heart Disease
	Feeling palpitation		Tachycardia Supraventricular arrhythmia, predominantly atrial fibrillation
Vascular disorders
	Hyperemia (including "tides") Increase blood pressure^3,14		Hypertension^3,22 Cooling limbs Orthostatic hypotension² Fainting²	Hypertensive crisis^3,6
Disturbances from the respiratory system, chest and mediastinal organs
	Yawn Pain in the oropharynx		Feeling tight in the throat Nose bleed
Disorders from the gastrointestinal tract
Nausea (24.3%) Dry mouth (12.8%)	Diarrhea Vomiting Dyspepsia (including abdominal discomfort) Flatulence Abdominal pain⁹ Constipation		Gastro-intestinal bleeding⁷ Gastroenteritis Belching Gastritis Dysphagia	Stomatitis Smell from the mouth Hematocheia
Disturbances from the liver and bile ducts
			Hepatitis³ Acute liver damage	Hepatic failure⁶ Jaundice⁶
Disturbances from the skin and subcutaneous tissues
	Increased sweating Rash Itching		Night sweating Hives Contact dermatitis Cold sweat Photosensitivity Increased bruising	Stevens-Johnson Syndrome⁶ Angioedema edema⁶	Contusion fabrics
Disturbances from musculoskeletal and connective tissue
	Musculoskeletal pain¹⁷ Muscular spasms		Muscular convulsions Stiffness muscles¹⁶	Lockjaw
Disorders from the kidneys and urinary tract
	Increasing urination Dizuria		Retention of urine Difficult start urination Nocturia Polyuria Attenuation of the flow of urine	Unusual smell of urine
Violations of the genitals and mammary gland
	Erectile dysfunction Violation ejaculation²¹ Delay ejaculation		Sexual dysfunction Gynecological bleeding Violation of the menstrual cycle Pain in the testicles	Symptoms of menopause Galactorrhea Hyperprolactinemia
General disorders and disorders at the site of administration
		Falls⁸ Change gustatory sensations Increased fatigue¹³	Chest pain²² Atypical Feel Feeling cold Thirst Chills Malaise Feeling of heat Violation of gait
Laboratory and instrumental data
	Weight loss		Weight gain Increase in the concentration of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, bilirubin, creatine phosphokinase, pathological deviation of hepatic enzymes. Increase in the concentration of potassium in the blood	An increase in the concentration of cholesterol in the blood

¹Cases of seizures and noise in the ears were also noted after treatment with duloxetine.

²Orthostatic hypotension and syncope were noted especially at the beginning of the treatment.

³See section "Special instructions".

⁴Cases of aggression and hostility were noted especially at the beginning of treatment with duloxetine or after its completion.

⁵Cases of suicidal thoughts or suicidal behavior were noted during duloxetine therapy or in the early period after completiontreatment.

⁶The estimated frequency of the undesired reaction. Not observed during clinical trials.

⁷Also includes hemorrhagic diarrhea, bleeding from the lower sections of the gastrointestinal tract, vomiting of blood, hemorrhoidal bleeding, melena, rectal bleeding, ulcer bleeding.

⁸Falls were more common in the elderly (≥ 65 years old).

⁹Including pain in the upper and lower abdomen, anterior abdominal wall tension, abdominal discomfort, gastrointestinal pain.

¹⁰Including internal trembling, motor anxiety, tension, psychomotor agitation.

¹¹Including awakenings in the middle of the night, early morning awakening, difficulty falling asleep.

¹²Including hypersomnia, sedation.

¹³Including asthenia.

¹⁴Including an increase in systolic arterial pressure, diastolic pressure, systolic arterial hypertension, diastolic hypertension, hypertension, hypertension.

¹⁵Including anorexia.

¹⁶Including muscle rigidity.

¹⁷Including myalgia and neck pain.

¹⁸Including hypoesthesia, hypesthesia of the face area, hypoesthesia of the genital area, paresthesia of the oral cavity,Very rarely (<0.01%) the sensation of electric shock (when therapy is discontinued).

¹⁹Including confusion.

²⁰Including nightmares.

²¹Including absence of ejaculation.

²²There were no statistically significant differences with placebo.

The abolition of duloxetine (in particular, one-stage) often leads to the emergence of the "withdrawal" syndrome, including the following symptoms: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), weakness, drowsiness, agitation or anxiety, nausea and / or vomiting, tremor, headache, irritability, diarrhea, hyperhidrosis and vertigo.

In general, with the use of SSRIs and serotonin and noradrenaline reuptake inhibitors (SSRIs), these phenomena have a weak or moderate degree of severity and limited character. However, in some patients, these phenomena may be more severe and / or prolonged. For this reason, with the abolition of duloxetine, a gradual dose reduction is recommended.

With short-term duloxetine intake (up to 12 weeks) in patients with painful form of peripheral diabetic neuropathy, a slight increase in fasting blood glucose was observed while maintaining a stable concentration glycosylated hemoglobin, as in the duloxetine, and in the placebo group. With prolonged therapy with duloxetine (up to 52 weeks), there was a slight increase in the concentration of glycosylated hemoglobin, which was 0.3% the corresponding indicator in patients receiving other treatment. With regard to the fasting glucose and total cholesterol in the blood in patients taking duloxetine, there was a slight increase in these indicators compared with a slight decrease noted in the control group of patients.

Corrected (relative to the heart rate) value of the QT interval in patients who took duloxetine, did not differ from that in the placebo group. Clinically significant differences between QT, PR, QRS, or QTcV interval in the group of patients taking duloxetine, and in the placebo group was not.

Overdose:

It is known about cases of overdose in clinical studies with simultaneous ingestion of up to 3000 mg of duloxetine, either alone or in combination with other drugs. In this case, one of these cases ended in a fatal outcome. However, spontaneous (postmarketing) reports contained descriptions of lethal acute overdoses, usually with a combined intake of several drugs,in which the dose of duloxetine was not more than 1000 mg. An overdose of duloxetine (isolated or combined) can be accompanied by the following symptoms: drowsiness, coma, clonic convulsions, serotonin syndrome, vomiting and tachycardia. In preclinical studies (in animals), the main signs of intoxication associated with overdose were disorders of the central nervous and digestive systems and included such manifestations as tremor, clonic convulsions, ataxia, vomiting and decreased appetite.

Treatment for overdose. A specific antidote is not known, however, in the case of the development of serotonin syndrome, it is possible to correct treatment with cyproheptadine and apply methods of normalizing body temperature. A sufficient supply of fresh air should be ensured. It is recommended to monitor cardiac activity and monitor the main indicators of vital activity, along with the conduct of symptomatic and supportive treatment. Gastric lavage can be indicated if there is little time left from the time of taking the drug inside, or within the symptomatic treatment.In order to limit the absorption can be applied Activated carbon. Duloxetine characterized by a large volume of distribution, and therefore the effectiveness of forced diuresis, hemoperfusion, exchange perfusion is questionable.

Interaction:

Inhibitors of monoamine oxidase (MAOI). Because of the risk of developing serotonin syndrome duloxetine should not be used in combination with MAOI, and for at least 14 days after discontinuation treatment of MAOI. Based on the duration of the half-life of duloxetine, you should take a break, at least 5 days after the end of duloxetine intake before taking MAOI.

For selective MAOI reversible action, such as moclobemide, the risk of a serotonin syndrome is lower. However, the combined use of MAO reversible action and duloxetine is not recommended.

Inhibitors of the isoenzyme CYP1A2. Due to the fact that the CYP1A2 isoenzyme is involved in the metabolism of duloxetine, simultaneous administration of duloxetine with potential inhibitors of the CYP1A2 isoenzyme is likely to lead to an increase in the concentration of duloxetine. A powerful inhibitor of the isoenzyme CYP1A2 fluvoxamine (100 mg once a day) reduced the average plasma clearance of duloxetine by approximately 77%. Caution should be exercised when prescribing duloxetine with inhibitors of the CYP1A2 isoenzyme (eg some quinolone antibiotics) and smaller duloxetine should be used.

Preparations, affecting the central nervous system. Caution should be exercised when using duloxetine along with other drugs and agents that affect the central nervous system, especially those that have a similar mechanism of action, including alcohol. Simultaneous use with other drugs that have a serotonergic effect (eg, SSRI, SSRIs, triptans and tramadol), can lead to the development of serotonin syndrome.

Serotonin syndrome. In rare cases, with the joint application of SSRIs (for example, paroxetine, fluoxetine) and serotonergic drugs, serotonin syndrome was observed. Caution should be exercised when using duloxetine in conjunction with serotonergic antidepressants, such as SSRIs, tricyclic antidepressants (clomipramine or amitriptyline), St. John 's wort, venlofaxine or triptans, tramadol, finidine and tryptophan.

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

Drugs metabolized by isoenzyme CYP2D6. Duloxetine is a moderate inhibitor of isoenzyme CYP2D6. When taking duloxetine in a dose of 60 mg 2 times a day, together with a single dose of desipramine, an isoenzyme substrate CYP2D6, AUC desipramine is increased 3 times. Simultaneous administration of duloxetine (40 mg twice daily) increased the equilibrium 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 isoenzyme system CYP2D6 and have a narrow therapeutic index.

Inhibitor inhibitors CYP2D6. Since the isoenzyme CYP2D6 participates in the metabolism of duloxetine, the simultaneous use of duloxetine with potential inhibitors of the isoenzyme CYP2D6 may lead to an increase in duloxetine concentrations. Paroxetine (20 mg 1 once a day) reduced the average clearance of duloxetine by about 37%. When duloxetine is used with isoenzyme inhibitors CYP2D6 (eg, SSRIs), care should be taken.

Oral contraceptives and other steroid preparations. Research results in vitro evidence that duloxetine does not induce the catalytic activity of the CYP3A isoenzyme. Specific studies of drug interactions in vivo not conducted.

Anticoagulants and antithrombotic drugs. In connection with the potential increased risk of bleeding associated with pharmacodynamic interaction, caution should be exercised when duloxetine and anticoagulants or antithrombotic agents are combined. In addition, with the combined use of duloxetine and warfarin, the importance of the international normalized relationship (INR) has increased. However, simultaneous use of duloxetine and warfarin in stable conditions in healthy volunteers within the framework of a clinical pharmacology study did not reveal a clinically significant change in the INR from the mean or a change in the pharmacokinetics of the right-handed or levorotatory isomer of warfarin.

Antacids and antagonists H₂-gistaminovyh receptors. The combined use of duloxetine and aluminum-and magnesium-containing antacids or duloxetine and famotidine did not significantly affect the extent of absorption of duloxetine when a dose of 40 mg

Inductors of the isoenzyme CYP1A2. Population pharmacokinetic analysis showed that compared with non-smokers in smokers, the concentration of duloxetine in plasma is almost 50% lower.

Preparations, highly binding to blood proteins. Duloxetine largely binds to plasma proteins (> 90%). Therefore, the appointment of duloxetine to a patient who takes another drug that binds highly to plasma proteins can lead to an increase in the concentration of free fractions of both drugs.

Special instructions:

An aggravation of the manic / hypomanic state. As with the use of similar drugs that affect the central nervous system, duloxetine should be used with caution in patients with manic episodes in the anamnesis.

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

Middrias. There were cases of mydriasis with duloxetine, therefore caution should be exercised in appointing duloxetine to patients with elevated intraocular pressure or in persons at risk of developing acute, closed-angle glaucoma.

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

Impaired liver or kidney function. In patients with severe renal dysfunction (CK <30 ml / min) or severe hepatic insufficiency, an increase in the concentration of duloxetine in plasma is observed. If 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 danger can persist until the onset of remission.As a result, patients who have the highest risk of committing suicide should be under careful medical supervision in the process of pharmacotherapy. Just like taking other drugs that have a pharmacological action mechanism similar to duloxetine (SSRIs, SSRIs), taking duloxetine during treatment, or stopping it in some cases was associated with the development of suicidal thoughts and suicidal behavior. The use of duloxetine in patients younger than 18 years of age has not been studied, and this drug is not intended for use in such patients. The causal relationship between duloxetine intake and the occurrence of suicidal phenomena in patients of this age group has not been established. At the same time, some analytical reviews of a number of studies using antidepressants for the treatment of mental disorders indicate an increased risk of suicidal ideation and / or suicidal behavior in children, adolescents and adults younger than 25 years compared with placebo. Doctors should convince patients at any time to report all their thoughts and feelings that concern them.

Increased risk of bleeding. SSRIs and SSRIs, including duloxetine, may increase the risk of bleeding, including gastrointestinal (see "Side effects"). therefore duloxetine caution should be given to patients taking anticoagulants and / or drugs that affect platelet function (eg, NSAIDs, aspirin) and patients with a history of bleeding.

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

Hyponatremia can manifest in the form of nonspecific symptoms (such as dizziness, weakness, nausea, vomiting, confusion, drowsiness, lethargy). Symptoms and symptoms manifested in more severe cases included fainting, falling and convulsions.

Inhibitors of monoamine oxidase (MAOI). In patients taking a serotonin reuptake inhibitor in combination with MAOI, there have been cases of serious reactions,sometimes with a fatal outcome, among which there were hyperthermia, rigidity, myoclonus, peripheral disorders with possible sharp fluctuations in vital signs and changes in mental status, including pronounced agitation with transition to delirium and to whom. These reactions were also observed in patients who, shortly before the appointment of MAOI, the serotonin reuptake inhibitor was canceled. In some cases, patients exhibited symptoms characteristic of malignant neuroleptic syndrome. Effects of combined use of duloxetine and MAOI were not evaluated in either humans or animals. Therefore, given the fact that duloxetine is a reuptake inhibitor and serotonin, and norepinephrine, it is not recommended to take duloxetine in combination with MAOI or for at least 14 days after discontinuation of MAOI treatment. Based on the duration of the half-life of duloxetine, you should take a break, at least 5 days after the end of duloxetine intake before taking MAOI.

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

Effect on the ability to drive transp. cf. and fur:

Against the background of taking duloxetine, sedation, drowsiness and other side effects can occur. In this regard, patients receiving duloxetine, caution should be exercised when managing dangerous mechanical means, including by car.

Form release / dosage:Capsules intestinal soluble 30 mg or 60 mg.

Packaging:

14 capsules per blister. For 1, 2 or 6 blisters together with instructions for use in a cardboard pack.

Storage conditions:

At a temperature of 15-30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N016058 / 01

Date of registration:19.11.2009 / 24.10.2013

The owner of the registration certificate:Eli Lilly East SAEli Lilly East SA Switzerland

Manufacturer: & nbsp

LILLY, S.A. Spain

ELI LILLY & Company USA

Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland

Information update date: & nbsp24.01.16

Illustrated instructions

Instructions

Simbalta® (Cymbalta®)