Ixel - instructions for use, dose, side effects, contraindications

Active substanceMilnacipranMilnacipran

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capsules inwards

Pierre Fabre Medication Production France

Dosage form: & nbspcapsules

Composition:

	Amount, mg
	*capsules 25 mg*	*capsules 50 mg*
Active substance:
milnacipran hydrochloride	25,00	50,00
Excipients:
calcium hydrogen phosphate dihydrate	50,925	101,85
carmellose calcium	22,150	44,30
Povidone KZO	2,10	4,20
Silica colloidal dioxide	0,625	1,25
magnesium stearate	2,10	4,20
talc	2,10	4,20
Capsule shell:	Cover / casing	Cover / casing
titanium dioxide	0,286/0,494	0,392 / 0,294
dye iron oxide red	0,024 / 0,042	0,033 /0,139
dye iron oxide yellow	0,036/0,062	0,049/0,132
gelatin	up to 14,3 / 24,7	to 19.6 / 29.4

Description:

Capsules 25 mg:

Hard gelatin capsules number 4, the lid - orange-pink color with a black print "IXEL", the case is orange-pink in color with a black" 25 "print.

Capsules 50 mg:

Hard gelatin capsules number 3, the lid - orange-pink color with a black print "IXEL", the case is of an orange-brown color with a black" 50 "print.

The contents of capsules for both dosages: powder from white to almost white, conglomerates (lumps) are allowed, which when pressed with a glass rod are easily turned into powder.

Pharmacotherapeutic group:Antidepressant

ATX: & nbsp

N.06.A.X.17 Milnacipran

Pharmacodynamics:

Milnacipran is a selective inhibitor of monoamine reuptake (serotonin (5 HT) and norepinephrine).

Milnacipran does not bind to m-cholinergic receptors, α1-adrenoreceptors, H₁-histamine receptors, as well as D₁ and D₂dopaminergic, benzodiazepine and opioid receptors.

Milnacipran has virtually no effect on repolarization or conduction of the heart.

Milnacipran has no effect on cognitive function and has a minor sedative effect.

Milnacipran is effective in sleep disorders in patients with depressive conditions: the time of falling asleep decreases, the number of nocturnal awakenings decreases, the time period before the onset of the fast sleep phase increases, the total duration of sleep increases.

The efficacy of milnacipran is comparable to that of selective serotonin reuptake inhibitors and tricyclic antidepressants, but is inferior to clomipramine.

Pharmacokinetics:

Suction

After oral administration milnacipran well absorbed. Bioavailability is about 85% and does not depend on the characteristics and diet. The maximum concentration in the blood plasma (C_m_Oh) is reached after approximately 2 hours (T_m_Oh) after ingestion. After taking the drug in a single dose of 50 mg C_m_Oh is about 120 ng / ml. Dose-dependent increase in C_m_Oh was noted when taking the drug in doses up to 200 mg. After repeated receptions of the equilibrium concentration of the drug attained within 2-3 days, while it is 70% - 100% greater than after a single dose (C_m_Oh: 216 ng / ml). Interindividual variability is low.

Distribution

Binding to blood plasma proteins is low (13%) and unsaturated. The volume of distribution of milnacipran is about 5 l / kg with a total clearance of about 40 l / h. Kidney and nepochechny clearance is the same.

Metabolism

Milnacipran is practically not metabolized, the active metabolite is not

exists, conjugates with glucuronic acid.

Excretion

The half-life (T1 / 2) of milnacipran is about 8 hours. Excretion in an unchanged form mainly through the kidneys (90% of the administered dose) due to tubular secretion.

At the end of the course treatment milnacipran completely excreted from the body within 2-3 days after discontinuation of the drug.

Special patient groups

Patients with hepatic impairment

Disturbance of liver function does not lead to significant changes in the pharmacokinetic parameters of milnacipran.

Patients with renal insufficiency

The rate of excretion of milnacipran decreases in proportion to the degree of change in renal function.

Patients over 65 years of age

The pharmacokinetic parameters of milnacipran in elderly patients do not change significantly. However, when choosing a dose, it is necessary to take into account the physiological change in kidney function in elderly patients.

Pre-clinical safety data

According to preclinical research, the target organ for multiple administration of milnacipran is the liver. Undesirable effects developed with the use of high doses, about 10 times higher than the therapeutic dose, and were reversible. Preclinical data obtained during toxicity, genotoxicity and reproductive toxicity studies of milnacipran did not reveal potential risks to human health. Milnacipran is neither mutagenic nor carcinogenic.

Indications:Treatment of a large depressive episode in adults.

Contraindications:Hypersensitivity to milnacipran or other components of the drug; combined use with irreversible monoamine oxidase inhibitors; the period of breastfeeding; uncontrolled arterial hypertension, severe or unstable course of coronary heart disease (as these conditions can be aggravated by the side effects of the drug).

It is not recommended to use Ixell in patients less than 18 years of age due to the lack of long-term safety and efficacy data.

Carefully:

Patients with insomnia or nervousness at the initial stage of treatment may need temporary symptomatic therapy.

The use of milnacipran in patients with a history of mania and / or hypomania should be carried out with caution in connection with the potential for exacerbation of these conditions. If a patient experiences a transition to severe mania, the use of milnacipran should be discontinued.

If there are signs of liver damage against the background of taking Ixel, its use should be discontinued until the cause is clarified.

Data on the interaction of milnacipran with alcohol are absent, however, it is recommended to avoid drinking alcohol during the period of application of Ixell.

Milnacipran should be administered with caution in the following cases:

- In patients with renal insufficiency: a dose reduction may be required due to elongation T_1/2milnacipran.

In patients who have a history of impaired urine outflow, in particular,in patients with prostatic hyperplasia and other diseases of the genitourinary system: in connection with the noradrenergic component of the mechanism of action milnacipran potentially can cause (increase) the violation of outflow of urine, which requires appropriate control.

- In patients with hypertension or heart disease: milnacipran can potentially cause increased blood pressure and increased heart rate. Before starting treatment with milnacipran, during the selection of doses and during the period of treatment, it is required to control the level of arterial pressure and the heart rate. Patients with high blood pressure and / or diseases of the cardiovascular system should prescribe effective therapy before prescribing milnacipran. In the case of a persistent increase in blood pressure or heart rate, consideration should be given to discontinuing therapy with milnacipran.

- In patients with high intraocular pressure or the risk of developing an angle-closure glaucoma.

- In patients with epilepsy (including history): in the event of seizures, the use of Ixell should be completely discontinued.

There have been cases of hyponatremia in the use of serotonin reuptake inhibitors, possibly in connection with the syndrome of inadequate secretion of antidiuretic hormone. Caution is necessary when using milnacipran in elderly patients, in patients taking diuretics or other drugs that cause hyponatremia, as well as in patients with cirrhosis or malnutrition.

The cases of development of bleeding, sometimes serious, with the use of serotonin reuptake inhibitors are described. Caution is needed when using milnacipran together with oral anticoagulants, antiplatelet agents (including acetylsalicylic acid, other nonsteroidal anti-inflammatory drugs), as well as other drugs that increase the risk of bleeding. Care should also be taken with milnacipran in patients who have a history of clotting disorders.

Pregnancy and lactation:

Pregnancy

Clinical data on the use of milnacipran during pregnancy are absent.

Preclinical studies showed no direct or indirect adverse effects on the course of pregnancy, development of the embryo and fetus, childbirth or postnatal development.

Neonatal risk (newborn risk) has been reported following the use of serotonin reuptake inhibitors during pregnancy. This risk can be associated with the syndrome of early termination of the drug or with the toxicity of serotonin. It is not recommended to use the drug Ixel during pregnancy.

Breast-feeding

Milnacipran penetrates into breast milk. The drug Ixel is contraindicated in the period of breastfeeding.

Dosing and Administration:

The drug is taken orally, preferably during meals.

Patients with normal renal function:

the recommended daily dose is 100 mg. The daily dose is taken in 2 divided doses of 50 mg (one 50 mg capsule in the morning and evening).

Patients with renal insufficiency:

It is necessary to reduce the dose of the drug depending on the degree of decrease in kidney function.

The following dose selection scheme is recommended:

Creatinine clearance (CK) (ml / min)	Daily dose
QC≥60	50 mg x 2 times
60LC≥30	25 mg x 2 times
30LC≥10	25 mg

Duration of therapy

Antidepressant therapy is symptomatic. The effectiveness of milnacipran is manifested in an average of 1-3 weeks of continuous intake.To prevent recurrence, treatment should continue for several months (usually about 6 months). Duration of the drug is prescribed by the attending physician.

The safety and effectiveness of milnacipran when used in a daily dose of more than 100 mg to treat a major depressive episode are not established. If there is no effectiveness in taking Ixel at a dose of 100 mg per day, the drug should be discontinued.

Discontinuation of therapy

To avoid the development of withdrawal syndrome, cessation of therapy should be carried out gradually. You can not allow a sharp cessation of treatment after prolonged use of the drug.

Side effects:

Undesirable reactions are systematized according to system-organ classes

and are listed in accordance with the following gradation:

very frequent (≥1/10), frequent (from ≥1/100 to <1/10),

infrequent ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000),

very rare (<1/10000), the frequency is unknown (single messages, frequency can not be estimated from available data).

Violations of the blood and lymphatic system

The frequency is unknown: hemorrhages in the skin and mucous membranes (ecchymosis).

Immune system disorders

Infrequent: hypersensitivity.

Rarely: anaphylactic shock.

Disorders from the endocrine system

Rarely: syndrome of inadequate secretion of antidiuretic hormone.

Disorders from the metabolism and nutrition

Infrequently: hyperlipidemia, weight loss.

Frequency unknown: hyponatremia.

Disorders of the psyche

Often: agitation, anxiety, depression, eating disorders, sleep disorders, suicidal behavior (suicide attempts and suicidal thoughts).

Infrequently: panic attack, confusion, delusions, hallucinations, mania, decreased libido, nightmarish dreams, suicidal tendencies of thinking.

Rarely: derealization, pathological thinking, mental disorder. Frequency unknown: aggression.

Disturbances from the nervous system

Very often: headache.

Often: migraine, tremor, dizziness, dysesthesia (a sensitivity disorder), drowsiness.

Infrequent: memory impairment, akathisia, imbalance, a violation of taste perception, fainting.

Rarely: acute disturbance of cerebral circulation, dyskinesia, trembling paralysis (parkinsonism), convulsions.

The frequency is unknown: serotonin syndrome (see "Interactions with Other Drugs" for a description), convulsions.

Disturbances on the part of the organ of sight

Infrequent: dry eyes, pain in the eyes, mydriasis, violation

accommodation, blurred vision, impaired vision.

Hearing disorders and labyrinthine disorders

Infrequent: sensation of noise in the ears, vertigo.

Heart Disease

Often: tachycardia, palpitation.

Infrequent: violation of the heart rhythm, blockade of the bundle branch, extrasystole, myocardial infarction. Rarely: stenocardia.

Vascular disorders

Often: a sensation of "tides" of blood to the head, an increase in blood pressure.

Infrequently: Raynaud's disease, lowering of blood pressure, orthostatic hypotension.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: cough, dyspnoea, dry nasal mucosa, pharyngeal disorders.

Disorders from the gastrointestinal tract

Very often: nausea. Hasto: constipation, diarrhea, abdominal pain, indigestion, vomiting, dry mouth. Infrequently: colitis, gastritis, a violation of the motility of the gastrointestinal tract, a feeling of discomfort in gastrointestinal tract, bloating, peptic ulcer and duodenal ulcer, hemorrhoids, stomatitis.

Disturbances from the liver and bile ducts

Infrequently: increase in the concentration of liver enzymes in the blood plasma.

Rarely: hepatitis, hepatocellular disorders.

Frequency unknown: cytolytic hepatitis.

Disturbances from the skin and subcutaneous tissues

Often: itching, rash, increased sweating

Infrequent: allergic reaction (urticaria), dermatitis, dermatosis.

Rarely: sensitization reactions

Frequency Unknown: Stevens-Johnson Syndrome

Disturbances from the musculoskeletal system and connective tissue

Often: musculoskeletal pain

Infrequent: stiff muscles, myalgia.

Disorders from the kidneys and urinary tract

Often: difficulty urinating, frequent urination.

Infrequently: chromaturia, urinary incontinence, urinary retention.

Violations of the genitals and mammary gland

Often: violations of ejaculation, erectile dysfunction, testicular pain.

Infrequently: amenorrhea, hypermenorrhea, menstruation, uterine bleeding, dysfunction of the prostate gland.

General disorders and disorders at the site of administration

Often: feeling tired.

Infrequently: fever, chest pain, chills, poor health, general malaise.

Overdose:

Symptoms:

After taking a dose of 200 mg: nausea, increased sweating, constipation. After taking a dose of 800 mg to 1000 mg (in monotherapy): vomiting, shortness of breath, tachycardia.

After taking a dose of 1900 mg to 2800 mg (in combination with other drugs, in particular, benzodiazepines), the symptoms described above are accompanied by drowsiness, hypercapnia, and impaired consciousness.

Treatment:

There is no specific antidote to milnacipran. Treatment is symptomatic. It is recommended urgent gastric lavage, reception of activated charcoal. Medical supervision of the patient should last at least 24 hours.

Interaction:The information presented in this section is based on studies of drug interactions of milnacipran in adult patients.

Serotonin syndrome

Serotonin syndrome can develop with the joint application of milnacipran with drugs,which affect the serotonergic neurotransmitter system (irreversible monoamine oxidase (MAO) inhibitors (iproniazide), selective MAO inhibitors of type A (linezolid, moclobemide, methylene blue), pethidine, tramadol, most of antidepressants, St. John's wort (Nourerisieverforatum)). Serotonin syndrome presents a potential danger to the life of the patient. Symptoms: digestive disorders (diarrhea), changes in mental state and behavior (agitation, confusion, hypomania), impaired motor function (tremor, rigidity, myoclonia, hyperreflexia, ataxia), autonomic nervous system disorders (unstable blood pressure, tachycardia, tremor, hyperthermia, possible coma).

Contraindicated combinations

In the joint use of milnacipran with irreversible monoamine oxidase (MAO) inhibitors (iproniazide) - the risk of the occurrence of serotonin syndrome. The interval between the end of therapy with an MAO inhibitor and the initiation of therapy with Ixel should be at least two weeks. The interval between the completion of therapy with Ixel and the initiation of therapy with an MAO inhibitor should be at least one week.

Unrecommended combinations

When combined with alpha and beta-adrenomimetic agents (for parenteral administration) - the risk of paroxysmal hypertension with possible arrhythmia (inhibition of the capture of catecholamines by sympathetic nerve fibers).

When combined with reversible MAO inhibitors (linezolid, moclobemide, toloxaton, methylene blue) - the risk of developing serotonin syndrome. If the use of this combination can not be avoided, then careful medical supervision of the patient should be carried out. The combination should be started at the lowest recommended dose.

Combinations that require caution

Caution should be exercised when combined with epinephrine (for administration subcutaneously or in the gum) - the risk of a serious violation of the ventricular rhythm as a result of increased excitability of the myocardium. It is necessary to limit the rate of epinephrine administration to less than 0.1 mg / 10 min or 0.3 mg / 1 hour.

When combined with lithium preparations, the risk of developing serotonin syndrome. Regular medical supervision is necessary.

Caution should be exercised when combined with oral anticoagulants, with drugs,affecting the function of platelets (for example, non-steroidal anti-inflammatory drugs, aspirin) or other drugs that increase the risk of bleeding.

When combined with cardiac glycosides (digoxin) - (parenteral route of administration) - the risk of increased hemodynamic effects.

When combined with levomepromazinom system exposure milnacipran increased by 20% in healthy volunteers. A more significant increase can be expected in elderly patients or patients with impaired renal function.

Special instructions:

Suicide, suicidal thoughts or worsening of clinical symptoms

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk persists until a significant remission occurs. Careful observation is necessary the patient's state during the first few weeks of treatment or more, until the onset of improvement in clinical symptoms. According to the accumulated clinical experience, the risk of suicide may increase in the early stages of recovery.

It is known that patients with a history of suicidal events, or patients,manifesting a significant suicidal thinking even before starting treatment, have a higher risk of suicidal thoughts or suicide attempts. These patients should be carefully monitored during the treatment period. A meta-analysis of placebo-controlled clinical trials of antidepressants with adult patients with mental disorders showed that patients younger than 25 years of age had a higher risk of suicidal behavior when taking antidepressants compared with placebo.

Drug therapy, especially at the initial stage and when adjusting the dose, should be accompanied by careful medical supervision, especially for patients from the high-risk group.

Patients, as well as persons caring for patients, should be warned about the need to monitor any manifestations of clinical impairment, suicidal behavior or thoughts, and unusual changes in behavior, and immediately seek professional advice if these symptoms appear.

Use in patients under the age of 18 years

Suicidal behavior (suicide attempt and suicidal ideation) and hostility (aggression, oppositional behavior and anger) were more frequent in clinical studies in children and adolescents taking antidepressants compared to patients taking placebo.

There are no long-term data on the safety of milnacipran in children and adolescents regarding growth, maturation, cognitive and behavioral development.

Ixel is not recommended for patients under the age of 18 years.

Effect on the ability to drive transp. cf. and fur:In studies in healthy volunteers, no changes were reported from cognitive or psychomotor functions. However, with the use of the drug, it is possible to reduce the mental and physical abilities necessary to carry out potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Capsules 25 mg, 50 mg.

Packaging:For 14 capsules in a blister of PVC and aluminum foil.

For 2 or 4 blisters together with instructions for medical use in a cardboard box.

Storage conditions:At a temperature of no higher than 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 N011787 / 01

Date of registration:21.09.2011

Expiration Date:Unlimited

The owner of the registration certificate:Pierre Fabre Medication ProductionPierre Fabre Medication Production France

Manufacturer: & nbsp

PIERRE FABRE MEDICAMENT PRODUCTION France

Representation: & nbspPIER FABR PIER FABR France

Information update date: & nbsp09.11.2017

Illustrated instructions

Instructions

Ixelles (Ixel)