Composition, form of production and packaging
Capsules are hard gelatinous, size 4, the lid is orange-pink with an impression "IXEL" in black, the body is orange-pink with a "25" print in black; the contents of the capsules are powder from white to almost white, conglomerates (lumps) are allowed, which when pressed with a glass rod are easily turned into a powder.
milnacipran hydrochloride 25 mg
Excipients: calcium hydrophosphate dihydrate - 50.925 mg, carmellose calcium - 22.15 mg, povidone K30 - 2.1 mg, silicon dioxide colloid - 0.625 mg, magnesium stearate - 2.1 mg, talc - 2.1 mg.
The capsule capsule composition: titanium dioxide 0.286 mg, iron oxide red oxide 0.024 mg, iron oxide yellow oxide 0.036 mg, gelatin up to 14.3 mg.
The composition of the capsule body: titanium dioxide - 0.494 mg, iron oxide red oxide - 0.042 mg, iron oxide oxide yellow - 0.062 mg, gelatin - up to 24.7 mg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
Capsules are hard gelatinous, size 3, the lid is orange-pink with an impression of "IXEL" black, the body is orange-brown with a "50" print in black; the contents of the capsules are powder from white to almost white, conglomerates (lumps) are allowed, which when pressed with a glass rod are easily turned into a powder.
milnacipran hydrochloride 50 mg
Excipients: calcium hydrophosphate dihydrate - 101.85 mg, carmellose calcium - 44.3 mg, povidone K30 - 4.2 mg, silicon dioxide colloid - 1.25 mg, magnesium stearate - 4.2 mg, talc - 4.2 mg.
Composition of capsule capsule: titanium dioxide 0.392 mg, iron oxide red oxide 0.033 mg, iron oxide yellow oxide 0.049 mg, gelatin up to 19.6 mg.
The composition of the capsule body: titanium dioxide - 0.294 mg, iron oxide red oxide - 0.139 mg, iron oxide oxide yellow - 0.132 mg, gelatin - up to 29.4 mg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
A broad-spectrum antidepressant, a selective monoamine reuptake inhibitor (norepinephrine and serotonin).
Milnacipran does not bind to m-holinoretseptorami,? 1- adrenoreceptors, histamine H 1 -receptors, as well as with dopamine D 1 and D 2 receptors, benzodiazepine and opioid receptors.
Has no sedative effect, physiologically improves night sleep, does not have a negative effect on cognitive function.
Milnacipran has virtually no effect on the conduction system of the heart and blood pressure, which is especially important for elderly patients who are constantly taking cardiotropic drugs.
After ingestion, milnacipran is well absorbed. Bioavailability is about 85% and does not depend on the characteristics and diet. C max in plasma is reached after approximately 2 h (T max ) after ingestion. After taking the drug in a single dose of 50 mg C max is about 120 ng / ml, C max is directly proportional to the value of the dose taken.
After repeated administration of the drug, C ss is reached after 36-48 hours, while it is 70-100% more than after taking a single dose. Binding to plasma proteins is 13%. V d of milnacipran is about 5 l / kg.
Milnacipran is practically not metabolized, there is no active metabolite, it is conjugated to glucuronic acid.
T 1/2 of milnacipran is 6-8 hours after a single dose, while T 1/2 of the active D isomer is 8-10 hours, and the L isomer is 4-6 hours. The renal and extrarenal clearance is equivalent, the kidneys are unchanged 55% of the dose administered (24% of the L isomer and 31% of the D isomer) is withdrawn, 17% of the L isomer and only 2% of the D isomer are conjugated with glucuronic acid. About 8% is displayed as N-desethylmethylnacipran. The total ground clearance is about 40 l / h.
Against the background of course treatment, milnacipran is completely eliminated from the body within 2-3 days after discontinuation of the drug.
Pharmacokinetics in specific patient groups
In patients with impaired renal function, the rate of release of milnacipran decreases in proportion to the severity of the disease. AUC in patients with chronic renal failure is mild (CC is 50-80 ml / min), mean (QA 30-49 ml / min) and severe (QC 5-29 ml / min), compared with healthy volunteers, respectively, by 16 %, 52% and 199%, and T 1/2 - by 38%, 41% and 122%.
In patients with mild and moderate hepatic insufficiency (class A and B on the Child-Pugh scale), AUC and T 1/2 do not differ from the corresponding parameters in healthy volunteers. In patients with severe hepatic insufficiency (class C on the Child-Pugh scale), these parameters are higher than in healthy subjects by 31% and 55%, respectively, and therefore some caution is required when prescribing Ixell in this category of patients, although dosage regimens and not required.
With max and AUC milnacipran in elderly patients (over 65 years) compared with younger individuals is higher by 30% (due to a decrease in CK with age), however, no special correction of the dosing regimen in elderly patients with intact renal function it takes.
With max and AUC of milnacipran in women 20% higher than in men, a change in the dosage regimen is not required.
- Major depressive episode in patients older than 18 years.
Ixel is taken by mouth during meals.
The average daily dose of the drug in adults is 100 mg. The daily dose should be divided into 2 divided doses of 50 mg (1 capsule morning and evening).
Patients with renal failure need a dose adjustment. The daily dose is reduced depending on the degree of impaired renal function. The following dose selection scheme is recommended:
CK (ml / min) Daily dose
? 60 50 mg? 2 times
30-60 25 mg? 2 times
10-30 25 mg
As with the use of other antidepressants, the effectiveness of milnacipran is manifested in an average of 1-3 weeks of continuous intake. To prevent recurrence, treatment should be continued for several months (usually 6 months).
Duration of the drug is set individually.
To avoid the development of the withdrawal syndrome, stopping the drug Ixel should be carried out gradually and with careful monitoring of the patient.
Adverse reactions are classified according to the system-organ classes and are listed according to the following gradation: very often - 1/10 appointments (? 10%);often - 1/100 of appointments (? 1% but <10%); infrequently - 1/1000 appointments (? 0.1% but <1%); rarely - 1/10 000 appointments (? 0.01% but <0.1%); very rarely - less than 1/10 000 appointments (<0.01%); frequency is unknown - single post-marketing messages, the frequency can not be estimated from available data.
On the part of the hematopoiesis system: the frequency is unknown - the ecchymosis.
From the immune system: infrequently - hypersensitivity; rarely anaphylactic shock.
From the endocrine system: rarely - violation of ADH secretion.
From the side of metabolism: infrequently - hyperlipidemia; frequency is unknown - hyponatremia.
Mental disorders: often - agitation, anxiety, depression, eating disorder, sleep disturbance, 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.
From the nervous system: very often - headache; often - migraine, tremor, dizziness, dysesthesia, drowsiness; infrequently - memory impairment, akathisia, imbalance, violation of taste sensations, fainting; rarely - acute disturbance of cerebral circulation, dyskinesia, parkinsonism, convulsions; the frequency is unknown - serotonin syndrome (psychiatric symptoms (agitation, confusion, hypomaniacal state, coma), motor symptoms (myoclonus, tremor, hyperreflexia, rigidity, hyperactivity), autonomic (hypo- or hypertension, tachycardia, tremors, hyperthermia, increased sweating), gastrointestinal (diarrhea)), convulsions.
From the side of the organ of vision: infrequent - a feeling of dry eyes, pain in the eyes, mydriasis, disruption of accommodation, blurred vision, impaired vision.
From the side of the organ of hearing and labyrinthine disturbances: infrequently - the sensation of noise in the ears, vertigo.
From the cardiovascular system: often - tachycardia, a feeling of palpitations, a sensation of hot flushes to the head, hypertension; infrequent - violation of the heart rhythm, blockade of the bundle of the bundle, Extrasystole, myocardial infarction, Raynaud's disease, arterial hypotension, orthostatic hypotension; rarely - angina.
On the part of the respiratory system: infrequently - cough, dyspnoea, dryness of the nasal mucosa, pharyngeal disorders.
From the digestive tract: very often - nausea; often - 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 the digestive tract, bloating, peptic ulcer of the stomach and duodenum, hemorrhoids, stomatitis.
From the side of the liver and bile ducts: infrequently - increased activity of liver enzymes; rarely - hepatitis, hepatocellular disorders; frequency unknown - cytolytic hepatitis.
From the skin and subcutaneous tissues: often - itching, rash, increased sweating; infrequently - hives, dermatitis, dermatosis; rarely photosensitization reactions.
From the musculoskeletal system: often - musculo-skeletal pain; infrequently - rigidity of muscles, myalgia.
From the urinary system: often - difficulty urinating, frequent urination; infrequently - chromaturia, urinary incontinence, urinary retention.
From the genitals and the breast: often - ejaculation disorders, erectile dysfunction, testicular pain; infrequently - amenorrhea, hypermenorrhea, menstruation, uterine bleeding, dysfunction of the prostate gland.
Other: often - a feeling of fatigue; infrequently - fever, chest pain, chills, deterioration of well-being, feeling of malaise, weight loss.
- simultaneous reception of nonselective and selective MAO inhibitors of types A and B, as well as agonists of serotonin 5HT1D receptors (including sumatriptan), digoxin;
- simultaneous use with epinephrine, norepinephrine, clonidine and similar compounds;
- uncontrolled arterial hypertension, severe or unstable course of IHD, as these conditions can be aggravated due to side effects of the drug;
- concomitant obstruction of the urinary tract (mainly, with prostatic hyperplasia);
- the period of lactation (breastfeeding);
- age up to 18 years;
- Hypersensitivity to milnacipran and other components of the drug.
Caution should be given to patients with renal insufficiency (a dose reduction may be required due to elongation of T 1/2 of milnacipran); angle-closure glaucoma;arterial hypertension or heart disease, in which an increase in heart rate is undesirable; epilepsy (including in the anamnesis); cirrhosis of the liver or malnutrition;patients who have a history of indications of a violation of urine outflow (especially in patients with prostatic hyperplasia and other diseases of the urinary tract);patients who have a history of blood clotting disorders (in the treatment of serotonin reuptake inhibitors, cases of bleeding are described); patients taking diuretics or other drugs that can cause hyponatremia (cases of hyponatremia have been reported with the use of serotonin reuptake inhibitors, which may be due to the syndrome of inappropriate ADH secretion); patients receiving indirect anticoagulants (eg, warfarin), antiplatelet agents (including acetylsalicylic acid and other NSAIDs) or other drugs that may increase the risk of bleeding; patients of advanced age.
PREGNANCY AND LACTATION
In view of the lack of data on the efficacy and safety of milnacipran in pregnant women, it is not recommended to prescribe Ixel during pregnancy.
Milnacipran is excreted in breast milk. The drug Ixel is contraindicated in the period of breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated use of the drug with concomitant obstruction of the urinary tract.
Caution should be given to patients with renal insufficiency (a dose reduction may be required due to elongation of T 1/2 of milnacipran), patients with a history of urinary tract dysfunction (especially in patients with prostatic hyperplasia and other urinary tract diseases).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be given to patients with cirrhosis of the liver.
APPLICATION FOR CHILDREN
Contraindication: children and adolescence under 18 years.
APPLICATION IN ELDERLY PATIENTS
Caution should be given to elderly patients.
With the combined use of drugs that affect the reuptake of serotonin, with drugs that inhibit its metabolism (including MAO inhibitors and neuroleptics), the development of serotonin syndrome is possible. Serotonin syndrome (manifested by increased nervous excitability, the development of hallucinations, coma, tachycardia, AD lability, hyperthermia, hyperreflexia, impaired coordination of movements, nausea, vomiting, diarrhea) presents a potential danger to the life of the patient. The drug Ixel can be prescribed not earlier than 2 weeks after the abolition of MAO inhibitors. The time interval from the moment of stopping the use of Ixel before starting therapy with MAO inhibitors should be at least 1 week.
Ixel should be used with extreme caution in patients with prostatic hyperplasia, epileptic seizures, as well as in patients with hypertension or hypertrophic cardiomyopathy (especially obstructive).
In children, adolescents and patients under the age of 24, the risk of suicidal ideation and suicidal behavior increases with the appointment of antidepressants, and therefore, when appointing milnacipran for this category of people, the risk of suicide and the benefits of using the drug should be correlated.
In short-term studies in patients older than 24 years, the risk of suicide did not increase, and in individuals older than 65 years even slightly decreased. During treatment with antidepressants, all patients should be monitored for early detection of disorders or behavioral changes, as well as suicidal tendencies.
Drugs that inhibit the re-uptake of norepinephrine and serotonin (including milnacipran) may cause an increase in blood pressure and a rapid increase in heart rate.However, it should be noted that the severity of these phenomena against the background of taking the drug at recommended doses is usually minor, is not felt by patients and, as a rule, does not require medical correction. Studies on the effect of milnacipran on blood pressure in patients with concomitant uncontrolled arterial hypertension, as well as heart rate in patients with heart rhythm disorders, have not been conducted to date. Nevertheless, before starting treatment, during the selection of doses and during treatment, it is necessary to monitor blood pressure and heart rate. Persons suffering from hypertension or other diseases of the cardiovascular system should prescribe milnacipran effective therapy.
The cases of an increase in the activity of hepatic transaminases (up to 3 times higher than UGN) in patients with milnacipran are described. A clinically significant increase in bilirubin was not observed. In the literature there are separate reports on the development of toxic hepatitis in patients on the background of taking milnacipran, however, according to these reports, a clear cause-and-effect relationship can not currently be traced (due to the simultaneous use of other drugs and previous diseases of the hepatobiliary system). If there are signs of liver damage with milnacipran, the drug should be stopped. It is undesirable to prescribe milnacipran to people who abuse alcohol and / or have concomitant liver diseases.
During the period of treatment, it is not recommended to drink alcohol (milnacipran can potentially increase the negative effect of ethanol on the liver).
With the sharp cancellation of milnacipran, mood lability, excitement, weakness, paresthesia, anxiety, headache, drowsiness, emotional lability, convulsive syndrome are possible. The severity of these phenomena is usually insignificant, but with their development, the speed of drug withdrawal should be reduced.
The administration of milnacipran to patients with a history of mania and / or hypomania should be carried out with caution because of the potential for exacerbation of these conditions.
Proceeding from the mechanism of action, it can be assumed that milnacipran can potentially cause (increase) disturbances in urinary outflow (primarily in patients with concomitant hypertrophy of the prostate and prostatitis), which requires appropriate control.
Milnacipran, causing the dilatation of the pupil, can promote increased intraocular pressure (patients with initially high ophthalmotonus against a poorly controlled angle-closure glaucoma).
Symptoms: with an accidental overdose, one of the first symptoms is nausea, vomiting, increased sweating, constipation. After taking the drug at a dose of more than 800-1000 mg - vomiting, shortness of breath, tachycardia. After taking the drug at an excessively high dose (1900-2800 mg) in combination with other psychotropic drugs (most often benzodiazepines), the symptoms described above are supplemented with drowsiness, hypercapnia, and impaired consciousness. Manifestations of cardiotoxicity were observed with an overdose of milnacipran.
Treatment: gastric lavage, activated charcoal, symptomatic therapy. It is recommended to monitor the patient's condition at least a day. Milnacipran specific antidote does not exist.
Milnacipran (even at concentrations 25 times greater than sredneterapevticheskih) does not affect the system of microsomal oxidation in hepatocytes (CYP1A2, CYP2A6, CYP2B6, CYP2C8 , CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5), which is why one should not expect interaction with inductors and inhibitors of microsomal oxidation.
Carbamazepine, fluoxetine, Lorazepam: interactions with milnacipran were found.
clomipramine:when transferring patients with clomipramine (75 mg / day) to milnacipran (100 mg / day), a significant change in the pharmacokinetic parameters of the last detected. However, in these cases the patients required more careful observation, because with such a translation (without period "washout") states of euphoria and increased heart attacks postural hypotension, increased risk for serotonin syndrome.
Non-selective MAO inhibitors (iproniazid): increased risk of serotonin syndrome. After treatment MAO inhibitor before therapy milnacipran course necessary to break of 2 weeks, and a break after treatment with milnacipran before receiving MAO inhibitor should not be less than 1 week.
Selective MAO-B inhibitors (selegiline): increased risk of sudden increase of blood pressure. After the treatment, a selective inhibitor of MAO type B before a course of therapy lasting milnacipran required break in 2 weeks, after treatment interruption milnacipran before receiving selective MAO-B inhibitor should be at least 1 week.
Agonists, serotonin 5-HT1D receptors (sumatriptan and other) increases the risk of pronounced increase in blood pressure, coronary artery spasm as a result of cumulation serotonergic action of drugs. It is necessary to take a break between the end of treatment with milnacipran and the beginning of a course of therapy agonist of serotonin 5-HT 1D receptors for a period of 1 week.
Cardiac glycosides (digoxin and others):increased risk of increasing the severity of effects on the cardiovascular system (especially with parenteral administration of digoxin).
Diuretics: increased risk of hyponatremia.
Of lithium drugs: increased risk of serotonin syndrome, the milnacipran has no effect on the pharmacokinetics of lithium products.
Milnacipran is not recommended for combination with the following drugs:
- with epinephrine, norepinephrine (for parenteral administration), because increases the risk of a sharp rise in blood pressure with probability of heart rhythm disorders (suppression of catecholamines capture sympathetic nerve fibers);
- clonidine and other drugs with the same mechanism of action as reduced hypotensive effect of clonidine (antagonism with adrenergic receptors);
- with selective inhibitors of MAO-A (moclobemide toloksaton) as significantly increases the risk of serotonin syndrome.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 3 years.