More info
Active ingredients
Milnacipran
Release form
Capsules
Composition
Active ingredient: Milnacipran (Milnacipranum); Concentration of active ingredient (mg): 25
Pharmacological effect
A broad spectrum antidepressant, a selective monoamine reuptake inhibitor (norepinephrine and serotonin) .; Milnacipran does not bind to m-cholinergic receptors, 1-adrenergic receptors, histamine H1 receptors, as well as dopamine D1 and D2 receptors, benzodiazepine and opioid receptors .; It does not have a sedative effect, physiologically improves night sleep, does not adversely affect cognitive function .; Milnacipran has almost no effect on the conducting system of the heart and blood pressure, which is especially important for elderly patients who are constantly taking cardiotropic drugs.
Pharmacokinetics
Absorption; After oral administration, milnacipran is well absorbed. Bioavailability is about 85% and does not depend on the characteristics and diet. Cmax in plasma is reached in approximately 2 hours (Tmax) after ingestion. After taking the drug in a single dose of 50 mg C max is about 120 ng / ml, Cmax is directly proportional to the size of the dose. Distribution; After repeated administration of Css is achieved in 36-48 hours, while it is 70-100% more than after taking a single dose. Binding to plasma proteins is 13%. Vd of milnacipran is about 5 L / kg. Metabolism; Milnacipran is practically not metabolized, there is no active metabolite, it conjugates with glucuronic acid .; Withdrawal; T1 / 2 milnacipran is 6-8 hours after a single dose, with T1 / 2 active D-isomer - 8-10 hours, and L-isomer - 4-6 hours. Renal and extrarenal clearance are equivalent, the kidneys in unchanged 55% of the administered dose is eliminated (24% of the L-isomer and 31% of the D-isomer), 17% of the L-isomer and only 2% of the D-isomer as a conjugate with glucuronic acid. About 8% is excreted in the form of N-desetilmilnatsiprana. Total clearance - about 40 l / h; Against the background of a course of treatment, milnacipran is completely excreted from the body within 2-3 days after stopping the drug intake .; Pharmacokinetics in special groups of patients; In patients with impaired renal function, the rate of elimination of milnacipran decreases in proportion to the severity of the disease.AUC in patients with chronic renal failure mild (CK is 50-80 ml / min), moderate (CK 30-49 ml / min) and severe (CK 5-29 ml / min) degree compared with healthy volunteers is increased by 16 %, 52% and 199%, and T1 / 2 - by 38%, 41% and 122%; In patients with mild and moderate hepatic impairment (class A and B on the Child-Pugh scale), AUC and T1 / 2 do not differ from those in healthy volunteers. In patients with severe hepatic impairment (Child-Pugh class C), these parameters are higher than in healthy ones by 31% and 55%, respectively, and therefore some caution is required when administering Ixel to this category of patients, although the dosage regimen is corrected and not required.; Cmax and AUC of milnacipran in elderly patients (over 65) compared with younger people are 30% higher (due to a decrease in QC with age), however, no special correction of the dosage regimen in elderly patients with undisturbed kidney function is required ; Cmax and AUC of milnacipran in women are 20% higher than in men, a change in dosing regimen is not required.
Indications
Depressive disorders of varying severity
Contraindications
Absolute; - children and adolescents up to 15 years (due to the lack of clinical data); - simultaneous use of non-selective and selective inhibitors of MAO type B, sumatriptan; - hypersensitivity to the components of the drug .; Relative; - urinary tract obstruction (mainly with prostatic hyperplasia); - pregnancy; - lactation (breastfeeding); - simultaneous reception with adrenaline, norepinephrine, clonidine and its derivatives; - simultaneous administration of selective inhibitors of MAO type A, digoxin.
Use during pregnancy and lactation
Due to the lack of data regarding 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.
Dosage and administration
Ixel is intended for oral administration .; The average daily dose is 100 mg; The drug should be taken in 2 divided doses in the morning.Depending on the severity of symptoms, the dose may be increased to 250 mg / day; The drug is preferably taken with meals .; The duration of therapy is determined individually .; In patients with renal insufficiency (CC 50–10 ml / min), a decrease in the daily dose is recommended depending on the CC values.
Side effects
From the side of the central nervous system: possible - anxiety, dizziness; rarely - tremor, headache .; On the part of the digestive system: rarely - dry mouth, nausea, vomiting, constipation; in some cases, a moderate increase in transaminase activity without clinical manifestations .; Other: possible - increased sweating, flushing, difficulty urinating; rarely - palpitations, rash; in some cases - serotonin syndrome .; Side effects are rare, mainly during the first 2 weeks of therapy, are mild, usually stop themselves as the depression symptoms regress and do not require discontinuation of the drug. Reducing the severity and number of side effects can be with a gradual increase in the dose of the drug during treatment.
Overdose
Symptoms: in case of an accidental overdose, one of the first symptoms is nausea, vomiting, increased sweating, constipation. After taking the drug in a dose of more than 800-1000 mg - vomiting, shortness of breath, tachycardia. After taking the drug in an excessively high dose (1900-2800 mg) in combination with other psychotropic drugs (most often benzodiazepines), drowsiness, hypercapnia, and impaired consciousness are added to the symptoms described above. Manifestations of cardiotoxicity in overdose of milnacipran are not observed .; Treatment: gastric lavage, taking activated charcoal, conducting symptomatic therapy. It is recommended to monitor the patient's condition for at least a day. There is no specific antidote for milnacipran.
Interaction with other drugs
Milnacipran (even at concentrations up to 25 times higher than the average therapeutic ones) does not affect the microsomal oxidation system in hepatocytes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5), due to the pressure of the mothers, the mothers have 100% and inhibitors of microsomal oxidation .; Carbamazepine, fluoxetine, lorazepam: no interaction with milnacipran was found .; Clomipramine: when transferring patients from clomipramine (75 mg / day) to milnacipran (100 mg / day), no significant change in the pharmacokinetic parameters of the latter was found.At the same time, in these cases more careful observation is required for patients, since with such a translation (without a period of “washing out”), there is an increase in attacks of euphoria and postural hypotension, the risk of developing serotonin syndrome increases; Non-selective MAO inhibitors (iproniazid): increases the risk of serotonin syndrome. After the end of treatment with an MAO inhibitor, before a course of treatment with milnacipran, a break of 2 weeks is necessary, and a break after the end of treatment with milnacipran before taking the MAO inhibitor should be at least 1 week .; Selective inhibitors of MAO type B (selegilin): the risk of a sharp increase in blood pressure increases. After the end of treatment with a selective MAO type B inhibitor, before a course of treatment with milnacipran, a break of 2 weeks is necessary, and a break after the end of treatment with milnacipran before taking a selective MAO type B inhibitor should be at least 1 week; Serotonin 5-HT1D receptor agonists (sumatriptan and others): the risk of a pronounced increase in blood pressure, spasm of the coronary arteries as a result of the accumulation of serotonergic drugs increases. There should be a break between the end of treatment with milnacipran and the start of a course of therapy with serotonin 5-HT1D receptor agonists for a period of 1 week; Cardiac glycosides (digoxin and others): increases the risk of increased severity of action on the cardiovascular system (especially when parenteral administration of digoxin) .; Diuretics: increased risk of hyponatremia .; Lithium preparations: the risk of developing serotonin syndrome increases, while milnacipran does not affect the pharmacokinetics of lithium preparations .; Milnacipran is not recommended to be used simultaneously with the following drugs: - with epinephrine, norepinephrine (for parenteral administration), because the risk of a sharp increase in blood pressure increases with the likelihood of heart rhythm disturbances (suppression of the capture of catecholamines by sympathetic nerve fibers); - with clonidine and other drugs with a similar mechanism of action, since the hypotensive effect of clonidine is reduced (antagonism with adrenoreceptors); - with selective inhibitors of MAO type A (moclobemide, toloxaton), becausesignificantly increases the risk of serotonin syndrome.
special instructions
With the combined use of drugs that affect serotonin reuptake, with drugs that suppress its metabolism (including MAO inhibitors and neuroleptics), serotonin syndrome may develop. Serotonin syndrome (manifested by increased nervous excitability, the development of hallucinations, coma, tachycardia, blood pressure lability, hyperthermia, hyperreflexia, impaired coordination of movements, nausea, vomiting, diarrhea) is a potential danger to the patient's life. Ixel can be prescribed no earlier than 2 weeks after discontinuation of MAO inhibitors. The time interval from the moment of discontinuation of the drug Ixel before the start of therapy with MAO inhibitors should be at least 1 week .; Ixel should be used with extreme caution in patients with prostatic hyperplasia, with a history of epileptic seizures, as well as in patients with arterial hypertension or hypertrophic cardiomyopathy (especially obstructive) .; In children, adolescents and patients under the age of 24, when prescribing antidepressants, the risk of suicidal thoughts and suicidal behavior increases, and therefore, when prescribing milnacipran in this category of persons, 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 people older than 65 years it even somewhat decreased. During treatment with antidepressants, all patients should be monitored for early detection of abnormalities or behavioral changes, as well as suicidal tendencies .; Drugs that inhibit the reuptake of norepinephrine and serotonin (including milnacipran), can cause an increase in blood pressure and increased heart rate. However, it should be noted that the severity of these phenomena on the background of taking the drug in recommended doses is usually insignificant, is not felt by patients, and, as a rule, does not require medical correction. Studies on the effect of milnacipran on the level of blood pressure in patients with concomitant uncontrolled arterial hypertension, as well as on heart rate in patients with cardiac arrhythmias, have not yet been conducted.However, before starting treatment, during the period of dose selection and during treatment, it is necessary to monitor blood pressure and heart rate. Persons suffering from arterial hypertension or other diseases of the cardiovascular system before the appointment of milnacipran, it is desirable to choose an effective therapy .; Cases of increased activity of hepatic transaminases (up to 3 times higher than VGN) in patients with milnacipran have been described. No clinically significant increase in bilirubin was observed. In the literature there are separate reports on the development of toxic hepatitis in patients with milnacipran intake, however, according to these reports it is not possible to trace a clear causal relationship (due to the simultaneous use of other drugs and previous diseases of the hepatobiliary system). If there are signs of liver damage while taking milnacipran, taking the drug should be discontinued. It is undesirable to prescribe milnacipran to persons abusing alcohol and / or having concomitant liver diseases .; Alcohol is not recommended during treatment (milnacipran can potentially increase the negative effect of ethanol on the liver) .; With the abrupt cancellation of milnacipran, mood lability, agitation, weakness, paresthesia, anxiety, headache, drowsiness, emotional lability, and convulsive syndrome are possible. The severity of these phenomena is usually insignificant, but during their development, the rate of drug withdrawal should be reduced. The appointment of milnacipran in patients with a history of indications of mania and / or hypomania should be made with caution because of the potential for exacerbation of these conditions. Based on the mechanism of action, it can be assumed that milnacipran can potentially cause (intensify) disorders of urine outflow (primarily in patients with concomitant prostatic hypertrophy and prostatitis), which requires appropriate control .; Milnacipran, causing pupil dilation, may contribute to an increase in intraocular pressure (patients with initially high intraocular pressure in patients with poorly controlled angle-closure glaucoma).