It inhibits the reuptake of serotonin and norepinephrine, resulting in increased serotonergic and noradrenergic neurotransmission in the central nervous system. Weakly inhibits dopamine uptake, without a significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine has a central mechanism for the suppression of pain, which is primarily manifested by an increase in the threshold of pain sensitivity in pain syndrome of neuropathic etiology.
It is well absorbed when taken orally. Absorption begins 2 hours after taking the drug. TCmax - 6 hours. Eating does not affect the value of Cmax, but increases TCmax up to 10 hours, which indirectly reduces the degree of absorption (approximately 11%). Communication with plasma proteins - more than 90% (mainly with albumin and acid alpha1-glycoprotein). Renal and hepatic insufficiency do not affect the degree of protein binding. It is actively metabolized, metabolites do not have pharmacological activity and are mainly excreted in the urine. Both CYP2D6 and CYP1A2 catalyze the formation of two major metabolites (4-hydroxyduloxetine glucuronic conjugate, 5-hydroxy-6-methoxyduloxetine sulfate conjugate). T1 / 2 - 12 hours, clearance - 101 l / h. Differences in pharmacokinetics between men and women were revealed (the clearance of duloxetine is lower in women), as well as in patients of middle and old age (increased AUC and T1 / 2 in the elderly), but this does not require dose adjustment depending on the gender or age of the patients. In patients with end-stage chronic renal failure, on hemodialysis, Cmax and AUC of duloxetine increase by 2 times. In patients with clinical signs of liver failure, a slowdown in metabolism and excretion of duloxetine is observed. 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), duloxetine clearance increased by 15%, AUC - 5 times, T1 / 2 - 3 times, Cmax did not change .
Hypersensitivity, liver diseases accompanied by liver failure, concomitant use of non-selective irreversible MAO inhibitors, potent CYP1A2 inhibitors (fluvoxamine, ciprofloxacin, enoxacin), severe CRF (CC less than 30 ml / min), uncontrolled arterial hypertension up to 18 years, lactation, no application experience). For sucrose-containing drugs (optional): congenital fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltose deficiency.
Pregnancy and lactation
Duloxetine is contraindicated in pregnancy and lactation (breastfeeding).
It is not known whether Duloxetine is excreted in breast milk. Given the possibility of adverse events in infants, if necessary, use of the drug during lactation should decide on the termination of breastfeeding. Women of reproductive age should use adequate methods of contraception during treatment. Duloxetine can be prescribed to women of reproductive age only if the probability of pregnancy is very low, and the patient is informed about the possible risk to the fetus during therapy.
Frequency: very often (1/10 m more), often (more than 1/100 and less than 1/10), infrequently (1/1000 and less than 1/100), rarely (1/10000 and less than 1/1000), very rarely (less than 1/10000), the frequency is unknown (cannot be estimated from the available data). From the nervous system: very often - headache, drowsiness; often - dizziness, tremor, lethargy, paresthesia, insomnia, unusual dreams, anxiety, agitation; infrequently - dyskinesia, poor quality of sleep, nervousness, myoclonus, impaired concentration, sleep disturbance, apathy, disorientation, bruxism; rarely - mania, aggressiveness, anger; the frequency is unknown - serotonin syndrome, convulsions, akathisia, psychomotor anxiety, extrapyramidal syndrome, suicidal attempts, suicidal thoughts, hallucinations. From the digestive system: very often - nausea, dryness of the oral mucosa; often - diarrhea, constipation, vomiting, dyspepsia, flatulence, abdominal pain; infrequently - gastroenteritis, stomatitis, gastritis, belching, taste disorder, hepatitis, acute liver failure, increased activity of “liver” transaminases (ALT, AST, alkaline phosphatase); rarely - unpleasant odor when breathing, unchanged blood in the feces; frequency unknown - gastrointestinal bleeding, jaundice, liver failure. From the genitourinary system: often - erectile dysfunction, decreased libido, a change in the ability to test feelings of orgasm; infrequently - urinary retention, intermittent urination, dysuria, nocturia, polyuria, decreased urine flow, impaired sexual function, impaired ejaculation, including delayed ejaculation, gynecological bleeding; rarely - symptoms of menopause; frequency unknown - change in the smell of urine. From the CCC: often - palpitations, "flushing" of blood; infrequently - tachycardia, fainting and orthostatic hypotension (which were reported only at the beginning of treatment), increased blood pressure, cold extremities; rarely - supraventricular arrhythmia, mainly atrial fibrillation; frequency unknown - hypertensive crisis. From the sensory organs: often - blurred visual perception, tinnitus; infrequently - impaired vision, mydriasis, vertigo, earache; rarely - glaucoma. From the respiratory system: often - yawning; infrequently - nosebleeds, sensation of throat constriction. From the skin: often - rash, excessive sweating, night sweats, infrequently - photosensitivity, increased tendency to subcutaneous hemorrhage, contact dermatitis, urticaria, cold sweat; frequency unknown - angioedema, Stevens-Johnson syndrome. From the musculoskeletal system: often - muscle spasm, musculoskeletal pain, muscle stiffness; infrequently - muscle twitching; rarely - trismus. From the endocrine system: rarely - hypothyroidism.
From the side of metabolism: often - loss of appetite; infrequently - hyperglycemia (reported mainly in patients with diabetes mellitus); rarely - dehydration, syndrome of inadequate secretion of antidiuretic hormone, hyponatremia. Infections: infrequently - laryngitis. Other: often - fatigue, weight loss; infrequently - weight gain, malaise, impaired gait, impaired sensitivity, a feeling of cold, a feeling of warmth, thirst, chills, increased CPK; rarely - hypercholesterolemia; frequency unknown - chest pain. Allergic reactions: infrequently - hypersensitivity reactions; rarely - anaphylactoid reactions.
With abrupt cancellation - “withdrawal” syndrome, the most common symptoms of which were dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia, intense dreams), agitation or anxiety, nausea and / or vomiting , tremor, headache, irritability, diarrhea, hyperhidrosis, vertigo.
The simultaneous use of duloxetine (60 mg 2 times a day) did not significantly affect the pharmacokinetics of theophylline metabolized by CYP1A2.The concomitant use of duloxetine with potential CYP1A2 inhibitors can lead to an increase in the concentration of duloxetine. The CYP1A2 inhibitor fluvoxamine (100 mg once daily) reduces the plasma clearance of duloxetine by approximately 77% and increases the AUC by 6 times, therefore, duloxetine should not be used in combination with potential CYP1A2 inhibitors such as fluvoxamine. Duloxetine is a moderate inhibitor of CYP2D6. When taking duloxetine at a dose of 60 mg 2 times a day, along with a single dose of desipramine (substrate CYP2D6), AUC of desipramine increases 3 times. The simultaneous administration of duloxetine (40 mg 2 times a day) increases the AUC of tolterodine (2 mg 2 times a day) by 71%, but does not affect the pharmacokinetics of 5-hydroxyl metabolite. Caution should be exercised when using duloxetine with drugs that are metabolized mainly by the CYP2D6 system and have a narrow therapeutic index. The simultaneous use of duloxetine with potential CYP2D6 inhibitors can lead to increased concentrations of duloxetine.Paroxetine (20 mg once a day) reduces the clearance of duloxetine by about 37%. Caution is advised when using duloxetine with CYP2D6 inhibitors.
Caution should be exercised when using duloxetine simultaneously with other drugs affecting the central nervous system (including benzodiazepines, antipsychotic drugs, phenobarbital, antihistamines with sedative effect, ethanol), especially with a similar mechanism of action.The simultaneous use of duloxetine with drugs that highly bind to plasma proteins can lead to an increase in the concentration of free fractions of both drugs.In patients receiving a serotonin reuptake inhibitor in combination with non-selective irreversible MAO inhibitors, there have been cases of the development of severe adverse reactions (hyperthermia, muscle rigidity, myoclonus, peripheral disorders with possible sharp fluctuations in vital signs and changes in mental status, including marked excitement with the transition to delirium and to whom) sometimes fatal. These reactions were also observed in patients who, shortly before the appointment of an MAO inhibitor, a serotonin reuptake inhibitor was canceled.
In some cases, patients had symptoms characteristic of a malignant antipsychotic syndrome. The effects of the combined use of duloxetine and MAO inhibitors have not been evaluated in humans or animals. Therefore, given the fact that duloxetine is an inhibitor of both serotonin and norepinephrine, it is not recommended to take duloxetine in combination with non-selective irreversible MAO inhibitors or for at least 14 days after their withdrawal. Based on the duration of T1 / 2 of duloxetine, a break should be made at least 5 days after the end of duloxetine before taking MAO inhibitors.With respect to selective reversible MAO inhibitors, such as moclobemide, the risk of developing serotonin syndrome is low, however, the simultaneous use of the drug with selective reversible MAO inhibitors is not recommended.Anticoagulants and antiplatelet drugs - the risk of bleeding. Cases have been reported of an increase in INR with concomitant use with warfarin.In rare cases, the development of serotonin syndrome has been reported with the use of SSRIs (including paroxetine, fluoxetine) with serotonergic drugs. Caution should be exercised while using duloxetine with serotonergic antidepressants, such as SSRIs, tricyclic antidepressants, such as clomipramine and amitriptyline, Hypericum perforatum, venlafaxine or tryptans, tramadol, pethidine and tryptophan.
Dosage and administration
Inside, regardless of the meal. Capsules should be swallowed whole without chewing or crushing. Do not add the drug to food or mix it with liquids, as it can damage the enteric coating of pellets.
The recommended starting dose is 60 mg once daily. If necessary, it is possible to increase the dose to a maximum dose of 120 mg per day in 2 divided doses.
Symptoms: vomiting and loss of appetite, tremors, clonic convulsions, ataxia.
Treatment: symptomatic and supportive. Control of CVS and other vital signs. The specific antidote is not known.
Several cases of overdose have been reported with simultaneous ingestion of up to 1400 mg of the drug, which did not have fatal consequences.
A systematic assessment of taking the drug in a dose of over 120 mg was not carried out.
There have been cases of mydriasis when taking duloxetine, therefore caution should be exercised when prescribing duloxetine to patients with intraocular hypertension or in individuals at risk of developing acute angle-closure glaucoma.
In patients with severe chronic renal failure (CC less than 30 ml / min) or severe liver failure, an increase in plasma concentration of duloxetine is observed. If duloxetine is clinically justified in such patients, lower initial doses should be used.With depression, there is the likelihood of suicidal attempts, which can persist until a stable remission occurs. Careful monitoring of patients at risk is necessary.The withdrawal of the drug should be carried out gradually in order to avoid the "withdrawal" syndrome.Due to insufficient experience with duloxetine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the mother significantly exceeds the potential risk to the fetus. Patients should be warned that in the event of pregnancy or planning pregnancy during treatment with Duloxetine, they need to inform their doctor.
Due to the lack of experience with the use of duloxetine in women during lactation, breastfeeding during therapy with duloxetine is not recommended.During the studies of duloxetine, there were no violations of psychomotor reactions, cognitive functions and memory. However, taking the drug may be accompanied by drowsiness. In this regard, patients taking duloxetine should be careful when engaging in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions, including driving a car.