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Duloxetine Inhibits serotonin and noadrenaline reuptake, resulting in increased serotonergic and noradrenergic neurotransmission in the central nervous system. Weakly inhibits the capture of dopamine, not having 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 pain sensitivity in pain syndrome of neuropathic etiology.
Pharmacokinetics: 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 by 11%).
Communication with plasma proteins - more than 90% (mainly with albumin and acid alpha1-glycoprotein). Renal and hepatic impairment do not affect protein binding.
Actively metabolized, metabolites do not possess pharmacological activity and are mainly excreted in the urine.
Both CYP2D6 and CYP1A2 catalyze the formation of two major metabolites (glucuronic conjugate 4-hydroxiduloxetine, sulfate conjugate 5-hydroxy, 6-methoxydioxetine).
T1 / 2 - 12 h, clearance - 101 l / h.
Differences in pharmacokinetics were found in men and women (duloxetine clearance is lower in women), as well as in middle-aged and elderly patients (increased AUC and T1 / 2 in the elderly), but this does not require dose adjustment depending on gender or age of patients.
In patients with end-stage chronic renal failure, who are on hemodialysis, Сmax and AUC of duloxetine increase by 2 times.
In patients with clinical signs of liver failure, a slowdown in metabolism and duloxetine elimination is observed. After a single dose of 20 mg of duloxetine in 6 patients with cirrhosis of the liver with moderate liver dysfunction (Child-Pyugu class B), the duloxetine clearance increased by 15%, AUC - 5 times, T1 / 2 - 3 times, Cmax did not change .
Depression, diabetic peripheral neuropathy (pain form).
Duloxetine is marketed under different brands and generic names, and comes in different dosage forms:
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Dosage and Administration
Orally, regardless of the meal. Capsules should be swallowed whole, not chewed or crushed. You can not add the drug in food or mix it with liquids, because This may damage the enteric shell of the capsule contents (pellets).
The recommended starting dose is 60 mg once a day. If necessary, you can increase the dose to a maximum dose of 120 mg per day in 2 divided doses.
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).
On the part of 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; frequency is unknown - serotonin syndrome, convulsions, akathisia, psychomotor anxiety, extrapyramidal syndrome, suicidal attempts, suicidal thoughts, hallucinations.
On the part of 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 disturbance, hepatitis, acute liver failure, increased activity of "liver" transaminases (ALT, AST, alkaline phosphatase); rarely - an unpleasant smell when breathing, unchanged blood in the feces; frequency is unknown - gastrointestinal bleeding, jaundice, liver failure.
On the part of the genitourinary system: often - erectile dysfunction, decreased libido, changes in the ability to experience feelings of orgasm; infrequently - urinary retention, intermittent urination, dysuria, nocturia, polyuria, decreased urine flow, impaired sexual function, impaired ejaculation, incl. delayed ejaculation, gynecological bleeding; rarely, menopause symptoms; frequency unknown - change in the smell of urine.
From the side of the cardiovascular system: often - the heartbeat, "tides" of blood infrequently - tachycardia, syncope and orthostatic hypotension (which were reported only at the beginning of treatment), increased blood pressure, cooling of the extremities; rarely - supraventricular arrhythmia, mainly atrial fibrillation; frequency is unknown - hypertensive crisis.
On the part of the senses: often - blurred visual perception, tinnitus; infrequently - blurred vision, mydriasis, vertigo, pain in the ears; rarely glaucoma.
On the part of the respiratory system: often - yawning; infrequently - nose bleeding, feeling of squeezing of a throat.
On the part of the skin: often - a rash, excessive sweating, night sweats, infrequently - photosensitivity, increased tendency to subcutaneous hemorrhage, contact dermatitis, urticaria, cold sweat; frequency is unknown - angioedema, Stevens-Johnson syndrome.
On the part of the musculoskeletal system: often - muscle spasm, musculoskeletal pain, muscle stiffness; infrequently - muscle twitching; rarely - trismus.
On the part of the endocrine system: rarely - hypothyroidism.
On the part of the 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.
Others: often - fatigue, weight loss; infrequently - weight gain, malaise, gait disturbance, loss of sensitivity, feeling cold, feeling warm, thirst, chills, raising CPK; rarely, hypercholesterolemia; frequency unknown - chest pain.
Allergic reactions: infrequently - hypersensitivity reactions; rarely anaphylactoid reactions.
With abrupt cancellation - the syndrome of "cancellation", the most frequent symptoms of which were dizziness, sensory disturbances (including paresthesia), sleep disorders (including insomnia, intense dreams), agitation or anxiety, nausea and / or vomiting , tremor, headache, irritability, diarrhea, hyperhidrosis, vertigo.
Hypersensitivity, liver disease, accompanied by liver failure, simultaneous use of non-selective irreversible MAO inhibitors, potent inhibitors of CYP1A2 (fluvoxamine, ciprofloxacin, enoxacin), severe CRF (CC less than 30 ml / min), unsuperfluid periodypodipation, etc. no application experience).
For LF containing sucrose (optional): congenital fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltase deficiency.
Carefully. Mania and bipolar disorder (including history), convulsions (including history), intraocular hypertension or the risk of developing an acute attack of angle-closure glaucoma, suicidal thoughts and attempts at anamnesis, increased risk of hyponatremia (elderly patients, cirrhosis liver, dehydration, diuretic), pregnancy.
The simultaneous use of duloxetine (60 mg 2 times a day) had no significant effect on the pharmacokinetics of theophylline, metabolized by CYP1A2.
Simultaneous administration of duloxetine with potential inhibitors of CYP1A2 may lead to an increase in duloxetine concentration. The CYP1A2 inhibitor fluvoxamine (100 mg 1 time per day) reduces the plasma clearance of duloxetine by about 77% and increases AUC 6 times, so duloxetine should not be used in combination with potential CYP1A2 inhibitors, such as fluvoxamine.
Duloxetine is a moderate inhibitor of CYP2D6. When taking duloxetine in a dose of 60 mg 2 times a day along with a single dose of desipramine (CYP2D6 substrate), the AUC of desipramine increases 3 times. 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 the 5-hydroxyl metabolite. Caution must 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 inhibitors of CYP2D6 can lead to an increase in duloxetine concentrations.
Paroxetine (20 mg 1 time per day) reduces the clearance of duloxetine by approximately 37%. When using duloxetine with CYP2D6 inhibitors, caution should be exercised.
Caution should be exercised when using duloxetine simultaneously with other drugs that affect the central nervous system (including benzodiazepines, antipsychotic drugs, phenobarbital, antihistamine drugs with sedative effect, ethanol), especially with a similar mechanism of action.
The simultaneous use of duloxetine with drugs, highly associated with 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 severe adverse reactions (hyperthermia, muscle rigidity, myoclonus, peripheral abnormalities with possible sharp fluctuations in vital signs and changes in mental status, including pronounced stimulation with transition delirium and to whom) is sometimes fatal. These reactions were also observed in patients who, shortly before prescribing an MAO inhibitor, a serotonin reuptake inhibitor was canceled. In some cases, patients had symptoms characteristic of neuroleptic malignant 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 duloxetine, you should take a break of at least 5 days after stopping duloxetine before taking MAO inhibitors. With respect to selective reversible MAO inhibitors, such as moclobemide, the risk of developing serotonin syndrome is low, however, 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 the INR when used simultaneously with warfarin.
In rare cases, the development of serotonin syndrome has been reported with the use of SSRIs (including paroxetine, fluoxetine) with serotonergic drugs. Care must be taken when simultaneously using Duloxetine with serotonergic antidepressants such as SSRIs, tricyclic antidepressants such as clomipramine and amitriptyline, venous finum or triptocylone, tramadol, petidine and tryptophanom.
A systematic assessment of the drug intake in a dose of more than 120 mg was not carried out.
Cases of mydriasis have been observed when taking duloxetine, so care should be taken when prescribing duloxetine in patients with intraocular hypertension or in individuals at risk of developing acute angle-closure glaucoma.
In patients with severe chronic renal failure (CK less than 30 ml / min) or severe liver failure, there is an increase in plasma duloxetine concentration. If these patients are clinically based on duloxetine, lower initial doses should be used.
With depression, there is the likelihood of suicidal attempts, which may persist until the onset of persistent remission. Careful observation of patients at risk is needed.
The abolition of the drug should be carried out gradually in order to avoid the syndrome of "cancellation."
Due to insufficient experience with duloxetine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the mother greatly exceeds the potential risk to the fetus. Patients should be warned that in the event of the onset or planning of pregnancy during the period of treatment with duloxetine, they should be informed about this by their doctor.
Due to the lack of experience with duloxetine in women during lactation, breastfeeding during duloxetine therapy is not recommended.
In the course of studies of duloxetine, no psychomotor reactions, cognitive functions, and memory were identified. However, the drug may be accompanied by drowsiness. In this regard, patients taking duloxetine should be cautious when practicing potentially hazardous activities that require increased concentration and psychomotor speed, including driving a car.
Symptoms: vomiting and loss of appetite, tremor, clonic convulsions, ataxia. Treatment: symptomatic and supportive. Monitoring of cardiovascular system and other vital signs. The specific antidote is not known.
Reported several cases of overdose with simultaneous ingestion of up to 1400 mg of the drug that did not have fatal consequences.
- Brand name: Duloxetine
- Active ingredient: Duloxetine
- Dosage form: Capsules enteric solid gelatin number 1, the body and the lid is blue; The contents of the capsules are spherical microgranules from almost white to yellowish white.
- Manufacturer: Canonpharma
- Country of Origin: Russia
Studies and clinical trials of Duloxetine (Click to expand)
- Spectrophotometric and spectrodensitometric determination of paracetamol and drotaverine HCl in combination
- Cellular electrophysiological effects of chronic fluoxetine and duloxetine administration on serotonergic responses in the aging hippocampus
- Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer
- A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder
- Duloxetine (Cymbalta), a Dual Inhibitor of Serotonin and Norepinephrine Reuptake.
- Polymer-Supported Chiral Sulfonamide Catalyzed One-Pot Reduction of β-Keto Nitriles: A Practical Synthesis of (R)-Fluoxetine and (R)-Duloxetine.
- ChemInform Abstract: Novel Acid Catalyzed Rearrangement of Duloxetine.
- ChemInform Abstract: Advances in Development of Methods for the Synthesis of Dual Selective Serotonin and Norepinephrine Reuptake Inhibitors (SSNRIs) [Venlafaxine Hydrochloride (Effexor), Milnacipran Hydrochloride (Ixel, Dalcipran) and Duloxetine Hydrochloride (Cymbalta)]
- ChemInform Abstract: Highly Enantioselective Friedel—Crafts Reaction of Thiophenes with Glyoxylates: Formal Synthesis of Duloxetine.
- Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms
- Duloxetine in treatment of anxiety symptoms associated with depression
- Time course of depression-symptom improvement during treatment with duloxetine
- The combination of duloxetine and bupropion for treatment-resistant major depressive disorder
- Duloxetine for the treatment of major depressive disorder: safety and tolerability associated with dose escalation
- Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial
- Efficacy of duloxetine in the treatment of generalized anxiety disorder in patients with clinically significant pain symptoms
- Long-term tolerability and effectiveness of duloxetine in the treatment of major depressive disorder
- Anxiety does not predict response to duloxetine in major depression: results of a pooled analysis of individual patient data from 11 placebo-controlled trials
- Duloxetine decreases pain of diabetic neuropathy
- Evaluating the maintenance of effect of duloxetine in patients with diabetic peripheral neuropathic pain
- Duloxetine in the treatment of binge eating disorder with depressive disorders: A placebo-controlled trial
- Duloxetine and care management treatment of older adults with comorbid major depressive disorder and chronic low back pain: results of an open-label pilot study
- Duloxetine in acute major depression: review of comparisons to placebo and standard antidepressants using dissimilar methods
- Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study
- Duloxetine in obese binge eater outpatients: preliminary results from a 12-week open trial