Duloxetine
When ATH:
N06AX21
Pharmacological action
Antidepressant, reuptake inhibitor and a norepinephrine (noradrenaline). Weakly inhibits dopamine uptake, It has no significant affinity to histamine, dopamine, cholinergic and adrenergic receptors. The mechanism of action of duloxetine is to suppress reuptake of serotonin and norepinephrine (noradrenaline). Duloxetine has a central mechanism for suppressing pain, which is primarily manifested by increased sensitivity to pain in the etiology of neuropathic pain syndrome.
Pharmacokinetics
After oral duloxetine is well absorbed from the gastrointestinal tract, absorption begins 2 h after administration, Cmax achieved through 6 h after administration. Admission at the same time with food increases the time to reach Cmax to 10 no, which reduces the extent of absorption (approximately 10%), but no effect on the Cmax.
Plasma protein binding is high (more 90%), mainly to albumin and α1-globulin. Disorders of the liver or kidneys no effect on protein binding. Duloxetine actively biotransformiruetsya with uchastiem izofermentov CYP2D6 and CYP1A2, which catalyze the formation of two major metabolites (glucuronic conjugates 4 gidroksiduloksetina, sulphate conjugate of 5-hydroxy,6-metoksiduloksetina). Circulating metabolites do not possess pharmacological activity. T1/2 is 12 no. The average clearance of duloxetine 101 l /. Excreted in the urine as metabolites.
In patients with end-stage renal disease, hemodialysis, C valuesmax and AUC increased in duloxetine 2 times. In this connection, should consider reducing the dose in patients with clinically severe impaired renal function.
In patients with clinical signs of liver failure may occur slowing metabolism and excretion of duloxetine. After receiving a single dose of duloxetine 20 mg 6 patients with cirrhosis and mild hepatic impairment (Class B for Child-Pugh) the duration T1/2 duloxetine was about 15% higher, than in healthy individuals of the corresponding age and gender with a five-fold increase in mean AUC values. Despite, that Cmax patients with cirrhosis had a, as in healthy humans, T1/2 about 3 times.
Testimony
Depression, painful form of diabetic neuropathy.
Dosage regimen
The recommended starting dose is 60 mg 1 time / day.
If necessary, the daily dose can be increased to 60 mg to a maximum of 120 mg / day 2 admission.
In patients with severe renal impairment (CC<30 ml / min) initial dose should be 30 mg 1 time / day. In patients with impaired hepatic function should be to reduce the initial dose of the drug or to reduce the multiplicity of reception.
Side effect
CNS: often – dizziness (Additionally vertigo), sleep disorders (drowsiness or insomnia), headache (Headache was observed less frequently, than in patients receiving placebo); sometimes – tremor, weakness, blurred vision, lethargy, alarm, zevota; rarely – glaucoma, midriaz, visual impairment, excitation, disorientation.
From the digestive system: often – dry mouth, nausea, constipation; sometimes – diarrhea, vomiting, decreased appetite, change in taste, violations of liver function tests; rarely – hepatitis, jaundice, increased activity of alkaline phosphatase, GOLD, AST and bilirubin; belching, gastroenteritis, stomatitis.
On the part of the musculoskeletal system: sometimes – muscle tension and / or twitching; rarely – bruxism.
Cardio-vascular system: sometimes – heartbeat; rarely – orthostatic hypotension, syncope (especially early in treatment), tachycardia, increased blood pressure, cold extremities.
On the part of the reproductive system: sometimes – anorgazmija, decreased libido, delay, and abnormal ejaculation, erectile dysfunction.
From the urinary system: sometimes – shortness mocheispuskannie; rarely – nocturia.
Other: sometimes – weight loss, increased perspiration, tides, night sweat; rarely – anaphylactic reactions, thirst, giponatriemiya, chills, angioedema, rash, Stevens-Johnson syndrome, hives, bad feeling, feeling hot and / or cold, weight gain, degidratatsiya, photosensitivity. If you cancel frequently observed dizziness, nausea, headache. Patients with painful diabetic neuropathy, the form may be a slight increase in fasting blood glucose.
Contraindications
Nekompensirovannaya zakrыtougolynaya glaucoma, concurrent use with MAO inhibitors, Hypersensitivity to duloxetine.
Pregnancy and lactation
Use of the drug during pregnancy is possible only in cases, when the intended benefits to the mother outweighs the potential risk to the fetus, tk. clinical experience with duloxetine during pregnancy is not enough.
If necessary, use during lactation should decide the issue of termination of breastfeeding (due to lack of experience with).
Patients should be warned, that in the event or planning a pregnancy during the period of use of duloxetine they need to inform your doctor.
Cautions
To use caution during exacerbation of mania / hypomania, seizures, midriaze, abnormal liver function or kidney, in patients with a penchant for suicide attempts.
In the appointment of serotonin reuptake inhibitors in combination with MAO inhibitors there have been cases of serious reactions, sometimes with fatal consequences (hyperthermia, rigidity, myoclonus, various violations with possible sharp fluctuations in vital signs of the body and changes in mental status, including expressed excitement with the transition to delirium and to whom). Such reactions are also possible in cases, When serotonin reuptake inhibitor was canceled shortly before the appointment of MAO inhibitors (may develop symptoms, incl. characteristic of neuroleptic malignant syndrome).
Effects of combined use of duloxetine and MAOIs have not been evaluated in humans or, nor in animals. The use of duloxetine concurrently with MAO inhibitors or prior 14 days after their withdrawal is not recommended, tk. Duloxetine is a serotonin reuptake inhibitor, and norepinephrine (noradrenaline). MAO inhibitors should not be prescribed for a minimum of 5 days after discontinuation of duloxetine.
To apply caution in patients with a history of manic episodes, and with a history of seizures.
Depressive states are accompanied by a high risk of suicidal behavior. Consequently, patients diagnosed with depression, prinimayushtie duloxetine, You must inform the doctor about any troubling thoughts and feelings.
Against the background of the drug may develop mydriasis, caution should be exercised in the appointment of duloxetine in patients with increased intraocular pressure, or those at risk of acute angle-closure glaucoma.
In patients with hypertension and / or other diseases of the cardiovascular system it is recommended to control blood pressure.
Effects on ability to drive vehicles and management mechanisms
Patients, prinimayushtie duloxetine, You must be careful during the occupation of potentially hazardous activities (because of the possible occurrence of sleepiness).
Drug Interactions
Concomitant use of duloxetine (dose 60 mg 2 times / day) It had no significant effect on the pharmacokinetics of theophylline, metabolized by CYP1A2. Duloxetine hardly clinically significant effect on the metabolism of other drugs – субстратов CYP1A2.
Simultaneous administration of duloxetine with potent inhibitors of CYP1A2 (eg, ftorkhinolony) may lead to increased concentrations of duloxetine, tk. CYP1A2 is involved in duloxetine metabolism (the appointment of such a combination requires caution and reduce doses of duloxetine).
Strong CYP1A2 inhibitor fluvoxamine (upon receiving a dose 100 mg 1 time / day) reduced mean plasma clearance of duloxetine by about 77%.
In the appointment of duloxetine with drugs, metabolized by CYP2D6 and have a narrow therapeutic index, caution should be exercised (tk. Duloxetine is a moderate inhibitor of CYP2D6). While the use of duloxetine 60 mg 2 times / day AUC of desipramine (the CYP2D6 substrate) increases 3 times. The simultaneous use of duloxetine (dose 40 mg 2 times / day) increases the stability of the AUC of tolterodine (It is applied at a dose of 2 mg 2 times / day) on 71%, but it had no effect on the pharmacokinetics of 5-hydroxy metabolite. Concomitant use of duloxetine with potent inhibitors of CYP2D6 may lead to increased concentrations of duloxetine. Paroxetine (at an application rate 20 mg 1 time / day) reduced the average clearance of duloxetine by about 37%. When using duloxetine with inhibitors of CYP2D6 (eg, with selective serotonin reuptake inhibitors) Caution should be exercised.
With simultaneous use of duloxetine and other drugs, affecting the central nervous system and have a similar mechanism of action (including ethanol and drugs etanolsoderzhaschie), possible mutual reinforcement effects (this combination requires caution).
Duloxetine largely bound to plasma proteins, therefore concurrent use with other drugs, highly bound to plasma proteins, may lead to increased concentrations of free fractions of both drugs.
