Cymbalta®
Exacerbation of manic/hypomanic state.
As with similar drugs that affect the central nervous system, duloxetine should be used with caution in patients with a history of manic episodes.
Epileptic seizures.
As with similar drugs that act on the central nervous system, duloxetine should be used with caution in patients with a history of epileptic seizures.
Mydriaz.
Cases of mydriasis have been observed when taking duloxetine, so caution should be exercised when prescribing duloxetine to patients with elevated intraocular pressure or in individuals at risk of developing acute angle-closure glaucoma.
Increased blood pressure.
In isolated cases, a rise in blood pressure was observed during treatment with duloxetine. In patients with arterial hypertension and/or other cardiovascular diseases, it is recommended to measure blood pressure.
Impaired liver or kidney function.
In patients with severe renal impairment (creatinine clearance <30 ml/min) or severe liver failure, increased plasma concentrations of duloxetine are observed.
If duloxetine is clinically justified in such patients, lower initial doses of the drug should be used. Suicidal behavior.
The risk of committing suicide exists in all patients with depression and some other mental disorders. This danger may persist until remission occurs. As a result, patients at greatest risk of committing suicide should be under close medical supervision during pharmacotherapy. As well as taking other drugs that have a mechanism of pharmacological action similar to duloxetine (SSRIs, SNRIs), taking duloxetine during treatment or upon its cessation in a number of cases was associated with the development of suicidal thoughts and suicidal behavior. Duloxetine has not been studied in patients under 18 years of age and this drug is not intended for use in such patients. A cause-and-effect relationship between taking duloxetine and the occurrence of suicidal events in patients of this age group has not been established. However, some analytical reviews of the results of a number of studies using antidepressants for the treatment of mental disorders indicate an increased risk of developing suicidal thoughts and/or suicidal behavior in children, adolescents and adults under 25 years of age compared with placebo. Clinicians should encourage patients to report any disturbing thoughts and feelings at any time.
Increased risk of bleeding.
SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding, including gastrointestinal bleeding (see section "Side effects"). Therefore, duloxetine should be prescribed with caution to patients taking anticoagulants and/or drugs that affect platelet function (eg, NSAIDs, aspirin) and to patients with a history of bleeding.
Hyponatremia.
Very rarely, cases of hyponatremia have been reported (in some cases, serum sodium levels were lower than 110 mmol/l). Most of these cases occurred in elderly patients, especially in combination with a recent history of altered fluid balance or in the presence of conditions predisposing to altered fluid balance.
Hyponatremia may manifest as nonspecific symptoms (such as dizziness, weakness, nausea, vomiting, confusion, drowsiness, lethargy). Signs and symptoms seen in more severe cases included fainting, falls and seizures.
Monoamine oxidase inhibitors (MAOIs).
Severe reactions, sometimes fatal, have been reported in patients taking a serotonin reuptake inhibitor in combination with a MAOI, including pyrexia, rigidity, myoclonus, peripheral disturbances with possible dramatic fluctuations in vital signs, and mental status changes including marked agitation with transition to delirium and coma. These reactions have also been observed in patients who were discontinued with a serotonin reuptake inhibitor shortly before being prescribed an MAOI. In some cases, patients experienced symptoms consistent with neuroleptic malignant syndrome. The effects of combined use of duloxetine and MAOIs have not been evaluated in humans or animals. Therefore, given the fact that duloxetine is a reuptake inhibitor of both serotonin and norepinephrine, it is not recommended to take duloxetine in combination with an MAOI or for at least 14 days after stopping treatment with an MAOI. Based on the length of the half-life of duloxetine, you should wait at least 5 days after stopping duloxetine before taking an MAOI.
Increased activity of liver enzymes.
Some patients treated with duloxetine in clinical studies experienced increased liver enzyme activity. The observed deviations were, as a rule, transient in nature and disappeared spontaneously or after discontinuation of duloxetine. Serious increases in liver enzyme activity (10 times or more above the upper limit of normal), as well as liver damage of cholestatic or mixed origin, were rare, and in some cases were associated with excessive alcohol consumption or pre-existing liver disease. It is recommended to use duloxetine with caution in patients who drink significant quantities of alcohol, as well as with existing liver disease.
Release form, composition and packaging
capsules
, size No. 1, opaque, blue/green, with a dosage of “60 mg” printed in white ink and identification code “9542”; the contents of the capsules are pellets from white to grayish-white.
| 1 caps. | |
| duloxetine (as hydrochloride) | 60 mg |
Excipients:
sucrose, hypromellose, granulated sugar (no more than 91.5% sucrose, starch), talc, hypromellose acetate succinate, triethyl citrate, white dye (titanium dioxide, hypromellose).
Shell composition:
indigo carmine, titanium dioxide, sodium lauryl sulfate, gelatin, iron oxide yellow dye.
7 pcs. - blisters (1) - cardboard packs. 7 pcs. - blisters (2) - cardboard packs. 7 pcs. - blisters (4) - cardboard packs. 14 pcs. - blisters (1) - cardboard packs. 14 pcs. - blisters (2) - cardboard packs. 14 pcs. - blisters (6) - cardboard packs.
Dosage regimen
The recommended initial dose of the drug is 60 mg 1 time / day.
If necessary, you can increase the daily dose from 60 mg to a maximum dose of 120 mg/day (divided into 2 doses). A systematic assessment of the safety of the drug at doses above 120 mg has not been carried out.
In patients with severe renal impairment (creatinine clearance<30 ml/min)
the initial dose should be 30 mg 1 time/day.
In patients with impaired liver function
The initial dose of the drug should be reduced or the frequency of administration should be reduced.
Clinical experience with the drug in patients under 18 years of age
No.
Capsules should be swallowed whole, without chewing or crushing. Do not add the drug to food or mix it with liquids, because this may damage the enteric coating of the pellets. The drug can be taken regardless of meals.
Drug interactions
The simultaneous use of duloxetine (at a dose of 60 mg 2 times / day) did not have a significant effect on the pharmacokinetics of theophylline, which is metabolized by CYP1A2. Duloxetine is unlikely to have a clinically significant effect on the metabolism of other drugs that are CYP1A2 substrates.
Concomitant use of duloxetine with potential inhibitors of CYP1A2 (for example, fluoroquinolones) may lead to increased concentrations of duloxetine, because CYP1A2 is involved in the metabolism of duloxetine (prescribing this combination requires caution and a reduction in duloxetine doses).
The potent CYP1A2 inhibitor fluvoxamine (when taken at a dose of 100 mg 1 time / day) reduced the average plasma clearance of duloxetine by approximately 77%.
When prescribing duloxetine with drugs metabolized by CYP2D6 and having a narrow therapeutic index, caution should be exercised (since duloxetine is a moderate inhibitor of CYP2D6). When used simultaneously with duloxetine at a dose of 60 mg 2 times / day, the AUC of desipramine (CYP2D6 substrate) increases 3 times. Co-administration with duloxetine (at a dose of 40 mg 2 times / day) increased the stable part of the AUC of tolterodine (used at a dose of 2 mg 2 times / day) by 71%, but did not affect the pharmacokinetics of the 5-hydroxyl metabolite. Concomitant use of duloxetine with potential CYP2D6 inhibitors may result in increased duloxetine concentrations. Paroxetine (when used at a dose of 20 mg 1 time / day) reduced the average clearance of duloxetine by approximately 37%. Caution should be exercised when using duloxetine with CYP2D6 inhibitors (eg, selective serotonin reuptake inhibitors).
With the simultaneous use of duloxetine and other drugs that affect the central nervous system and have a similar mechanism of action (including ethanol and ethanol-containing drugs), mutual enhancement of the effects is possible (this combination requires caution).
Duloxetine is highly bound to plasma proteins, therefore, simultaneous use with other drugs that are highly bound to plasma proteins may lead to an increase in the concentration of free fractions of both drugs.
pharmachologic effect
Antidepressant, serotonin and norepinephrine (norepinephrine) reuptake inhibitor. Weakly inhibits dopamine uptake and does not have significant affinity for histamine, dopamine, cholinergic and adrenergic receptors. The mechanism of action of duloxetine is to inhibit the reuptake of serotonin and norepinephrine (norepinephrine). Duloxetine has a central mechanism for suppressing pain, which is primarily manifested by an increase in the threshold of pain sensitivity in pain of neuropathic etiology.
Overdose
There are known cases of overdose with simultaneous oral administration of up to 2000 mg of duloxetine, either alone or in combination with other drugs.
Symptoms
(mainly in cases of combined overdose): serotonin syndrome, drowsiness, vomiting, clonic convulsions. Fatal consequences have been reported extremely rarely and also predominantly in cases of combined overdose.
Treatment:
recommend monitoring the state of the cardiovascular system and other vital signs; If necessary, carry out symptomatic therapy. In case of development of serotonin syndrome, treatment with cyproheptadine and the use of methods to normalize body temperature are possible. There is no specific antidote.
Side effect
Side effects are presented by organ system, indicating the frequency of occurrence in accordance with the following criteria: often - ≥10%; sometimes - from ≥1% to <10%; very rarely - ≤1%.
From the side of the central nervous system:
often - dizziness (except vertigo), sleep disturbances (drowsiness or insomnia), headache (headache was observed less frequently than when taking placebo); sometimes - tremor, weakness, blurred vision, lethargy, anxiety, yawning; very rarely - glaucoma, mydriasis, visual impairment, agitation, disorientation.
From the digestive system:
often - dry mouth, nausea, constipation; sometimes - diarrhea, vomiting, loss of appetite, change in taste, abnormal liver function tests; very rarely - hepatitis, jaundice, increased activity of alkaline phosphatase, ALT, AST and bilirubin levels; belching, gastroenteritis, stomatitis.
From the musculoskeletal system:
sometimes - muscle tension and/or twitching;
very rarely - bruxism .
From the cardiovascular system:
sometimes - palpitations; very rarely - orthostatic hypotension, syncope (especially at the beginning of therapy), tachycardia, increased blood pressure, cold extremities.
From the reproductive system:
sometimes - anorgasmia, decreased libido, delayed and impaired ejaculation, erectile dysfunction.
From the urinary system:
sometimes - difficulty urinating; very rarely - nocturia.
Other:
sometimes - weight loss, increased sweating, hot flashes, night sweats; very rarely - anaphylactic reactions, thirst, hyponatremia, chills, angioedema, rash, Stevens-Johnson syndrome, urticaria, feeling unwell, feeling hot and/or cold, weight gain, dehydration, photosensitivity. When discontinuing the drug, dizziness, nausea, and headache were often observed. Patients with painful diabetic neuropathy may experience a slight increase in fasting blood glucose.
Pharmacokinetics
Suction
After oral administration, duloxetine is well absorbed from the gastrointestinal tract, absorption begins 2 hours after administration, Cmax is achieved 6 hours after administration. Taking with food increases the time to reach Cmax by up to 10 hours, which reduces the degree of absorption (by approximately 10%), but does not affect the Cmax value.
Distribution
Plasma protein binding is high (more than 90%), mainly with albumin and α1-globulin. Hepatic or renal disorders do not affect the degree of protein binding.
Metabolism
Duloxetine is actively biotransformed with the participation of the CYP2D6 and CYP1A2 isoenzymes, which catalyze the formation of two main metabolites (4-hydroxyduloxetine glucuronic conjugate, 5-hydroxy,6-methoxyduloxetine sulfate conjugate). Circulating metabolites do not have pharmacological activity.
Removal
T1/2 is 12 hours. The average clearance of duloxetine is 101 l/hour. Excreted in the urine in the form of metabolites.
Pharmacokinetics in special clinical situations
Studies have established some differences between the pharmacokinetic processes in men and women (the average clearance of duloxetine is lower in women), but there is no need for dose adjustment depending on gender.
Studies have established some differences between the pharmacokinetic processes between middle-aged and elderly patients (AUC is higher and T1/2 is greater in the elderly), but there is no need for dose adjustment depending only on the age of the patients.
In patients with end-stage chronic renal failure on hemodialysis, the Cmax and AUC values of duloxetine increased 2-fold. In this regard, the advisability of reducing the dose of the drug in patients with clinically significant renal impairment should be considered.
Patients with clinical signs of liver failure may experience a slower metabolism and elimination of duloxetine. After a single dose of duloxetine 20 mg in 6 patients with cirrhosis and moderate liver dysfunction (Child-Pugh class B), the T1/2 duration of duloxetine was approximately 15% higher than in healthy people of the same sex and age with a fivefold an increase in the average AUC value. Despite the fact that Cmax in patients with cirrhosis was the same as in healthy people, T1/2 was approximately 3 times greater.
Use of the drug during pregnancy and lactation
The use of the drug during pregnancy is possible only in cases where the expected benefit to the mother outweighs the potential risk to the fetus, because There is insufficient clinical experience with the use of duloxetine during pregnancy.
If it is necessary to use the drug during lactation, the issue of stopping breastfeeding should be decided (due to lack of experience in use).
Patients should be warned that if they become pregnant or plan to become pregnant while using duloxetine, they should inform their doctor.
