Симбалта®

General characteristics. Structure:

The substance operating е: 30 mg or 60 mg of a duloksetin in the form of a duloksetin of a hydrochloride.

Excipients. Capsule contents: sucrose, a gipromelloza, the sugar granulated (no more than 91,5% of sucrose, starch), talc, acetate gipromelloza succinate, triethyl citrate, dye white (titanium dioxide, a gipromelloz).

Capsule cover - indigo carmine, titanium dioxide, sodium lauryl sulfate, gelatin, dye ferrous oxide yellow (only for capsules of 60 mg).

Pharmacological properties:

Pharmacodynamics. Duloksetin is antidepressant, inhibitor of the return serotonin reuptake and Norepinephrinum, and poorly suppresses dopamine capture, without having significant affinity to gistaminergichesky, dofaminergichesky, cholinergic and adrenergic receptors. The mechanism of action of a duloksetin at treatment of a depression consists in suppression of the return serotonin reuptake and Norepinephrinum therefore serotonergic and noradrenergichesky neurotransmission in TsNS raises.

Duloksetin possesses the central mechanism of suppression of a pain syndrome that, first of all, is shown by increase in a threshold of painful sensitivity at a pain syndrome of a neyropatichesky etiology.

Pharmacokinetics. Absorption. Duloksetin is well soaked up at intake. Absorption begins in 2 hours after administration of drug. The maximum concentration of drug is reached 6 hours later after reception.

Meal does not influence the maximum concentration of drug, but increases time of achievement of the maximum concentration from 6 to 10 o'clock that indirectly reduces extent of absorption (approximately by 11%).

Distribution. Duloksetin well contacts proteins of plasma (> 90%), generally albumine and α1 - globulin, but disturbances from a liver or kidneys do not exert impact on extent of linkng with proteins.

Metabolism. Duloksetin is actively metabolized, and his metabolites are generally removed with urine.

Both CYP2D6, and CYP1A2 catalyze formation of two main metabolites (a glucuronic conjugate of a 4-gidroksiduloksetin, sulfate of conjugates of 5 hydroxies, a 6-metoksiduloksetina).

The circulating metabolites have no pharmacological activity.

Removal. Duration of an elimination half-life of a duloksetin makes 12 hours. The average clearance of a duloksetin makes 101 l/h.

Separate groups of patients. Floor: in spite of the fact that distinctions of pharmacokinetics between men and women (the average clearance of a duloksetin is lower at women) were revealed, these distinctions are not so big that there was a need for dose adjustment depending on a floor.

Age: in spite of the fact that distinctions of pharmacokinetics between patients of middle and advanced age (AUC - the area under a curve concentration/time is higher also drug elimination half-life duration more at elderly) were revealed, these distinctions are not enough for change of a dose in dependence only on age of patients.

Renal failure: at the patients with heavy renal failures (HPN end-stage - a chronic renal failure) who are on a hemodialysis, Cmax values (the maximum concentration) and AUC of a duloksetin increased twice. In this regard it is necessary to consider expediency of reduction of a dose of drug at patients with clinically expressed renal failure.

Abnormal liver function: at patients with clinical signs of a liver failure delay of metabolism and removal of a duloksetin can be observed. After a single dose of 20 mg of a duloksetin at 6 patients with cirrhosis with a moderate abnormal liver function (A class B on Child-Pugh) duration of an elimination half-life of a duloksetin was about 15% higher, than at healthy people of the corresponding gender and age with fivefold increase in average exposure (AUC). In spite of the fact that patients with cirrhosis had same Cmax, as well as at healthy people, the elimination half-life was, about, 3 times longer.

Indications to use:

- depression;

- painful form of diabetic neuropathy;

- generalized alarming frustration.

Route of administration and doses:

Inside. Capsules should be swallowed entirely, without chewing and without crushing. It is impossible to add drug to food or to mix it with liquids as it can damage an enterosoluble cover of pellets.

The recommended initial dose of a duloksetin makes 60 mg regardless of meal once a day. At some patients for achievement of good result it is necessary to increase a dose from 60 mg to the maximum dose of 120 mg a day in two steps once a day. Systematic assessment of administration of drug in a dose over 120 mg was not carried out.

At patients with a renal failure: the initial dose has to make 30 mg at patients with heavy renal failures (HPN end-stage) once a day (clearance of creatinine <30 ml/min.).

At patients with an abnormal liver function: it is necessary to lower an initial dose of drug or to reduce frequency rate of reception at patients with cirrhosis.

Age: use of drug for patients ≥ is recommended 18 years. There is no clinical experience of use of a duloksetin for patients up to 18 years.

Features of use:

Monoamine oxidase inhibitors (IMAO). At the patients receiving inhibitor of the return serotonin reuptake in a combination with IMAO cases of serious reactions, sometimes with a lethal outcome among which the hyperthermia, rigidity, a myoclonus, peripheral disturbances met possible sharp fluctuations of indicators of the vital functions and the changes of the mental status including the expressed excitement with transition to a delirium and a coma were noted. These reactions were also observed at patients to whom shortly before purpose of IMAO inhibitor of the return serotonin reuptake was cancelled. In certain cases at patients the symptoms characteristic of an antipsychotic malignant syndrome were observed. Effects of the combined use of a duloksetin and IMAO were not estimated neither at people, nor at animals. Therefore, considering the fact that дулоксетин is inhibitor of both serotonin, and Norepinephrinum, it is not recommended to accept дулоксетин in a combination with IMAO or within, at least, 14 days after the termination of treatment of IMAO. Based on duration of an elimination half-life of a duloksetin, it is necessary to take a break, at least, for 5 days after the end of reception of a duloksetin before reception of IMAO.

Aggravation of a maniacal/hypomaniacal state: as well as at use of the similar drugs making impact on TsNS дулоксетин it is necessary to apply with care at patients with maniacal episodes in the anamnesis.

Epileptic seizures: as well as at use of the similar drugs making impact on TsNS дулоксетин it is necessary to apply with care at patients with epileptic seizures in the anamnesis.

Mydriasis: mydriasis cases at reception of a duloksetin therefore patients should show care at purpose of a duloksetin with the increased intraocular pressure or at persons with risk of development of acute closed-angle glaucoma were observed.

Abnormal liver function or kidneys: at patients with a heavy renal failure (the clearance of creatinine <30 ml/min.) or a heavy liver failure is observed increase in concentration of a duloksetin in plasma. If at such patients reception of a duloksetin is clinically reasonable, it is necessary to apply lower initial doses of drug.

Suicide attempts: at depressions there is a probability of suicide attempts which can remain before permanent remission. Careful observation of the patients belonging to risk group is necessary.

Driving of the car and performance of work, requiring special attention. During the researches of a duloksetin disturbances of psychomotor reactions, cognitive functions and memory were not revealed. However administration of drug can be followed by drowsiness. In this regard the patients accepting дулоксетин should show care at management of dangerous mechanical means, including the car.

Use during pregnancy and breastfeeding. Because of insufficient experience of use of a duloksetin during pregnancy, it is necessary to appoint drug during pregnancy only if the potential advantage for the patient considerably exceeds potential risk for a fruit. Patients have to be warned that in case of approach or planning of pregnancy during treatment duloksetiny, they need to report about it to the attending physician.

In view of lack of experience of use of a duloksetin for women during breastfeeding feeding is not recommended by a breast during therapy duloksetiny.

Side effects:

Most often (≥ 10%) in clinical trials were noted: dizziness (except вертиго), dryness in a mouth, nausea, a lock, sleep disorders (drowsiness or sleeplessness) and a headache. The headache was noted less than against the background of placebo reception.

Less often (from ≥ 1 to <10%) were noted: diarrhea, vomiting, a tremor, a loss of appetite, weight reduction, weakness, the increased sweating, inflows, a sight illegibility, an anorgazmiya, decrease in a libido, a delay and disturbance of an ejaculation and erectile dysfunction.

Dizziness, nausea, headache were noted as frequent adverse effects at cancellation of a duloksetin.

Influence on concentration of glucose at patients with a painful form of diabetic neuropathy: insignificant increase in glucose in blood on an empty stomach against the background of reception of a duloksetin can be observed.

Interaction with other medicines:

The drugs which are metabolized CYP1A2. Simultaneous use of a duloksetin (60 mg 2 times a day) did not exert considerable impact on pharmacokinetics of the theophylline which is metabolized CYP1A2. Duloksetin hardly exerts clinically significant impact on metabolism of CYP1A2 substrates.

CYP1A2 inhibitors. Because CYP1A2 participates in metabolism of a duloksetin, the concomitant use of a duloksetin with potential CYP1A2 inhibitors will probably lead to increase in concentration of a duloksetin. Powerful CYP1A2 inhibitor флувоксамин (100 mg once a day) reduced average plasmatic clearance of a duloksetin approximately by 77%. It is necessary to show care at purpose of a duloksetin with CYP1A2 inhibitors (for example, some hinolonovy antibiotics) and it is necessary to use smaller doses of a duloksetin.

The drugs which are metabolized CYP2D6. Duloksetin is moderate CYP2D6 inhibitor. At reception of a duloksetin in a dose of 60 mg 2 times a day together with a single dose of desipramine, CYP2D6, AUC substrate of desipramine raise by 3 times. The concomitant use of a duloksetin (40 mg 2 times a day) raised a stable part of AUC of a tolterodin (2 mg 2 times a day) for 71%, but 5 hydroxyl of a metabolite did not exert impact on pharmacokinetics. Thus, it is necessary to show care when using a duloksetin with drugs which are generally metabolized by the CYP2D6 system and have a narrow therapeutic index.

CYP2D6 inhibitors. As CYP2D6 participates in metabolism of a duloksetin, simultaneous use of a duloksetin with potential CYP2D6 inhibitors can lead to increase in concentration of a duloksetin.

Paroksetin (20 mg once a day) reduced average clearance of a duloksetin approximately by 37%. At use of a duloksetin (for example, SSRIs) should be careful with CYP2D6 inhibitors.

The drugs influencing TsNS. It is necessary to show care at use of a duloksetin together with other drugs and means influencing TsNS, especially with those which have the similar mechanism of action, including alcohol.

The drugs highly contacting blood proteins. Duloksetin substantially contacts proteins of plasma (> 90%). Therefore purpose of a duloksetin to the patient who accepts other drug highly contacting proteins of plasma can lead to increase in concentration of free fractions of both drugs.

Contraindications:

- Hypersensitivity to drug.
- Simultaneous use with monoamine oxidase inhibitors (IMAO) (see the section "Special Instructions").
- Noncompensated closed-angle glaucoma

With care: At an aggravation of a maniacal/hypomaniacal state, epileptic seizures, a mydriasis, abnormal liver function or kidneys, at probability of suicide attempts (see the section "Special Instructions").

Overdose:

It was reported about several cases of overdose at single-step intake to 1400 mg of drug which did not have fatal effects. The overdose can be followed by the following symptoms: tremor, clonic spasms, ataxy, vomiting and loss of appetite.

Treatment at overdose. The specific antidote is not known. It is recommended to carry out monitoring of cordial activity and to watch the main vital signs, along with performing the symptomatic and supporting treatment.

Storage conditions:

At a temperature of 15-30 °C, in places unavailable to children. List B. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

Capsules of 30 mg or 60 mg. On 7 capsules in the blister; on 1, 2 or 4 blisters together with the application instruction in a pack cardboard. On 14 capsules in the blister; on 1, 2 or 6 blisters together with the application instruction in a pack cardboard.