Лирика®

General characteristics. Structure:

Active agent: прегабалин 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg or 300 mg. Excipients: lactoses monohydrate (35 mg / 70 mg / 8,25 mg / 11 mg / 16,5 mg / 22 mg / 33 mg), starch corn (20 mg / 40 mg / 8,375 mg / 11,17 mg / 16,75 mg / 22,33 mg / 33,5 mg), talc (20 mg / 40 mg / 8,375 mg / 11,17 mg / 16,75 mg / 22,33 mg / 33,5 mg). Structure of the case of the capsule: dye ferrous oxide red (for a dosage of 100 mg – 1,7361%, for a dosage of 200 mg – 0,4398%), titanium dioxide (2,4423% / 2,4423% / 2,4423% / 0,409% / 2,4423% / 0,4144% / 2,4423%), gelatin (for all dosages to 100%). Structure of a lid of the capsule: dye ferrous oxide red (only for dosages of 75 mg, 100 mg – 1,7361%, for a dosage of 200 mg – 0,4398%, for a dosage of 300 mg – 0,7361%), titanium dioxide (2,4423% / 2,4423% / 0,409% / 0,409% / 2,4423% / 0,4144% / 0,409%), gelatin (for all dosages to 100%). The structure blackened: shellac (24-27%), ethanol (23-26%), isopropanol (0,5-3%), butanol (0,5-3%), propylene glycol (3-7%), ammonia the solution concentrated (1-2%), potassium hydroxide (0,05-0,1%), the water purified (15-18%), dye ferrous oxide black (24-28%).

Pharmacological properties:

Pharmacodynamics. Active ingredient is прегабалин - an analog of piperidic acid ((S)-3 (aminomethyl) - 5-methylhexane acid).

Action mechanism

It was established what прегабалин contacts additional subunit (a2 - a delta protein) potentsialzavisimy calcium channels in the central nervous system, it is irreversible replacing [3H] - габапентин. It is supposed that such binding can promote manifestation of its analgetic and anticonvulsant effects. 

Neyropatichesky pain

Efficiency of a pregabalin is noted at patients with diabetic neuropathy and post-herpetic neuralgia.

It is established that at reception of a pregabalin courses up to 13 weeks on two times a day and up to 8 weeks on three times a day, in general risk of development of side effects and efficiency of drug at receptions on two or on three times a day are identical.

At reception by a course lasting up to 13 weeks pain decreased within the first week, and the effect remained until the end of treatment.

Reduction of an index of pain by 50% at 35% of the patients receiving прегабалин and 18% of the patients accepting placebo was noted. Among the patients who were not testing drowsiness, the effect of such decrease in pain was noted at 33% of patients of group of a pregabalin and 18% of patients of group of placebo. 48% of the patients accepting прегабалин and at 16% of the patients accepting placebo had a drowsiness.

Fibromyalgia

The expressed decrease in the painful symptomatology connected with fibromyalgia is noted at use of a pregabalin in doses from 300 mg to 600 mg a day. Efficiency   of doses  450 and

600 mg a day it is comparable, however portability of 600 mg a day is usually worse.

Also use of a pregabalin is connected with noticeable improvement in functional activity of patients and decrease in expressiveness of sleep disorders. Use of a pregabalin in a dose of 600 mg a day led to more expressed improvement of a dream, in comparison with a dose of 300-450 mg a day.

Epilepsy

At administration of drug within 12 weeks on two or three times a day the development of side effects noted risk and efficiency of drug at these modes of dosing is identical. Reduction of frequency of spasms began within the first week.

Generalized alarming frustration

Reduction of symptomatology of generalized alarming frustration is noted on the first week of treatment. At use of drug within 8 weeks at 52% of the patients receiving прегабалин and at 38% of the patients receiving placebo 50% reduction of symptomatology on a scale of uneasiness of Hamilton (HAM-A) were noted. 

Pharmacokinetics. Parameters of pharmacokinetics of a pregabalin in an equilibrium state at healthy volunteers, at the patients with epilepsy receiving antiepileptic therapy and at the patients receiving it concerning chronic pain syndromes were similar.

Absorption

Pregabalin is quickly soaked up on an empty stomach. The maximum concentration of a pregabalin in plasma (Cmax) is reached in 1 hour as at single, and repeated use. Bioavailability of a pregabalin at intake makes ≥90% and does not depend on a dose.              At repeated use equilibrium concentration is reached in 24-48 hours. At use of drug after meal of Cmax decreases approximately by 25-30%, and time of achievement of the maximum concentration (tmax) increases approximately to 2,5 h. However meal does not exert clinically significant impact on the general absorption of a pregabalin.

Distribution

The seeming volume of distribution of a pregabalin after intake makes about 0,56 l/kg. Pregabalin does not contact proteins of plasma.

Metabolism

Pregabalin is practically not exposed to metabolism. After reception of a marked pregabalin about 98% of a radioactive label was defined in urine in not changed look. The share                    of N-metilirovannogo of a derivative pregabalin which is the main metabolite found in urine made 0,9% of a dose. Racemization signs are noted

S-enantiomera of a pregabalin in R-enantiomer.

Removal

Pregabalin is brought generally by kidneys in not changed look. 

The average elimination half-life makes 6,3 hours. Clearance of a pregabalin from plasma and renal clearance are directly proportional to clearance of creatinine (see the Renal failure point). At patients with an impaired renal function and the patients who are on a hemodialysis dose adjustment is necessary (see the section "Route of Administration and Doses" of tab. 1).

Linearity/nonlinearity

The pharmacokinetics of a pregabalin in the range of the recommended daily doses has linear character, interindividual variability low (<20%). The pharmacokinetics of a pregabalin at repeated use can be predicted on the basis of data of reception of a single dose. Therefore, there is no need for regular monitoring of concentration of a pregabalin.

Pharmacokinetics in special groups

The sex of the patient does not exert clinically significant impact on concentration of a pregabalin in plasma.

Renal failure

The clearance of a pregabalin is directly proportional to clearance of creatinine. Considering what прегабалин is generally removed by kidneys, at patients with an impaired renal function it is recommended to lower a dose of a pregabalin. Besides, прегабалин effectively is removed from plasma at a hemodialysis (after the 4-hour session of a hemodialysis of concentration of a pregabalin in plasma decrease approximately by 50%), after a hemodialysis it is necessary to appoint an additional dose of drug (see the section "Route of Administration and Doses" of tab. 1).

Abnormal liver function

The pharmacokinetics of a pregabalin at patients with an abnormal liver function specially was not studied. Pregabalin is practically not exposed to metabolism and is brought generally in not changed view with urine therefore the abnormal liver function should not change significantly concentration of a pregabalin in plasma.

Elderly patients (65 years are more senior)

The clearance of a pregabalin tends to decrease with age that reflects age decrease in clearance of creatinine. The drug dose decline can be required by elderly people with an impaired renal function (see the section "Route of Administration and Doses" of tab. 1).

 

Indications to use:

Neyropatichesky pain. Treatment of neyropatichesky pain at adults. Epilepsy. As additional therapy at adults with the partial convulsive attacks which are followed or not followed by secondary generalization. Generalized alarming frustration. Treatment of generalized alarming frustration at adults. Fibromyalgia Treatment of fibromyalgia at adults.

Route of administration and doses:

Inside irrespective of meal.

Drug is used in a dose from 150 to 600 mg/days in two or three receptions.

Neyropatichesky pain

Treatment pregabaliny begin 150 mg/days with a dose. Depending on the reached effect and portability in 3-7 days it is possible to increase a dose to 300 mg/days, and if necessary in 7 days - to the maximum dose of 600 mg/days.

Epilepsy

Treatment pregabaliny begin 150 mg/days with a dose. Taking into account the reached effect and portability in 1 week it is possible to increase a dose to 300 mg/days, and in a week - to the maximum dose of 600 mg/days.

Fibromyalgia

Treatment pregabaliny there begin with a dose 75 mg two times a day (150 mg/days). Depending on the reached effect and portability in 3-7 days it is possible to increase a dose to                    300 mg/days. In the absence of positive effect increase a dose to 450 mg/days, and if necessary in 7 days - to the maximum dose of 600 mg/days.

 Generalized alarming frustration

Treatment pregabaliny begin 150 mg/days with a dose. Depending on the reached effect and portability in 7 days it is possible to increase a dose to 300 mg/days. In the absence of positive effect increase a dose to 450 mg/days, and if necessary in           7 days - to the maximum dose of 600 mg/days.

Cancellation of a pregabalin

If treatment pregabaliny needs to be stopped, it is recommended to do it gradually within at least 1 week.

Patients with a renal failure

At patients with an impaired renal function the dose is selected individually taking into account the clearance of creatinine (CC) (tab. 1) which is calculated by the following formula: 

 KK (ml/min.) =
 [140 - age advanced in years] x body weight (kg)
 (x 0,85 for women)
 
72 x serumal creatinine (mg/dl)
 
  

At the patients receiving treatment by a hemodialysis, the daily dose of a pregabalin is selected taking into account function of kidneys. Directly after each 4-hour session of a hemodialysis appoint an additional dose (see tab. 1). 

Table 1. Selection of a dose of a pregabalin taking into account function of kidneys

 

Clearance of creatinine, ml/min.	Daily dose of a pregabalin		Frequency rate of reception in days
	Starting dose, mg/days	Maximum dose, mg/days
³60	150	600	2-3
³30 - <60	75	300	2-3
³15 - <30	25 – 50	150	1-2
<15	25	75	1
Additional dose after dialysis (mg)
	25	100	Once

 

 Use for patients with an abnormal liver function

With an abnormal liver function of dose adjustment it is not required from patients (see the section "Pharmacokinetics"). 

Use for children up to 12 years and teenagers (12-17 years, inclusive)

Safety and efficiency of a pregabalin at children aged up to 12 years and teenagers are not established. Use of drug for children is not recommended.

Use for elderly people (65 years are more senior)

The dose decline of a pregabalin in connection with depression of function of kidneys can be required by people of advanced age (see the section "Pharmacokinetics", use for patients with a renal failure).

In case of the admission of a dose of a pregabalin it is necessary to accept the following dose as soon as possible, however it is not necessary to accept the passed dose if time of reception following already approaches.

 

Features of use:

At a part of patients with a diabetes mellitus in case of a body weight increase against the background of treatment pregabaliny correction of doses of hypoglycemic means can be required.

Pregabalin it is necessary to cancel in case of development of symptoms of a Quincke's disease (such as, swelled persons, perioral swelled or puffiness of tissues of upper airways).

Antiepileptic drugs, including прегабалин, can increase risk of emergence of suicide thoughts or behavior. Therefore the patients receiving these drugs should be observed carefully regarding emergence or deterioration in a depression, emergence of suicide thoughts or behavior.

Treatment pregabaliny was followed by dizziness and drowsiness which increase risk of accidental injuries (falling) at elderly people. During post-marketing use of drug also cases of a loss of consciousness, confusion of consciousness and disturbance of cognitive functions were noted. Therefore until patients do not estimate possible effects of drug, they have to be careful.

Data on a possibility of cancellation of other anticonvulsants at suppression of spasms pregabaliny and expediency of monotherapy by this drug are insufficient.

There are messages on development of spasms, including the epileptic status and small attacks against the background of use of a pregabalin or right after the end of therapy.

At emergence in response to use of a pregabalin of such undesirable reactions as an illegibility of sight or other disturbances from an organ of sight, drug withdrawal can lead to disappearance of the specified symptoms.

Also cases of development of a renal failure were noted, in certain cases after cancellation of a pregabalin function of kidneys was recovered.

As a result of cancellation of a pregabalin after long or short-term therapy the following undesirable phenomena were observed: sleeplessness, headache, nausea, diarrhea, grippopodobny syndrome, depression, perspiration, dizziness, spasms and alarm. Data on frequency and expressiveness of manifestations of a syndrome of "cancellation" of a pregabalin depending on duration of therapy by the last and its dose are not available.

During post-marketing use of drug it was reported about development of chronic heart failure against the background of therapy pregabaliny at some patients. These reactions were preferential observed at the patients of advanced age who were suffering from dysfunctions of heart and receiving drug concerning neuropathy. Therefore прегабалин at this category of patients it has to be used with care. After cancellation of a pregabalin disappearance of manifestations of similar reactions is possible.

Frequency of the undesirable phenomena from the central nervous system (CNS), especially such as drowsiness, increases at treatment of the central neyropatichesky pain caused by damage of a spinal cord that, however, can be a consequence of summation of effects of a pregabalin and others in parallel the accepted means (for example, anti-spastic). This circumstance should be taken into account at purpose of a pregabalin according to this indication.

There are messages on cases of development of dependence at use of a pregabalin. Patients with medicinal dependence in the anamnesis need careful medical observation regarding symptoms of dependence on a pregabalin.

Encephalopathy cases, especially at patients with associated diseases which can lead to development of encephalopathy were noted.

Influence on ability to drive the car and to use a difficult technique

Pregabalin can cause dizziness and drowsiness and, respectively, to affect ability to drive the car and to use a difficult technique. Patients should not drive the car, use a difficult technique or carry out other potentially dangerous types of activity, it will not become clear yet whether this drug influences performance of such tasks by them.

Side effects:

By the available experience of a clinical use of a pregabalin at more than 12000 patients, dizziness and drowsiness were the most widespread undesirable phenomena. The observed phenomena were usually easy or moderate. Frequency of cancellation of a pregabalin and placebo because of undesirable reactions made 14 and 7% respectively. Dizziness (4%) and drowsiness (3%), depending on their subjective portability were the main undesirable effects demanding the treatment termination. Other side effects which are also leading to drug withdrawal: ataxy, confusion of consciousness, adynamy, disturbance of attention, sight illegibility, lack of coordination, peripheral hypostases. All undesirable phenomena which frequency exceeded that in group of placebo (observed more than at 1 person) are listed in the table. They are distributed on system and organ classes and frequency (very frequent (> 1/10), frequent (> 1/100, <1/10), infrequent (> 1/1000, <1/100) and rare (<1/1000)). The listed undesirable phenomena could be connected with a basic disease and/or the accompanying therapy.

Infections and invasions: Infrequent - the Nasopharyngitis Blood and lymphatic system Rare - the Neutropenia of Disturbance of metabolism and food Frequent - Increase in appetite Infrequent - Anorexia, a hypoglycemia Mental disorders Frequent Infrequent Euphoria, confusion of consciousness, decrease a libido, sleeplessness, irritability, a disorientation Depersonalization, an anorgazmiya, concern, a depression, agitation, lability of mood,  the suppressed mood, difficulties in selection of words, hallucinations, unusual dreams, increase in a libido, the panic attacks, apathy, strengthening of sleeplessness Rare: Disinhibition, high spirits

Neurologic frustration Very frequent - Dizziness, drowsiness Frequent - the Ataxy, disturbance of attention, an incoordination, a memory impairment, a tremor, a dysarthtia, paresthesia, balance disturbance, amnesia, sedation, a lethargy. Infrequent - Cognitive frustration, a hypesthesia, a nystagmus, disturbance of the speech, myoclonic spasms, weakening of reflexes, dyskinesia, psychomotor excitement, postural dizziness, a hyperesthesia, loss of flavoring feelings, a burning sensation on mucous membranes and skin, an intentsionny tremor, a stupor, a syncope Rare - the Hypokinesia, a parosmiya, a dysgraphia

Changes from an organ of sight Frequent a sight Illegibility, Nechastye's diplopia of the Vision disorder: narrowing of fields of vision, decrease in visual acuity, eye pain, an asthenopia, dryness in eyes, puffiness of eyes, the raised dacryagogue Rare Flashing of "sparks" before eyes, irritation of eyes, a mydriasis, an ostsillopsiya (subjective feeling of fluctuation of the considered objects), disturbance of perception of visual depth, loss of peripheral sight, squint, strengthening of brightness of visual perception of Change from an acoustic organ and a vestibular mechanism Frequent Vertigo Nechastye the Hyperacusia

From cardiovascular system Infrequent Tachycardia, atrioventricular block of the I degree, "inflows", lowering of arterial pressure, cold snap of extremities, increase in arterial pressure, dermahemia Rare Sinus tachycardia, sinus arrhythmia, sinus bradycardia

From respiratory system Infrequent Short wind, cough, a xeromycteria Rare a nose Congestion, bleeding from a nose, rhinitis, snore, feeling of "constraint" in a drink

From the alimentary system Frequent Dryness in a mouth, a lock, vomiting, a meteorism, abdominal distention Infrequent the Increased salivation, a gastroesophageal reflux, a hypesthesia of a mucous membrane of an oral cavity Rare Ascites, a dysphagy, pancreatitis

From integuments Infrequent Perspiration, papular rash Rare Cold sweat, a small tortoiseshell from a musculoskeletal system Infrequent Twitchings of muscles, a swelling of joints, muscular spasms, a mialgiya, an arthralgia, a dorsodynia, extremity pain, constraint of muscles the Rare Trachelism, neck pain, рабдомиолиз

From an urinary system Infrequent Dysuria, urine incontience Rare Oliguria, renal failure

From reproductive system Frequent Erectile dysfunction Infrequent an ejaculation Delay, sexual dysfunction the Rare Amenorrhea, pain in chest glands, allocations from mammary glands, a dysmenorrhea, increase in mammary glands in volume

Other Frequent Fatigue, hypostases, including peripheral, feeling of "intoxication", gait disturbance Infrequent the Adynamy, falling, thirst, feeling of constraint in breasts, generalized hypostases, a fever, pain, pathological feelings Rare the Hyperthermia Laboratory and  tool data Frequent Increase in body weight Infrequent Increase in activity of alaninaminotranspherase, a kreatinfosfokinaza, aspartate aminotransferase, decrease in number of thrombocytes Rare Increase in concentration of glucose  and  creatinine of blood, decrease in potassium concentration of blood, decrease in body weight, decrease in number of leukocytes in blood. The following side effects were noted at post-marketing observation (frequency is unknown): Neurologic frustration: headache, loss of consciousness, cognitive disturbances, spasms.

From the alimentary system: exceptional cases of a paraglossa, nausea, diarrhea.

From integuments: exceptional cases of a face edema, itch, Stephens-Johnson's syndrome. Changes from an organ of sight: keratitis, sight loss. 

Changes from immune system: Quincke's disease, allergic reactions, hypersensitivity.

From cardiovascular system: chronic heart failure, lengthening of an interval of QT.

From an urinary system: ischuria.

From respiratory system: fluid lungs.

From reproductive system: gynecomastia.

Others: increased fatigue.

Interaction with other medicines:

Pregabalin is brought by kidneys generally in not changed look, is exposed to the minimum metabolism at the person (in the form of metabolites kidneys remove less than 2% of a dose), does not inhibit metabolism of other medicinal substances in vitro and does not contact proteins of plasma therefore he is hardly capable to enter pharmacokinetic interaction.

Signs of clinically significant pharmacokinetic interaction of a pregabalin with Phenytoinum, carbamazepine, valproic acid, lamotridzhiny, gabapentiny, lorazepam, oxycodone and ethanol are not revealed. It is established that peroral hypoglycemic means, diuretics, insulin, phenobarbital, тиагабин and топирамат do not exert clinically significant impact on clearance of a pregabalin.

At use of the oral contraceptives containing Norethisteronum and/or ethinylestradiol along with pregabaliny the equilibrium pharmacokinetics of both drugs did not change.

It was reported about cases of disturbance of breath and approach of a coma at simultaneous use of a pregabalin with other drugs oppressing the central nervous system.

Also it was reported about negative influence of a pregabalin on activity of digestive tract (including, development of intestinal impassability, paralytic Ilheus, a lock) at simultaneous use with the medicines causing a lock (such as non-narcotic analgesics).

Repeated oral administration of a pregabalin with oxycodone, lorazepam or ethanol did not exert clinically significant impact on breath. Pregabalin, apparently, strengthens the disturbances of cognitive and motive functions caused by oxycodone. Pregabalin can strengthen effects of ethanol and lorazepam. 

Contraindications:

Hypersensitivity to active ingredient or any other component of drug.

Rare hereditary diseases, including intolerance of a galactose, lactose intolerance and disturbance of absorption of a glucose/galactose.

Children's and teenage age up to 17 years inclusive (there are no data on use).

With care

Renal (see the section "Route of Administration and Doses") and heart failure (see the section "Side effect").

Due to the registered isolated cases of uncontrolled use of a pregabalin, it is necessary to appoint it with care at patients with medicinal dependence in the anamnesis. Such patients need fixed medical observation during treatment by drug.

Use at pregnancy and during breastfeeding

There are no adequate data on use of a pregabalin for pregnant women.

At use for animals drug had toxic effect on reproductive function. In this regard прегабалин it is possible to apply at pregnancy only if the advantage for mother obviously outweighs possible risk for a fruit. At treatment pregabaliny women of reproductive age have to use adequate methods of contraception.

With breast milk women have no data on removal of a pregabalin, however is noticed that at rats he is brought with milk. In this regard during treatment pregabaliny it is not recommended to nurse.

Overdose:

At drug overdose (to 15 g) others (not described above) undesirable reactions were not registered. During post-marketing use the most frequent undesirable phenomena developing at overdose of a pregabalin were: affective frustration, drowsiness, confusion of consciousness, depression, agitation and concern.

Treatment: carry out the gastric lavage supporting treatment and if necessary a hemodialysis (see the section "Route of Administration and Doses" of tab. 1).

Storage conditions:

To store in the dry place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg or 300 mg. 10, 14 or 21 capsules in the blister from polyvinylchloride and aluminum foil. 1 or 4 blisters on 14 capsules, 4 blisters on 21 capsules or 10 blisters on 10 capsules in a cardboard pack together with the application instruction.