Linbag hard capsules 150 mg blister No. 30

Instructions for Linbag hard capsules 150 mg blister No. 30

Composition

active ingredient: pregabalin;

1 capsule contains pregabalin 25 mg or 50 mg, or 75 mg, or 150 mg, or 300 mg;

excipients: talc, pregelatinized starch, corn starch;

gelatin capsule: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172)*, red iron oxide (E 172)**, black iron oxide (E 172)***.

* Not included in 150 mg capsules.

** Not available in 50 mg and 150 mg capsules.

*** Available in 25 mg and 300 mg capsules.

Dosage form

The capsules are hard.

Main physicochemical properties:

25 mg capsules: hard gelatin capsules, size 4, containing a white or almost white powder as a filling mass. Upper part of the capsule shell (cap): opaque, yellowish-brown, pale. Lower part of the capsule shell (body): opaque, yellowish-brown, pale.

50 mg capsules: size 3 hard gelatin capsules containing a white or almost white powder as a filling mass. Upper part of the capsule shell (cap): opaque, light yellow. Lower part of the capsule shell (body): opaque, light yellow.

75 mg capsules: size 4 hard gelatin capsules containing a white or almost white powder as a filling mass. Upper part of the capsule shell (cap): opaque, carmine. Lower part of the capsule shell (body): opaque, white.

150 mg capsules: size 2 hard gelatin capsules containing a white to off-white powder as a filling mass. Upper part of the capsule shell (cap): opaque, white. Lower part of the capsule shell (body): opaque, white.

300 mg capsules: size 0 hard gelatin capsules containing a white or almost white powder as a filling mass. Upper part of the capsule shell (cap): opaque, carmine. Lower part of the capsule shell (body): opaque, pale yellowish-brown.

Pharmacotherapeutic group

Antiepileptic drugs. ATX code N03A X16.

Pharmacological properties

Pharmacodynamics.

The active substance, pregabalin, is an analogue of gamma-aminobutyric acid [(S)-3-(aminomethyl)-5-methylhexanoic acid].

Mechanism of action: Pregabalin binds to the auxiliary subunit (a2-d protein) of voltage-gated calcium channels in the central nervous system (CNS).

Pharmacokinetics.

The steady-state pharmacokinetics of pregabalin were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption. Pregabalin is rapidly absorbed in the fasted state and reaches peak plasma concentrations (Cmax) within 1 hour after single and multiple dosing. The estimated oral bioavailability of pregabalin is greater than 90% and is independent of dose. Steady state is reached within 24–48 hours after multiple dosing. The rate of absorption of pregabalin is reduced when administered with food, resulting in a decrease in Cmax of approximately 25–30% and a delay in time to peak concentration (tmax) of approximately 2.5 hours. However, co-administration of pregabalin with food had no clinically significant effect on the extent of absorption.

Distribution: Preclinical studies have shown that pregabalin crosses the blood-brain barrier in animals. Pregabalin also crosses the placenta in rats and is excreted in milk during lactation. In humans, the apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins.

Metabolism: Pregabalin undergoes minimal metabolism in humans. After a dose of radiolabeled pregabalin, approximately 98% of the radioactivity is excreted in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of the drug, was detected in the urine and accounted for 0.9% of the administered dose. In preclinical studies, there was no racemization of the S-enantiomer of pregabalin to the R-enantiomer.

Elimination: Pregabalin is eliminated from the systemic circulation unchanged primarily by renal excretion. The mean elimination half-life of pregabalin is 6.3 hours. The plasma and renal clearance of pregabalin are directly proportional to creatinine clearance.

Patients with impaired renal function and patients on hemodialysis require dose adjustments.

Linearity/non-linearity. The pharmacokinetics of pregabalin are linear over the recommended dose range. The inter-patient variability in the pharmacokinetics of pregabalin is low (less than 20%). Multiple-dose pharmacokinetics are predictable from single-dose data. Therefore, routine monitoring of pregabalin plasma concentrations is not required.

Renal impairment. Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, the plasma concentration of pregabalin is reduced by approximately 50%). Since renal excretion is the major route of drug elimination, the dose of the drug should be reduced in patients with renal impairment, and patients should receive an additional dose after hemodialysis.

Hepatic impairment: Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin is not extensively metabolized and is excreted primarily unchanged in the urine, it is unlikely that hepatic impairment will significantly affect pregabalin plasma concentrations.

Indication

• Neuropathic pain

The drug Linbag is prescribed for the treatment of neuropathic pain in adults with damage to the peripheral and central nervous system.

• Epilepsy

Linbag is prescribed as an adjunctive therapy for partial seizures with or without secondary generalization in adults.

• Generalized anxiety disorder

Linbag is prescribed for the treatment of generalized anxiety disorder in adults.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions

Since pregabalin is excreted primarily unchanged in the urine, undergoes minimal metabolism in humans (≤ 2% of the dose is excreted in the urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and is not bound to plasma proteins, it is unlikely that pregabalin could cause or be the target of pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

In vivo studies have shown no clinically significant pharmacokinetic interactions between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis has shown that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate have no clinically significant effect on the clearance of pregabalin.

Oral contraceptives, norethisterone and/or ethinyl estradiol

Co-administration of pregabalin with oral contraceptives, norethisterone and/or ethinyl estradiol does not affect the steady-state pharmacokinetics of either drug.

Drugs that affect the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. During post-marketing surveillance, cases of respiratory failure, coma and death have been reported in patients taking pregabalin in combination with opioids and/or other CNS depressants. Pregabalin is likely to potentiate the cognitive and gross motor impairments caused by oxycodone.

Interactions in elderly patients

Specific pharmacodynamic interaction studies have not been conducted in elderly volunteers. Drug interaction studies have only been conducted in adult patients.

Application features

Patients with diabetes

In accordance with current clinical practice, some patients with diabetes mellitus who gain weight during pregabalin therapy may require dose adjustment of their antidiabetic medicinal products.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, have been reported in post-marketing experience. If symptoms of angioedema such as facial swelling, perioral swelling or upper respiratory tract swelling occur, pregabalin should be discontinued immediately.

Dizziness, drowsiness, loss of consciousness, confusion and mental disorders

Pregabalin has been associated with dizziness and somnolence, which may increase the risk of falls in elderly patients. Loss of consciousness, confusion and mental impairment have also been reported in the post-marketing setting. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Vision disorders

In controlled trials, blurred vision was more frequently observed in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials in which ophthalmological examinations were performed, the incidence of visual acuity deterioration and visual field changes was higher in patients treated with pregabalin compared to patients in the placebo group; the incidence of fundus changes was higher in patients in the placebo group (see section "Pharmacodynamics").

Kidney failure

Cases of renal failure have been reported, which were sometimes reversible after discontinuation of pregabalin.

Withdrawal of concomitant antiepileptic drugs

There is currently insufficient data on whether concomitant antiepileptic drugs can be withdrawn once seizure control is achieved with the addition of pregabalin to therapy, in order to switch to pregabalin monotherapy.

Withdrawal symptoms

Some patients have experienced withdrawal symptoms after discontinuation of short-term or long-term pregabalin therapy. The following events have been reported: suicidal ideation and behavior, insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, nervousness, depression, pain, seizures, hyperhidrosis, and dizziness, which are indicative of physical dependence. This information should be communicated to the patient before initiating therapy.

Convulsions, including status epilepticus and grand mal seizures, may occur during pregabalin therapy or shortly after its discontinuation.

Data on pregabalin withdrawal after long-term use indicate that the incidence and severity of withdrawal symptoms may be dose-dependent.

Congestive heart failure

Congestive heart failure has been reported in some patients taking pregabalin since the introduction of pregabalin into the market. This reaction has been observed mainly during the treatment of neuropathic pain with pregabalin in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This phenomenon may resolve upon discontinuation of pregabalin.

Treatment of neuropathic pain of central origin due to spinal cord injury

During the treatment of central neuropathic pain caused by spinal cord injury, the frequency of adverse reactions in general and CNS adverse reactions, especially drowsiness, was increased. This may be due to the additive effect of concomitant medications (e.g. antispasticity drugs) required for the treatment of this condition. This should be taken into account when prescribing pregabalin for this condition.

Suicidal thinking and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for some indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with pregabalin.

Therefore, patients should be monitored closely for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal ideation or behavior emerge.

Deterioration of the function of the lower gastrointestinal tract

Post-marketing reports of events associated with lower gastrointestinal dysfunction (such as intestinal obstruction, paralytic ileus, constipation) have been reported when pregabalin was used with medicinal products that may cause constipation, such as opioid analgesics. Precautions should be taken to prevent constipation when pregabalin is used concomitantly with opioids (especially in women and the elderly).

Concomitant use with opioids

Caution is advised when prescribing pregabalin concomitantly with opioids due to the risk of CNS depression (see section 4.5). In a case-control study of opioid users, patients receiving pregabalin concomitantly with an opioid were at increased risk of opioid-related mortality compared with opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, 1.52 aOR [95% CI, 1.04–2.22]) with a trend toward increased risk at high doses of pregabalin (> 300 mg, 2.55 aOR [95% CI 1.24–5.06]).

Misuse, abuse or addiction

Cases of misuse, abuse and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse; the patient should be monitored for signs of misuse, abuse or dependence on pregabalin (cases of addiction, exceeding the prescribed dose, drug-seeking behavior have been reported).

Encephalopathy

Cases of encephalopathy have been reported, occurring predominantly in patients with underlying conditions that may predispose to encephalopathy.

Pregabalin clearance tends to be reduced in elderly patients. The decrease in pregabalin clearance after oral administration is consistent with the decrease in creatinine clearance associated with increasing age. Patients with age-related renal impairment may require a reduction in the dose of pregabalin (see table in the Dosage and Administration section). Elderly patients are more likely to experience adverse reactions such as dizziness, confusion, tremor, incoordination, and lethargy.

Respiratory depression

Pregabalin has been associated with respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants, and the elderly may be at greater risk of this adverse reaction. These patients may require dose adjustment.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with pregabalin treatment. Patients should be advised of the signs and symptoms and monitored closely for skin reactions when prescribing the medicinal product. If signs and symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment should be considered (if appropriate).

Use during pregnancy or breastfeeding

Women of reproductive age / contraceptives for women and men

Since the potential risk to humans is unknown, women of reproductive age should use effective contraception.

Pregnancy

There are no adequate data from the use of pregabalin in pregnant women.

Reproductive toxicity has been demonstrated in animal studies. The potential risk to humans is unknown.

Linbag should not be used during pregnancy unless clearly necessary (when the benefit to the mother clearly outweighs the potential risk to the fetus).

Breast-feeding

Small amounts of pregabalin have been detected in the milk of nursing women. Nursing women should be advised that breastfeeding is not recommended while taking pregabalin.

Fertility

There are no clinical data on the effect of pregabalin on female fertility.

In a clinical study of the effects of pregabalin on sperm motility, healthy male volunteers were treated with pregabalin at a dose of 600 mg/day. No effect on sperm motility was observed after 3 months of treatment.

In a fertility study in female rats, adverse effects on reproductive function were observed. In a fertility study in male rats, adverse effects on reproductive function and development were observed. The clinical relevance of these findings is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug Linbag may have minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and drowsiness. Therefore, patients should be advised to refrain from driving, operating complex machinery, or other potentially hazardous activities until it is known whether this drug affects their ability to perform such activities.

Method of administration and doses

Doses

The dose range can vary from 150 to 600 mg per day, divided into 2 or 3 doses.

• Neuropathic pain

Pregabalin therapy can be initiated at a dose of 150 mg/day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg/day after 3–7 days, and if necessary, to a maximum dose of 600 mg/day after another 7 days.

• Epilepsy

Pregabalin treatment can be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the efficacy and tolerability of the drug in the individual patient, the dose can be increased to 300 mg per day after the first week of treatment. After another 1 week, the dose can be increased to a maximum of 600 mg per day.

• Generalized anxiety disorder

The dose, divided into 2 or 3 doses, may vary between 150 and 600 mg per day. The need for continued treatment should be reassessed periodically.

Pregabalin treatment can be started at a dose of 150 mg per day. Depending on the effectiveness and tolerability of the drug in individual patients, the dose can be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose can be increased to 450 mg per day. After another week, the dose can be increased to a maximum of 600 mg per day.

Discontinuation of pregabalin treatment

In accordance with current clinical practice, it is recommended to discontinue pregabalin treatment gradually, over a period of at least one week, regardless of the indication.

Pregabalin is eliminated from the systemic circulation unchanged primarily by renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose reduction in patients with renal impairment should be individualized.

Pregabalin is effectively removed from plasma by haemodialysis (50% of the drug within 4 hours). For patients on haemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an additional dose of the drug should be administered immediately after each 4-hour haemodialysis session (see table).

Pregabalin dose adjustment according to renal function.

* The total daily dose (mg/day) should be divided by the number of doses to obtain mg/dose.

+ An additional dose is an additional single dose.

Patients with hepatic insufficiency

There is no need for dose adjustment for patients with hepatic insufficiency.

Use in elderly patients (aged 65 years and over)

Elderly patients may require a reduction in the dose of pregabalin due to impaired renal function.

Method of application

The drug Linbag is taken regardless of food intake.

The medicine is intended for oral use only.

Children.

The safety and efficacy of Linbag in children (under 18 years of age) have not been established. Currently available information is provided in the Adverse Reactions section, as well as in the Pharmacodynamics and Pharmacokinetics sections, but no dosage recommendations can be made for this patient population.

Overdose

The most frequently observed adverse reactions in cases of pregabalin overdose were drowsiness, confusion, agitation and restlessness. Convulsions have also been reported. Coma has been reported rarely.

Treatment of pregabalin overdose consists of general supportive measures and may include hemodialysis if necessary.

Adverse reactions

The most common adverse reactions reported were dizziness and somnolence. Adverse reactions were generally mild to moderate. The discontinuation rate due to adverse reactions was 12% in patients treated with pregabalin and 5% in patients treated with placebo. The most common adverse reactions leading to discontinuation from the pregabalin group were dizziness and somnolence.

All adverse reactions that occurred more frequently than placebo and in more than 1 patient are listed below; these adverse reactions are presented by class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (< 1/10,000), frequency unknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

These adverse reactions may also be related to the course of the underlying disease and/or concomitant use of other medications.

During the treatment of central neuropathic pain caused by spinal cord injury, the frequency of adverse reactions in general, the frequency of adverse reactions from the CNS and especially drowsiness increased (see section "Special instructions").

Additional adverse reactions reported during post-marketing experience are indicated in italics in the list below.

Infections and infestations: Common: nasopharyngitis.

Blood and lymphatic system disorders: Uncommon: neutropenia.

Immune system disorders: Uncommon: hypersensitivity. Rare: angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and metabolism: Common: increased appetite. Uncommon: loss of appetite, hypoglycemia, anorexia.

Nervous system disorders: Very common: dizziness, drowsiness, headache. Common: ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy. Uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive impairment, mental impairment, speech disorder, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise, apathy, paraoral paraesthesia, myoclonus. Uncommon: convulsions, parosmia, hypokinesia, dysgraphia, hypalgesia, dependence, mania, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders. Frequency unknown: mental disorders, rare: suicidal thoughts and behavior, parkinsonism.

From the side of the organs of vision. Common: blurred vision, diplopia, conjunctivitis. Uncommon: loss of peripheral vision, visual impairment, eye swelling, visual field defects, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, ocular hemorrhage, photophobia, retinal edema. Rare: loss of vision, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcers, exophthalmos, ocular muscle paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic atrophy, optic disc edema, ptosis, uveitis.

Hearing and vestibular disorders: Common: vertigo. Uncommon: hyperacusis.

Cardiac disorders: Uncommon: tachycardia, first degree atrioventricular block, sinus bradycardia, congestive heart failure. Rare: QT prolongation, sinus tachycardia, sinus arrhythmia.

Vascular disorders: Uncommon: hypotension, hypertension, hot flushes, flushing, feeling of coldness in the extremities.

Respiratory, thoracic and mediastinal disorders: Common: pharyngolaryngeal pain. Uncommon: dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness. Uncommon: pulmonary oedema, throat tightness, laryngospasm, apnoea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning. Frequency not known: respiratory depression.

From the digestive system. Common: vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis. Uncommon: gastroesophageal reflux disease, salivary hypersecretion, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal bleeding, melena, rectal bleeding. Rare: ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess.

Hepatobiliary disorders: Uncommon: increased liver enzymes*. Uncommon: jaundice. Rare: hepatic failure, hepatitis.

* Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Skin and subcutaneous tissue disorders: Common: pressure ulcers. Uncommon: papular rash, urticaria, hyperhidrosis, pruritus, alopecia, dry skin, eczema, hirsutism, skin ulceration, vesiculobullous rash. Uncommon: Stevens-Johnson syndrome, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, cutaneous and subcutaneous nodules. Rare: toxic epidermal necrolysis (TEN).

Musculoskeletal and connective tissue disorders: Common: muscle cramps, arthralgia, back pain, pain in extremity, neck muscle spasms. Uncommon: joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness. Rare: rhabdomyolysis.

Urinary system disorders: Uncommon: urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis. Rare: renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis.

Reproductive system and breast disorders: Common: erectile dysfunction, impotence. Uncommon: sexual dysfunction, ejaculation delayed, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia. Rare: amenorrhea, breast discharge, breast enlargement, gynaecomastia, cervicitis, balanitis, epididymitis.

General disorders: Common: peripheral oedema, oedema, gait disturbance, fall, feeling of intoxication, feeling abnormal, fatigue. Uncommon: generalised oedema, facial oedema, chest tightness, pain, fever, thirst, chills, general weakness, malaise, abscess, inflammation of the fatty tissue, photosensitivity reactions. Rare: fever, anaphylactoid reactions, granuloma, intentional harm, retroperitoneal fibrosis, shock.

Some patients have experienced withdrawal symptoms after discontinuation of short- or long-term treatment with pregabalin. The following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, seizures, nervousness, depression, pain, hyperhidrosis and dizziness, which are indicative of physical dependence. This information should be communicated to the patient before starting treatment.

Data on discontinuation of long-term pregabalin treatment suggest a dose-dependent relationship between the frequency and severity of withdrawal symptoms.

Children: The safety profile of pregabalin in two studies in children was similar to that observed in studies in adult patients (see sections 5.1, 5.2 and 5.2).

Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the benefit-risk balance of the medicinal product.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

Capsules of 25 mg or 50 mg, or 75 mg, or 150 mg: 10 capsules in a blister, 3 blisters in a box.

300 mg capsules: 7 capsules in a blister, 2 blisters in a box.

Vacation category

According to the recipe.

Producer

Salutas Pharma GmbH (full-cycle production)

or

Lek Pharmaceutical Company Ltd.

Location of the manufacturer and address of its place of business.

Otto-von-Hürike-Allee 1, 39179, Barleben, Saxony-Anhalt, Germany

or

Verovškova 57, Ljubljana 1526, Slovenia.