Maxgalin 150
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MAXGALIN 75 MAXGALIN 150
Composition:
Active substance: pregabalin;
1 capsule contains 75 mg of pregabalin;
Excipients: lactose monohydrate; talc; gelatin capsule No. 4*;
*Composition of the 75 mg gelatin capsule: gelatin, iron oxide red (E 172), titanium dioxide (E 171), sodium lauryl sulfate;
1 capsule contains 150 mg of pregabalin;
Excipients: lactose monohydrate; talc; gelatin capsule No. 1*;
*Composition of the 150 mg gelatin capsule: gelatin, titanium dioxide (E 171), sodium lauryl sulfate.
Pharmaceutical form. Capsules.
Main physicochemical properties:
75 mg capsules: hard gelatin capsules with a brown cap and a white or almost white body, marked in black ink with "688" on both the cap and the body, containing granular powder from white to almost white;
150 mg capsules: hard gelatin capsules with a white or almost white cap and body, marked in black ink with "690" on both the cap and the body, containing granular powder from white to almost white.
Pharmacotherapeutic group.
Antiepileptic agents. ATC code N03A X16.
Pharmacological Properties.
Pharmacodynamics.
The active substance – pregabalin, which is a gamma-aminobutyric acid analogue [(S)-3-(aminomethyl)-5-methylhexanoic acid].
Mechanism of action
Pregabalin binds to the auxiliary subunit (α2–δ protein) of voltage-dependent calcium channels in the central nervous system (CNS).
Clinical efficacy and safety
Neuropathic pain
The efficacy of the drug has been demonstrated in clinical trials for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of the drug in other types of neuropathic pain has not been studied.
Pregabalin was studied in 10 controlled clinical trials lasting up to 13 weeks with a dosing regimen of twice daily, and in trials lasting up to 8 weeks with a dosing regimen of three times daily. Overall, safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.
In controlled clinical trials lasting up to 12 weeks, in which the drug was used to treat neuropathic pain, reduction in peripheral and central origin pain was observed after the first week and persisted throughout the treatment period.
In controlled clinical trials of peripheral neuropathic pain, 35% of patients receiving pregabalin and 18% of patients receiving placebo experienced a 50% improvement on the pain assessment scale. Among patients who did not experience somnolence, such improvement was observed in 33% of patients receiving pregabalin and 18% of placebo patients. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.
In a controlled clinical trial of central neuropathic pain, a 50% improvement on the pain assessment scale was observed in 22% of patients receiving pregabalin and 7% of patients receiving placebo.
Epilepsy
Adjunctive therapy. Pregabalin was studied in three controlled clinical trials lasting 12 weeks with a dosing regimen of twice daily or three times daily. Overall, safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.
Reduction in seizure frequency was observed during the first week.
Children. The efficacy and safety of pregabalin as adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n=65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled study involving 295 children aged 4 to 16 years, a 14-day placebo-controlled study involving 175 children aged 1 month to 4 years, aimed at evaluating the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and a 1-year open-label safety study involving 54 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections "Pharmacokinetics", "Dosage and administration", and "Adverse reactions").
In the 12-week placebo-controlled study, children (aged 4 to 16 years) received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. A reduction of at least 50% in partial seizures compared to baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 vs placebo), in 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.2600 vs placebo), and in 22.6% of those receiving placebo.
In the 14-day placebo-controlled study, children (aged 1 month to 4 years) received pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. The median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, for pregabalin at 7 mg/kg/day; 5.4 and 1.4 for pregabalin at 14 mg/kg/day; and 2.9 and 2.3 for placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p=0.0223); pregabalin at 7 mg/kg/day did not demonstrate improvement compared to placebo.
Monotherapy (in patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a dosing regimen of twice daily. Pregabalin did not achieve comparable efficacy to lamotrigine, as assessed at 6 months by the primary endpoint of seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.
Generalized anxiety disorder
Pregabalin was studied in six controlled trials lasting 4–6 weeks, one 8-week trial involving elderly patients, and one long-term relapse prevention trial with a double-blind relapse prevention phase lasting 6 months.
Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as week 1.
In controlled clinical trials (lasting 4–8 weeks), a ≥50% improvement in the total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and 38% of patients in the placebo group.
During controlled trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of patients in the pregabalin group and 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and 2.1% in the placebo group.
Pharmacokinetics.
Pharmacokinetic parameters of pregabalin at steady state were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.
Absorption
Pregabalin is rapidly absorbed when administered on an empty stomach and reaches peak plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is dose-independent. At steady state, achieved after 24–48 hours of multiple dosing. The rate of pregabalin absorption is reduced when taken with food, resulting in approximately a 25–30% reduction in Cmax and prolongation of time to peak concentration (tmax) to approximately 2.5 hours. However, administration of pregabalin with food did not have a clinically significant effect on the extent of its absorption.
Distribution
Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. It has been established that pregabalin crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.
Metabolism
In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated metabolite of pregabalin—the main metabolite detected in urine—was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.
Elimination
Pregabalin is eliminated from systemic circulation unchanged, primarily via the kidneys. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see section "Pharmacokinetics. Renal impairment").
Dose adjustment is required for patients with renal impairment or patients undergoing hemodialysis (see section "Dosage and administration", table).
Linearity/Non-linearity
The pharmacokinetics of pregabalin are linear across the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (<20%). Pharmacokinetics after multiple doses are predictable based on data obtained from single-dose administration. Therefore, routine monitoring of plasma pregabalin concentrations is not necessary.
Gender
Clinical trial results indicate no clinically significant effect of gender on plasma pregabalin concentrations.
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, plasma pregabalin concentration decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and administration", table).
Hepatic impairment
Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted in urine predominantly unchanged, it is unlikely that hepatic impairment would have a significant effect on plasma pregabalin concentrations.
Children
Pregabalin pharmacokinetics were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) receiving doses of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, and 15 mg/kg/day in a pharmacokinetic and tolerability study.
After oral administration of pregabalin to children on an empty stomach, tmax was generally similar across all age groups, ranging from 0.5 to 2 hours after dosing.
Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight below 30 kg, AUC values were 30% lower, due to a 43% higher creatinine clearance adjusted for body weight in these patients compared to patients with body weight ≥30 kg.
The terminal elimination half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children aged 7 years and older.
In a population pharmacokinetic analysis, creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.
Pregabalin pharmacokinetics have not been studied in patients under 3 months of age (see sections "Pharmacodynamics", "Dosage and administration", and "Adverse reactions").
Elderly patients
Pregabalin clearance tends to decrease with age. This reduction in pregabalin clearance with oral administration is consistent with the age-related decline in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see section "Dosage and administration", table).
Lactation
Pregabalin pharmacokinetics following administration at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had a negligible effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose from breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or at the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the maternal daily dose normalized to mg/kg.
Clinical characteristics.
Indications.
Neuropathic pain
Treatment of peripheral or central neuropathic pain in adults.
Epilepsy
Adjunctive therapy for partial seizures with or without secondary generalization in adults.
Generalized anxiety disorder
Treatment of generalized anxiety disorder in adults.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Since pregabalin is predominantly excreted unchanged in urine, undergoes negligible metabolism in humans (less than 2% of the dose is excreted in urine as metabolites), does not inhibit \textit{in vitro} metabolism of other drugs, and does not bind to plasma proteins, it is unlikely that pregabalin would cause or be subject to pharmacokinetic interactions.
\textit{In vivo} studies and population pharmacokinetic analysis
In \textit{in vivo} studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate do not have a clinically significant effect on pregabalin clearance.
Oral contraceptives, norethisterone and/or ethinylestradiol
Concomitant administration of pregabalin with oral contraceptives, norethisterone and/or ethinylestradiol does not affect the steady-state pharmacokinetics of either agent.
Medicinal products affecting the CNS
Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing period, cases of respiratory depression, coma, and fatal outcomes have been reported in patients who took pregabalin concomitantly with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and gross motor function impairment caused by oxycodone.
Interaction in elderly patients
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies were performed only in younger adults.
Special precautions for use.
Patients with diabetes
According to current clinical practice, some patients with diabetes who experience weight gain during pregabalin treatment may require adjustment of their antidiabetic medication doses.
Hypersensitivity reactions
Post-marketing reports have indicated the development of hypersensitivity reactions, including angioedema. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.
Dizziness, somnolence, loss of consciousness, confusion, and psychiatric disturbances
Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of traumatic events (falls) in elderly patients. Post-marketing reports have also described loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of the medication.
Visual disturbances
During clinical trials, blurred vision was reported more frequently among patients receiving pregabalin compared to those receiving placebo. In most cases, this effect resolved with continued treatment. In studies involving ophthalmologic examinations, the incidence of decreased visual acuity and visual field changes was higher in patients receiving pregabalin compared to placebo group patients; however, the incidence of retinal changes was higher in the placebo group.
Adverse reactions affecting the eye, including vision loss, blurred vision, or other changes in visual acuity, have been reported, many of which were transient. Discontinuation of pregabalin may lead to resolution or reduction of these ocular symptoms.
Renal impairment
Cases of renal impairment have been reported. In some instances, this effect was reversible upon discontinuation of pregabalin.
Discontinuation of concomitant antiepileptic drugs
There is insufficient data regarding the discontinuation of concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to determine whether transition to pregabalin monotherapy is feasible.
Withdrawal symptoms
Withdrawal symptoms have been observed in some patients after discontinuation of short- or long-term pregabalin treatment. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to the patient prior to initiating treatment.
Seizures, including status epilepticus and generalized convulsions, may occur during pregabalin treatment or shortly after discontinuation.
Data on withdrawal after prolonged pregabalin use indicate that the frequency and severity of withdrawal symptoms may be dose-dependent.
Heart failure
Post-marketing reports have described cases of congestive heart failure in some patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve upon discontinuation of pregabalin.
Treatment of central neuropathic pain due to spinal cord injury
During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly CNS-related reactions such as somnolence, was increased. This may be related to the additive effects of concomitant medications (e.g., antispasmodic agents) required for managing this condition. This factor should be considered when prescribing pregabalin to such patients.
Respiratory depression
Cases of severe respiratory depression associated with pregabalin use have been reported. The risk of this serious adverse reaction may be higher in patients with respiratory or neurological disorders, impaired renal function, those receiving concomitant CNS depressants, and in elderly patients. Dose adjustments may be required for such patients (see section "Dosage and administration").
Suicidal thoughts and behavior
Cases of suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude the possibility of such risk with pregabalin.
Therefore, patients should be closely monitored for signs of suicidal thoughts or behavior, and appropriate treatment should be initiated if such signs occur. Patients (and caregivers) should seek immediate medical help if symptoms of suicidal thoughts or behavior emerge.
Lower gastrointestinal tract dysfunction
Events related to lower gastrointestinal tract dysfunction (such as intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use, particularly when co-administered with medications that may cause constipation, such as opioid analgesics. Preventive measures for constipation should be implemented when pregabalin is used concomitantly with opioids (especially in women and elderly patients).
Concomitant use with opioids
Caution is recommended when prescribing pregabalin together with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case-control study of opioid users, patients receiving pregabalin in combination with an opioid had an increased risk of opioid-related mortality compared to those receiving opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), and a trend toward increased risk was also observed at higher doses (>300 mg, aOR 2.55 [95% CI 1.24–5.06]).
Abuse, misuse, or dependence
Cases of abuse, misuse, and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse. Patients should be monitored for signs of pregabalin abuse, misuse, or dependence (cases of addiction, dose escalation, and drug-seeking behavior have been reported).
Encephalopathy
Cases of encephalopathy have occurred primarily in patients with comorbid conditions that may predispose to encephalopathy.
Skin reactions
Serious skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been rarely reported with pregabalin treatment, which may be life-threatening or fatal. Patients should be informed about characteristic adverse reactions associated with the drug and monitored closely for skin reactions. If symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).
Elderly patients (aged 65 years and older)
Pregabalin clearance tends to decrease with age. This reduction in oral pregabalin clearance is consistent with the age-related decline in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin. In elderly patients, adverse reactions such as dizziness, confusion, tremor, coordination disturbances, and lethargy may occur more frequently.
Lactose intolerance
The product contains lactose monohydrate. Patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding.
Women of childbearing potential/contraception for women and men
Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the developing fetus. Pregabalin should not be used during pregnancy unless the expected benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment.
Pregnancy
Reproductive toxicity has been demonstrated in animal studies.
Pregabalin has been shown to cross the placenta in rats (see section "Pharmacological properties"). Pregabalin may cross the human placenta.
Breastfeeding period
Pregabalin is excreted in human breast milk. The effect of pregabalin on newborns/infants is unknown. Therefore, breastfeeding is not recommended during pregabalin treatment.
Fertility
There are no clinical data on the effect of pregabalin on female fertility.
In a study assessing the effect of pregabalin on sperm motility, healthy male volunteers received 600 mg pregabalin daily. After 3 months of treatment, no effect on sperm motility was observed.
Major congenital malformations
Clinical data from over 2700 pregnant women indicate that pregabalin use during the first trimester of pregnancy is associated with a slightly increased risk of major congenital malformations in infants (live or stillborn).
Analysis of specific malformations showed a higher risk of malformations of the nervous system, eyes, face (craniofacial region), urinary system, and genital organs; however, risk estimates may be imprecise due to the small number of cases and limited observation period.
Pregabalin should not be used during pregnancy unless clearly necessary (i.e., when the expected benefit to the mother clearly outweighs the potential risk to the fetus).
Effect on ability to drive and use machines.
The medicinal product may have a negligible or moderate influence on the ability to drive and operate machinery. Pregabalin may cause dizziness and somnolence and may affect the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving or operating complex machinery or engaging in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform such tasks.
Dosage and Administration
For oral use. The medicinal product can be taken independently of food intake.
Dosage
The dosage range may vary between 150–600 mg per day. The daily dose should be divided into 2 or 3 doses.
Neuropathic pain
Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into two doses. Depending on efficacy and tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, to the maximum dose of 600 mg per day after an additional 7-day interval.
Epilepsy
Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into two or three doses. Depending on efficacy and tolerability in individual patients, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be further increased to the maximum of 600 mg per day.
Generalized anxiety disorder
The daily dose, divided into 2 or 3 doses, may range from 150 to 600 mg per day. The need for continued treatment should be periodically reassessed.
Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on efficacy and tolerability in individual patients, the dose may be increased to 300 mg per day after the first week. After another week, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.
Discontinuation of pregabalin treatment
According to current clinical practice, if pregabalin treatment needs to be discontinued, it is recommended to taper the dose gradually over at least one week, regardless of the indication.
Patients with renal impairment
Pregabalin is eliminated from systemic circulation unchanged, primarily via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (CrCl), dosage reduction in patients with impaired renal function should be individualized according to creatinine clearance (CrCl), as indicated in the table and calculated using the following formula:
CrCl (mL/min) = (
Pregabalin is effectively removed from plasma by hemodialysis (approximately 50% of the drug within 4 hours). For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, a supplemental dose should be administered immediately after each 4-hour hemodialysis session (see table).
Pregabalin dosage adjustment according to renal function
| Creatinine clearance (mL/min) |
Total daily dose of pregabalin * |
Dosing regimen |
|
| Initial dose (mg/day) |
Maximum dose (mg/day) |
||
| ≥ 60 |
150 |
600 |
2-3 times daily |
| ≥30 – <60 |
75 |
300 |
2-3 times daily |
| ≥15 – <30 |
25-50 |
150 |
1-2 times daily |
| < 15 |
25 |
75 |
Once daily |
| Additional dose after hemodialysis (mg) |
|||
| 25 |
100 |
Single dose |
|
*The total daily dose (mg/day) should be divided into the number of doses according to the dosing regimen in order to obtain mg/dose.
Patients with hepatic impairment
Dose adjustment is not required for patients with hepatic impairment (see section "Pharmacokinetics").
Use in elderly patients (aged 65 years and older)
In elderly patients, dose reduction of pregabalin may be required due to decreased renal function (see section "Special precautions").
Children.
The safety and efficacy of the drug in children (under 18 years of age) have not been established. Available information is presented in section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokinetics", however, based on this information, no dosing recommendations can be provided for this patient population.
Overdose.
The most commonly reported adverse reactions in cases of pregabalin overdose were somnolence, confusion, agitation, and restlessness. Seizures have also been reported. Cases of coma have been reported rarely.
Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Method of administration and dosage", table).
Adverse Reactions
The most commonly observed adverse reactions were dizziness and somnolence.
These adverse reactions may also be related to the course of the underlying disease and/or concomitant use of other medicinal products.
During treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions increased, particularly CNS-related adverse reactions and especially somnolence (see section "Special precautions for use").
Infections and infestations: nasopharyngitis.
Blood and lymphatic system disorders: neutropenia.
Immune system disorders: hypersensitivity, angioedema, allergic reaction, anaphylactoid reactions.
Metabolism and nutrition disorders: increased appetite, loss of appetite, hypoglycemia.
Psychiatric disorders: euphoric mood, confusion, irritability, decreased libido, disorientation, insomnia, hallucinations, panic attacks, agitation, restlessness, depression, depressed mood, mood changes, depersonalization, difficulty in word finding, pathological dreams, increased libido, anorgasmia, apathy, disinhibition, elevated mood, aggression. Rarely: disinhibition, suicidal thoughts and behavior.
Nervous system disorders: dizziness, somnolence, ataxia, coordination disorder, tremor, dysarthria, memory impairment, attention disturbance, paresthesia, sedation, balance disorder, lethargy, syncope, fatigue, headache, apathy, loss of consciousness, stupor, myoclonus, psychomotor hyperactivity, ageusia, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive impairment, speech disorder, hyporeflexia, hypoesthesia, amnesia, hyperesthesia, burning sensation, perioral paresthesia, myoclonus, hypalgesia, hypokinesia, parosmia, hypokinesia, dysphagia, hypalgesia, dependence, mania, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders, loss of consciousness, psychiatric disorders, convulsions, malaise, parkinsonism.
Eye disorders: blurred vision, diplopia, conjunctivitis, visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, dry eyes, increased lacrimation, accommodation disorder, blepharitis, subconjunctival hemorrhage, photophobia, retinal edema, peripheral vision loss, oscillopsia, altered depth perception, photopsia, eye irritation, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, extraocular muscle paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis, vision loss, keratitis.
Ear and labyrinth disorders: vertigo, hyperacusis.
Cardiac disorders: tachycardia, first-degree atrioventricular block, sinus tachycardia, sinus bradycardia, sinus arrhythmia, congestive heart failure, QT interval prolongation, flushing, hyperemia, arterial hypotension, arterial hypertension, cold sensation in extremities.
Respiratory, thoracic and mediastinal disorders: dyspnea, dryness of nasal mucosa, epistaxis, throat tightness, cough, nasal congestion, rhinitis, snoring, laryngospasm, pharyngolaryngeal pain, apnea, atelectasis, bronchiolitis, hiccup, pulmonary fibrosis, yawning, pulmonary edema, respiratory depression.
Gastrointestinal disorders: vomiting, dry mouth, constipation, flatulence, gastroenteritis, abdominal distension, gastroesophageal reflux disease, excessive salivation, oral hypoesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding, ascites, pancreatitis, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscesses, tongue swelling, diarrhea, nausea.
Hepatobiliary disorders: elevated liver enzymes (increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), jaundice, hepatic failure, hepatitis.
Skin and subcutaneous tissue disorders: papular rash, hyperhidrosis, pressure ulcers, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash, urticaria, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules, Stevens-Johnson syndrome, pruritus, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: muscle spasms, joint swelling, muscle cramps, myalgia, arthralgia, back pain, limb pain, muscle rigidity, rhabdomyolysis, muscle twitching, cervical spasm, neck pain, muscle stiffness.
Renal and urinary disorders: urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis, renal failure, oliguria, acute renal failure, glomerulonephritis, pyelonephritis, urinary retention.
Reproductive system and breast disorders: erectile dysfunction, impotence, ejaculation delay, sexual dysfunction, leukorrhea, menorrhagia, metrorrhagia, amenorrhea, galactorrhea, breast pain, dysmenorrhea, breast enlargement, cervicitis, balanitis, epididymitis, gynecomastia, leukorrhea.
General disorders and administration site conditions: gait disturbance, feeling drunk, increased fatigue, peripheral edema, unusual feelings, edema, falls, chest tightness, general weakness, thirst sensation, pain, hot flushes, malaise, chills, abscess, cellulitis, photosensitivity reactions, generalized edema, increased body temperature, anaphylactoid reactions, granuloma, self-harm, retroperitoneal fibrosis, shock, facial edema.
Investigations: weight gain, increased blood creatine phosphokinase, decreased platelet count, increased blood glucose, decreased blood potassium, decreased blood leukocyte count, increased blood creatinine, weight loss.
Withdrawal symptoms have been observed in some patients after discontinuation of short- or long-term pregabalin treatment. Reported events include insomnia, headache, nausea, anxiety, diarrhea, influenza-like syndrome, nervousness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to the patient prior to starting treatment.
Data on pregabalin discontinuation after long-term use indicate that the frequency and severity of withdrawal symptoms may depend on the dose.
Pediatric population. The safety profile of pregabalin established in four studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n=295; a 14-day efficacy and safety study in patients aged 1 month to 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and a 1-year open-label safety study, n=54) was similar to that observed in studies in adult patients with epilepsy. The most common adverse events observed in the 12-week pregabalin therapy study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most common adverse events observed in the 14-day pregabalin therapy study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and administration").
Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine.
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging.
Keep out of reach of children.
Packaging.
10 capsules per strip, 3 or 6 strips per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
San Pharmaceutical Industries Ltd.
Manufacturer's address and place of business.
Survey No. 214, Plot No. 20, Gavt. Indl. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.