Pregabio®
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pregabio® (Pregabio®)
Composition:
Active ingredient: pregabalin;
1 capsule contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg or 300 mg of pregabalin;
Excipients: pregelatinized starch, talc;
capsule shell: gelatin, titanium dioxide (E 171), black iron oxide\textsuperscript{1} (E 172), yellow iron oxide\textsuperscript{2} (E 172), red iron oxide\textsuperscript{3} (E 172); black printing ink\textsuperscript{4}: shellac, black iron oxide (E 172), propylene glycol; white printing ink\textsuperscript{5}: shellac, propylene glycol, potassium hydroxide, titanium dioxide (E 171).
\textsuperscript{1} for 200 mg, 225 mg, 300 mg capsules;
\textsuperscript{2} for 50 mg, 75 mg, 150 mg, 200 mg, 225 mg, 300 mg capsules;
\textsuperscript{3} for 100 mg, 150 mg, 200 mg, 225 mg, 300 mg capsules;
\textsuperscript{4} for 25 mg, 50 mg, 75 mg, 150 mg, 200 mg, 225 mg capsules;
\textsuperscript{5} for 100 mg, 300 mg capsules.
Pharmaceutical form. Capsules.
Main physicochemical properties:
- 25 mg capsules: hard gelatin capsules. Capsule body white, capsule cap white. On the cap, "P25" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 4;
- 50 mg capsules: hard gelatin capsules. Capsule body white, capsule cap bright yellow. On the cap, "P50" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 3;
- 75 mg capsules: hard gelatin capsules. Capsule body brownish-yellow, capsule cap brownish-yellow. On the cap, "P75" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 4;
- 100 mg capsules: hard gelatin capsules. Capsule body reddish-brown, capsule cap reddish-brown. On the cap, "P100" printed in white ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 3;
- 150 mg capsules: hard gelatin capsules. Capsule body white, capsule cap yellowish-brown. On the cap, "P150" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 2;
- 200 mg capsules: hard gelatin capsules. Capsule body brown, capsule cap brown. On the cap, "P200" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 1;
- 225 mg capsules: hard gelatin capsules. Capsule body white, capsule cap brown. On the cap, "P225" printed in black ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 1;
- 300 mg capsules: hard gelatin capsules. Capsule body white, capsule cap dark brown. On the cap, "P300" printed in white ink. The capsule contains a powder ranging from white to almost white. Capsule size No. 0.
Pharmacotherapeutic group. Agents acting on the nervous system. Analgesics. Other analgesics and antipyretics. Gabapentinoids. Gabapentin. Pregabalin. ATC code N02BF02.
Pharmacological Properties.
Pharmacodynamics.
The active substance, pregabalin, is a structural analogue of gamma-aminobutyric acid [(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 studies for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of pregabalin in other types of neuropathic pain has not been studied.
Pregabalin was evaluated in 10 controlled clinical trials lasting up to 13 weeks with a twice-daily dosing regimen and in trials lasting up to 8 weeks with a three-times-daily regimen. Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.
In clinical trials lasting up to 12 weeks, in which the drug was used for the treatment of neuropathic pain, reduction in both peripheral and central pain was observed after the first week and persisted throughout the treatment period.
In controlled clinical trials of peripheral neuropathic pain, a 50% improvement on the pain rating scale was observed in 35% of patients receiving pregabalin and in 18% of patients receiving placebo. Among patients who did not experience somnolence, such improvement was observed in 33% of patients receiving pregabalin and in 18% of placebo-treated 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 rating scale was observed in 22% of patients receiving pregabalin and in 7% of patients receiving placebo.
Epilepsy.
Adjunctive therapy.
Pregabalin was studied in three controlled clinical trials lasting 12 weeks with twice-daily or three-times-daily dosing regimens. Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.
Reduction in seizure frequency was observed as early as 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 observed in adults. Results from a 12-week placebo-controlled study involving 295 children aged 4 to 16 years and a 14-day placebo-controlled study involving 175 children aged 1 month to less than 4 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety studies of 1 year duration involving 54 and 431 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 "Posology and method of administration", "Adverse reactions", and "Pharmacokinetics").
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. At least a 50% reduction in partial seizures from baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 vs placebo), 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.2600 vs placebo), and 22.6% of those receiving placebo.
In the 14-day placebo-controlled study, children (aged 1 month to less than 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 7 mg/kg/day; 5.4 and 1.4 for pregabalin 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.
In a 12-week placebo-controlled study of patients with primary generalized tonic-clonic (PGTC) seizures, 219 patients aged 5 to 65 years (including 66 patients aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. At least a 50% reduction in PGTC seizure frequency was observed in 41.3%, 38.9%, and 41.7% of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 10 mg/kg/day, and placebo, respectively.
Monotherapy (in patients with newly diagnosed disease).
Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a twice-daily dosing regimen. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, 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, as measured by 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 in 38% of patients receiving placebo.
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 dilated fundus examination) 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 in 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of placebo-treated patients. Fundus changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.
Fibromyalgia.
The efficacy of pregabalin was established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). Patients enrolled in these trials had a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting ≥3 months and pain present in 11 or more of 18 specific tender points). The trials demonstrated a reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and fibromyalgia impact questionnaire.
Children. A placebo-controlled 15-week trial was conducted in 107 children aged 12–17 years with fibromyalgia who received pregabalin at doses of 75–450 mg/day. The primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed numerically greater improvement in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most common adverse reactions observed in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.
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 after oral administration on an empty stomach and reaches peak plasma concentrations within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is dose-independent. Steady-state concentrations are achieved within 24–48 hours after repeated administration. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% decrease in maximum concentration (Cmax) and an increase in tmax to approximately 2.5 hours. However, coadministration with food does not have a clinically significant effect on the extent of absorption.
Distribution.
Preclinical studies demonstrated that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. Pregabalin was shown to cross 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 unchanged in urine. The N-methylated derivative of pregabalin—the main metabolite detected in urine—accounted for 0.9% of the administered dose. Preclinical studies showed no racemization of the S-enantiomer of pregabalin to the R-enantiomer.
Excretion.
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").
Dosage adjustment is required for patients with renal impairment or patients undergoing hemodialysis (see section "Posology and method of administration", Table 1).
Linearity/Non-linearity.
The pharmacokinetics of pregabalin are linear across the entire recommended dose range. Inter-patient variability in pregabalin pharmacokinetics is low (<20%). Pharmacokinetics after multiple doses are predictable based on single-dose data. Therefore, routine monitoring of plasma concentrations of pregabalin is not necessary.
Gender.
Clinical study results indicate no clinically significant effect of gender on plasma concentrations of pregabalin.
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 concentrations of pregabalin decrease by approximately 50%). Since the drug is primarily eliminated by the kidneys, dosage reduction is required in patients with renal impairment, and supplemental dosing is needed after hemodialysis (see section "Posology and method of administration", Table 1).
Hepatic impairment.
Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted predominantly unchanged in urine, hepatic impairment is unlikely to have a significant effect on plasma concentrations of pregabalin.
Children.
The pharmacokinetics of pregabalin 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, 5, 10, and 15 mg/kg/day in a pharmacokinetic and tolerability study.
After oral administration of pregabalin to children under fasting conditions, the time to reach peak plasma concentration (tmax) was generally similar across all age groups, ranging from 0.5 to 2 hours post-dose.
Cmax and area under the concentration-time curve (AUC) of pregabalin increased linearly with dose in each age group. In children with body weight less than 30 kg, AUC values were 30% lower, due to a 43% higher creatinine clearance-adjusted body weight-corrected clearance 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.
Population pharmacokinetic analysis demonstrated that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, with this relationship being similar in children and adult patients.
The pharmacokinetics of pregabalin in patients under 3 months of age have not been studied (see sections "Posology and method of administration", "Adverse reactions", and "Pharmacodynamics").
Elderly patients.
Pregabalin clearance tends to decrease with age. This age-related decrease 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 (see section "Posology and method of administration", Table 1).
Lactation.
The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women who received pregabalin 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks postpartum. Breastfeeding had no effect or only a minimal effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations in breast milk being approximately 76% of maternal plasma concentrations. The calculated dose received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or 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 mother's total daily dose, normalized to mg/kg.
Clinical characteristics.
Indications.
Neuropathic pain.
Treatment of neuropathic pain in adults associated with peripheral and central nervous system damage.
Epilepsy.
Adjunctive therapy for partial seizures with or without secondary generalization in adults.
Generalized anxiety disorder.
Treatment of generalized anxiety disorder in adults.
Fibromyalgia.
Treatment of fibromyalgia in adults.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
Interaction with other medicinal products and other forms of interaction.
Since pregabalin is predominantly excreted unchanged in urine, undergoes minimal metabolism in humans (≤ 2% of the dose is excreted in urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin may cause or be subject to pharmacokinetic interactions.
In vivo studies and population pharmacokinetic analysis.
Thus, in 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 demonstrated that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no 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. During post-marketing surveillance, cases of respiratory depression, coma, and death have been reported in patients who received pregabalin concomitantly with opioids and/or other centrally acting depressant drugs. Pregabalin is likely to enhance cognitive and basic motor function impairment caused by oxycodone.
Interactions in elderly patients.
No specific pharmacodynamic interaction studies involving elderly volunteers have been conducted. Drug interaction studies have been performed only in adult patients.
Special precautions for use.
Patients with diabetes
According to current clinical practice, some diabetic patients whose body weight has increased during pregabalin therapy may require adjustment of antidiabetic drug doses.
Hypersensitivity reactions
Post-marketing reports have described 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.
Severe cutaneous adverse reactions (SCARs)
Rare cases of SCARs, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with pregabalin treatment. These reactions may be life-threatening or fatal. When prescribing pregabalin, patients should be informed about the signs and symptoms of such reactions, and closely monitored for their occurrence. If signs or symptoms suggestive of these reactions appear, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).
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 (e.g., falls) in elderly patients. Post-marketing reports have also described cases of loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.
Visual disorders
During controlled clinical trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. In clinical studies involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").
Post-marketing reports have also described ocular adverse reactions, including vision loss, blurred vision, or other changes in visual acuity, many of which were transient. These ocular symptoms may resolve or diminish after discontinuation of pregabalin.
Renal impairment
Cases of renal impairment, sometimes reversible after discontinuation of pregabalin, have been reported.
Discontinuation of concomitant antiepileptic drugs
There is insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin to the treatment regimen, to switch to pregabalin monotherapy.
Withdrawal symptoms
Withdrawal symptoms have been observed in some patients after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, pain, seizures, hyperhidrosis, and dizziness, indicating physical dependence. This information should be communicated to patients prior to initiating therapy.
Seizures, including status epilepticus and generalized seizures, may occur during pregabalin therapy or shortly after its discontinuation.
Data on withdrawal after long-term pregabalin use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.
Heart failure
Post-marketing reports have described cases of heart failure in some patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with pre-existing 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
When treating central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system and especially somnolence, increased. This may be related to additive effects of concomitant medications (e.g., antispastic agents) required for managing this condition. This factor should be considered when prescribing pregabalin for this indication.
Respiratory depression
Cases of severe respiratory depression have been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients may be at greater risk of this serious adverse reaction. Dose adjustment may be required for these patients.
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 data from 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. Cases of suicidal thoughts and behavior have been observed in patients receiving pregabalin during the post-marketing period (see section "Adverse reactions"). An epidemiological study using a self-controlled case series design (comparing treatment periods with non-treatment periods within individuals) demonstrated an increased risk of new-onset suicidal behavior and suicide death in patients receiving pregabalin.
If signs of suicidal thoughts or behavior emerge, patients (and caregivers) should seek immediate medical help. Patients should be monitored for signs of suicidal thoughts and behavior, and appropriate treatment considered. If suicidal ideation or behavior occurs, discontinuation of pregabalin therapy should be considered.
Worsening of lower gastrointestinal tract function
Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) when pregabalin was used concomitantly with medications that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be taken (especially in women and elderly patients).
Concomitant use with opioids
Caution is recommended when prescribing pregabalin concomitantly 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, an increased risk of opioid-related mortality was observed in patients receiving pregabalin concomitantly with an opioid 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]), with a trend toward higher risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).
Abuse, misuse, or dependence
Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at higher risk of pregabalin misuse, abuse, and dependence, and therefore should be treated with caution. The risk of abuse, misuse, or dependence should be carefully assessed before prescribing pregabalin.
Withdrawal symptoms
Withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The emergence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before starting treatment.
If pregabalin therapy needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").
Seizures, including status epilepticus and generalized seizures, may occur during pregabalin therapy or shortly after its discontinuation.
Data on withdrawal after long-term pregabalin use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.
Encephalopathy
Cases of encephalopathy have been reported, primarily in patients with comorbid conditions that may predispose to encephalopathy.
Women of childbearing potential / Contraception
Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy except when the benefit to the pregnant woman clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Use during pregnancy or breastfeeding").
Use during pregnancy or breastfeeding.
Women of childbearing potential / Contraception
Women of childbearing potential should use effective contraception (see section "Special precautions for use").
Pregnancy
Animal studies have demonstrated reproductive toxicity.
Pregabalin has been shown to cross the placenta in rats (see section "Pharmacokinetics"). Pregabalin may cross the human placenta.
Major congenital malformations
Data from a Scandinavian observational study of over 2700 pregnancies exposed to pregabalin during the first trimester showed a higher prevalence of major congenital malformations (MCMs) in children (live or stillbirths) born to mothers who received pregabalin compared to unexposed populations (5.9% vs. 4.1%).
The risk of MCMs in children whose mothers received pregabalin during the first trimester was slightly higher compared to children of unexposed mothers (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96–1.35)), and also compared to children whose mothers received lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).
Analysis of specific malformations showed higher risks for nervous system malformations, eye malformations, orofacial clefts, genitourinary malformations, but numbers were small and estimates imprecise.
Pregabalin should not be used during pregnancy except in cases of extreme necessity (i.e., when benefit to the pregnant woman clearly outweighs the potential risk to the fetus).
Breastfeeding
A small amount of pregabalin has been detected in human breast milk. Women who are breastfeeding should be advised that breastfeeding is not recommended during pregabalin treatment.
Fertility
Clinical data on the effect of pregabalin on female fertility are lacking.
In a clinical study assessing the effect of pregabalin on sperm motility in healthy male volunteers, pregabalin was administered at a dose of 600 mg/day. After 3 months of treatment, no effect on sperm motility was observed.
In fertility studies in female rats, adverse effects on reproductive function were observed. In fertility studies in male rats, adverse effects on reproductive function and development were observed. The clinical relevance of these findings is unknown.
Effect on ability to drive and use machines.
Pragabio® may have a minor or moderate effect on the ability to drive and operate machinery. Pragabio® may cause dizziness and somnolence, and thus may impair the ability to drive and operate machinery. Therefore, patients should be advised to avoid driving, operating complex machinery, or engaging in other potentially hazardous activities until they know how this medicinal product affects them.
Dosage and Administration.
Route of administration.
Prigabio® is taken independently of food intake.
This medicinal product is intended for oral use only.
Doses.
The dose range of the drug 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 2 or 3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg per day after 3–7 days, and if necessary, to the maximum dose of 600 mg per day after another 7 days.
Epilepsy.
Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be increased to the maximum of 600 mg per day.
Generalized anxiety disorder.
The daily dose, divided into 2 or 3 doses, may range from 150–600 mg per day. The necessity of continuing treatment should be periodically reassessed.
Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose may be increased to 450 mg per day. Following an additional week, the dose may be increased to the maximum of 600 mg per day.
Fibromyalgia.
The recommended dose of the drug for the treatment of fibromyalgia ranges from 300 to 450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has evaluated a dose of 600 mg per day, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Given the dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since Prigabio® is primarily eliminated by the kidneys, dosage adjustment is required in patients with renal impairment.
Discontinuation of pregabalin.
According to current clinical practice, discontinuation of pregabalin therapy should be gradual and take at least one week, regardless of the indication (see sections "Special instructions" and "Adverse reactions").
Renal impairment.
Pregabalin is eliminated from systemic circulation in unchanged form, primarily via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage in patients with renal impairment should be individually adjusted according to creatinine clearance (CLcr), as shown in the table below, calculated using the formula:
Pregabalin is effectively removed from plasma by hemodialysis (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 of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).
Table 1
Dosage adjustment of pregabalin according to renal function
| Creatinine clearance (CLcr), (mL/min) |
Total daily dose of pregabalin * |
Dosing regimen |
|
| Initial dose (mg/day) |
Maximum dose (mg/day) |
||
| ≥ 60 |
150 |
600 |
Twice or three times daily |
| ≥30 - <60 |
75 |
300 |
Twice or three times daily |
| ≥15 - <30 |
25–50 |
150 |
Once or twice 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 several doses according to the dosing regimen to obtain the single dose (mg/dose).
- Additional dose means an extra single dose.
Hepatic impairment.
Dose adjustment is not required for patients with impaired liver function (see section "Pharmacokinetics").
Elderly patients.
For elderly patients, dose reduction of pregabalin may be necessary due to impaired renal function (see section "Pharmacokinetics").
Children.
The safety and efficacy of Pregabio® in children (under 18 years of age) have not been established. Currently available information is presented in the section "Adverse reactions" and in the sections "Pharmacodynamics" and "Pharmacokinetics", however, based on this information, no dosing recommendations can be provided for this patient population.
Overdose.
Following marketing of the drug, the most commonly reported adverse reactions in cases of pregabalin overdose were somnolence, confusion, agitation, and restlessness. Seizures have also been reported.
Coma has been reported rarely.
Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Dosage and administration", Table 1).
Adverse reactions
In the clinical development program for pregabalin, more than 8900 patients received the drug, of whom 5600 were participants in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally of mild or moderate severity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of study medication in the pregabalin group were dizziness and somnolence.
Table 2 lists all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in descending order of severity.
The reported adverse reactions may also be related to 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 warnings and precautions for use").
Additional adverse reactions reported after pregabalin marketing are listed below and indicated in italics.
Table 2
| System Organ Classes |
Adverse Reactions to Pregabalin |
| 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 Nutrition Disorders |
|
| Common |
Increased appetite |
| Uncommon |
Loss of appetite, hypoglycemia |
| Psychiatric Disorders |
|
| Common |
Euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido |
| Uncommon |
Hallucinations, panic attacks, restlessness, excitement, depression, depressed mood, elevated mood, aggression, mood swings, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy |
| Rare |
Disinhibition, suicidal behavior, suicidal thoughts |
| Frequency not known |
Drug dependence |
| Nervous System Disorders |
|
| Very common |
Dizziness, somnolence, headache |
| Common |
Ataxia, coordination impairment, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedation, balance disorder, lethargy |
| Uncommon |
Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, psychiatric disorders, speech disorders, hyporeflexia, hyperesthesia, burning sensation, allgeisia, malaise, apathy, perioral paresthesia, myoclonus |
| Rare |
Seizures, parosmia, hypokinesia, dysphagia, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders, parkinsonism |
| Eye Disorders |
|
| Common |
Blurred vision, diplopia, conjunctivitis |
| Uncommon |
Peripheral vision loss, visual disturbance, eye swelling, visual field defects, reduced visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, eye hemorrhage, photophobia, retinal edema |
| Rare |
Loss of vision, keratitis, oscillopsia, change in visual depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, oculomotor paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis |
| Ear and Labyrinth Disorders |
|
| Common |
Vertigo |
| Uncommon |
Hyperacusis |
| Cardiac Disorders |
|
| Uncommon |
Tachycardia, first-degree atrioventricular block, sinus bradycardia, congestive heart failure |
| Rare |
QT interval prolongation, sinus tachycardia, sinus arrhythmia |
| Vascular Disorders |
|
| Uncommon |
Arterial hypotension, arterial hypertension, flushing, hyperemia, feeling of cold in extremities |
| Respiratory, Thoracic and Mediastinal Disorders |
|
| Common |
Pharyngolaryngeal pain |
| Uncommon |
Dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dryness of nasal mucosa |
| Rare |
Pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccup, pulmonary fibrosis, yawning |
| Frequency not known |
Respiratory depression |
| Gastrointestinal Disorders |
|
| Common |
Vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis |
| Uncommon |
Gastroesophageal reflux disease, hypersalivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding |
| Rare |
Ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess |
| Hepatobiliary Disorders |
|
| Uncommon |
Elevated liver enzymes* |
| Rare |
Jaundice |
| Very rare |
Liver failure, hepatitis |
| Skin and Subcutaneous Tissue Disorders |
|
| Common |
Pressure ulcers |
| Uncommon |
Papular rash, urticaria, hyperhidrosis, pruritus, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash |
| Rare |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules |
| Musculoskeletal and Connective Tissue Disorders |
|
| Common |
Muscle spasms, arthralgia, back pain, limb pain, neck muscle spasms |
| Uncommon |
Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness |
| Rare |
Rhabdomyolysis |
| Renal and Urinary 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 delay, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia |
| Rare |
Amenorrhea, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis |
| General Disorders and Administration Site Conditions |
|
| Common |
Peripheral edema, edema, gait disturbance, fall, feeling of intoxication, unusual sensations, increased fatigue |
| Uncommon |
Generalized edema, facial swelling, chest tightness, pain, warmth, thirst, chills, generalized weakness, malaise, abscess, fat tissue inflammation, photosensitivity reactions |
| Rare |
Granuloma, self-harm, retroperitoneal fibrosis, shock |
| Investigations |
|
| Common |
Weight increased |
| Uncommon |
Increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight decreased |
| Rare |
Decreased blood leukocyte count |
* Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Symptoms of drug withdrawal have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness. These symptoms may indicate drug dependence. This information should be communicated to the patient prior to initiating therapy. Data on pregabalin discontinuation after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").
Children.
The safety profile of pregabalin established in five 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 less than 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and two open-label, one-year safety studies, n=54 and n=431) was similar to the profile observed in clinical trials in adult patients with epilepsy. The most commonly reported adverse reactions in the 12-week pregabalin therapy study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most commonly reported adverse reactions in the 14-day pregabalin therapy study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Dosage and Administration", "Pharmacodynamics", and "Pharmacokinetics").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.
Packaging.
14 capsules in a blister; 1, 2, or 6 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer. KRKA, d.d., Novo mesto /KRKA, d.d., Novo mesto.
Manufacturer's address and place of business.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.