Ogranía®
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OGRANIA® (OGRANIA)
Composition:
Active substance: pregabalin;
1 capsule contains 75 mg, 150 mg, or 300 mg of pregabalin;
Excipients: lactose monohydrate; maize starch; microcrystalline cellulose; talc;
capsule shell composition for 75 mg: gelatin, iron oxide red (E 172), titanium dioxide (E 171);
capsule shell composition for 150 mg: gelatin, azorubine, carmoisine (E 122), iron oxide black (E 172), iron oxide red (E 172), titanium dioxide (E 171);
capsule shell composition for 300 mg: gelatin, azorubine, carmoisine (E 122), indigo carmine (E 132), titanium dioxide (E 171).
Pharmaceutical form. Capsules.
Main physicochemical properties:
75 mg capsules: hard gelatin capsule, cylindrical in shape, cap and body light pink in color. The capsule contents – white to almost white powder;
150 mg capsules: hard gelatin capsule, cylindrical in shape, cap pink in color, body white in color. The capsule contents – white to almost white powder;
300 mg capsules: hard gelatin capsule, cylindrical in shape, cap brown-red in color, body white in color. The capsule contents – white to almost white powder.
Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptics. ATC code N03AX16.
Pharmacological properties.
Pharmacodynamics.
The active substance pregabalin 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.
Clinical efficacy and safety
Neuropathic pain
Pregabalin is effective in the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of the drug has not been studied in other types of neuropathic pain.
Pregabalin was studied in 10 controlled clinical trials of up to 13 weeks' duration with a twice-daily dosing regimen and in trials of 8 weeks' duration with a three-times-daily dosing regimen. Overall, the safety profile and efficacy for twice- or three-times-daily dosing regimens were similar.
In clinical trials of up to 12 weeks' duration, when pregabalin was used to treat neuropathic pain associated with peripheral and central nervous system (CNS) injury, pain reduction was observed after the first week and persisted throughout the treatment period.
In controlled clinical trials studying peripheral neuropathic pain, 35 % of patients receiving pregabalin and 18 % of patients in the placebo group experienced a 50 % improvement on the pain rating scale. Among patients who did not experience somnolence, such improvement was observed in 33 % of patients receiving pregabalin and 18 % of patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48 % in the pregabalin group and 16 % in the placebo group.
In controlled clinical trials studying central neuropathic pain, a 50 % improvement on the pain rating scale was observed in 22 % of patients receiving pregabalin and in 7 % of patients in the placebo group.
Epilepsy
Adjunctive therapy
Pregabalin was studied in three controlled clinical trials of 12 weeks' duration with a dosing regimen of twice or three times daily. Overall, the safety profile and efficacy for twice- and three-times-daily dosing regimens were similar.
A reduction in seizure frequency was observed during the first week.
Children. The efficacy and safety of pregabalin as adjunctive therapy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study including 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 and a 14-day placebo-controlled study involving 175 children aged 1 month to under 4 years, designed to evaluate 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) were administered 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), 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 under 4 years) were administered 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.
Monotherapy (for patients with newly diagnosed disease)
Pregabalin was studied in one controlled clinical trial of 56 weeks' duration with a twice-daily dosing regimen. Pregabalin did not achieve greater efficacy compared to lamotrigine, based on assessment at 6 months of the primary endpoint—seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.
Generalized anxiety disorder
Pregabalin was studied in six controlled trials of 4–6 weeks' duration, one 8-week trial involving elderly patients, and one long-term relapse prevention study with a 6-month double-blind phase.
Improvement in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed during the first week of treatment.
In controlled clinical trials (4–8 weeks' duration), a ≥50 % improvement in total HAM-A score from baseline to endpoint was observed in 52 % of patients receiving pregabalin and in 38 % of patients in the placebo group.
During controlled trials, blurred vision was reported more frequently by patients receiving pregabalin compared to those receiving placebo. In most cases, this effect resolved with continued drug use. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients during controlled clinical trials. Among these patients, visual acuity worsened in 6.5 % of patients receiving pregabalin and in 4.8 % of patients in the placebo group. Visual field changes were detected in 12.4 % of patients receiving pregabalin and in 11.7 % of patients in the placebo group. Fundus changes were detected 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 with a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain present in 11 or more of 18 specific tender points) were enrolled in these trials. The trials demonstrated a reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global assessment and fibromyalgia impact questionnaire.
Children. A 15-week placebo-controlled study 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 commonly observed adverse reactions 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 when administered on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single and multiple doses. The estimated bioavailability of pregabalin after oral administration is 90 % or greater and is dose-independent. Steady-state concentrations are achieved within 24–48 hours after multiple dosing. The absorption rate of pregabalin is reduced when administered with food, resulting in approximately a 25–30 % reduction in Cmax and a prolongation of time to reach maximum concentration (tmax) by approximately 2.5 hours. However, administration of pregabalin with food did not have a clinically significant effect on the extent of absorption.
Distribution
Preclinical studies showed that pregabalin crosses the blood-brain barrier in rats, mice, and monkeys. Pregabalin also crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the apparent 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 radioactivity is excreted in urine as unchanged pregabalin. The N-methylated derivative of pregabalin—the main metabolite detected in urine—accounted for 0.9 % of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer was not observed during preclinical studies.
Elimination
Pregabalin is eliminated from systemic circulation unchanged primarily via renal excretion. 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 on hemodialysis (see section "Dosage and administration", Table 1).
Linearity/non-linearity
The pharmacokinetics of pregabalin are linear over the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (less than 20 %). Multiple-dose pharmacokinetics are predictable based on data obtained after single-dose administration. Therefore, routine monitoring of plasma pregabalin concentrations 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 pregabalin concentration decreases by approximately 50 %). Since renal excretion is the main elimination pathway of the drug, dosage reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and 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, it is unlikely that hepatic impairment would significantly affect 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 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, time to reach Cmax was generally similar across all age groups, ranging from 0.5 to 2 hours after administration.
Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with increasing dose in each age group. In children with body weight below 30 kg, AUC values were 30 % lower, due to a 43 % increase in body weight-adjusted clearance in these patients compared to patients with body weight ≥ 30 kg.
The terminal elimination half-life of pregabalin was 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.
The pharmacokinetics of pregabalin in patients under 3 months of age have not been studied (see sections "Pharmacodynamics", "Dosage and administration", and "Adverse reactions").
Elderly patients
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 renal impairment related to age may require a reduced dose of pregabalin (see section "Dosage and administration", Table 1).
Lactation period
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 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 was 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
Ogranía**®** is indicated for the treatment of neuropathic pain in adults due to damage of the peripheral and central nervous systems.
Epilepsy
Ogranía**®** is indicated as adjunctive therapy for partial seizures with or without secondary generalization in adults.
Generalized anxiety disorder
Ogranía**®** is indicated for the treatment of generalized anxiety disorder in adults.
Fibromyalgia.
Contraindications.
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 predominantly excreted unchanged in urine, undergoes minimal metabolism in the human body (less than 2% of the dose is excreted in urine as metabolites), does not inhibit in vitro metabolism of other drugs, and does not bind to plasma proteins, it is unlikely that pregabalin may cause pharmacokinetic interactions or be a subject of such interactions.
In vivo studies and population pharmacokinetic analysis
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 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 enhance the effects of ethanol and lorazepam. In controlled clinical trials, concomitant administration of multiple oral doses of pregabalin with oxycodone, lorazepam, or ethanol did not result in clinically significant effects on respiratory function. Post-marketing reports have described cases of respiratory depression, coma, and fatal outcomes in patients taking pregabalin together with other centrally acting medicinal products, particularly in patients who abused such drugs. Pregabalin is likely to potentiate cognitive and gross motor function impairment caused by oxycodone.
Interaction in elderly patients
Specific pharmacodynamic interaction studies involving elderly volunteers have not been conducted. Interaction studies have been performed only in adults.
Special precautions for use.
Patients with diabetes
Patients with diabetes who experience weight gain during pregabalin treatment may require adjustment of their antihyperglycemic medication doses.
Hypersensitivity reactions
Hypersensitivity reactions, including angioedema, have been reported. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.
Severe skin adverse reactions
Rare cases of severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with pregabalin treatment. These reactions may be life-threatening or fatal. Patients should be informed about the characteristic signs and symptoms, and skin reactions should be closely monitored. If symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment 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. Cases of loss of consciousness, confusion, and psychiatric disturbances have been reported. Patients should therefore be advised to exercise caution until they are aware of how the medication affects them.
Visual disorders
Blurred vision has been reported more frequently in patients receiving pregabalin compared to those receiving placebo. In most cases, this effect resolves with continued treatment. 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 "Pharmacological properties. Pharmacodynamics").
Adverse reactions related to 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 cases, this effect was reversible after discontinuation of pregabalin.
Discontinuation of concomitant antiepileptic drugs
There is insufficient data on the discontinuation of concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to support switching to pregabalin monotherapy.
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 patients prior to initiating treatment.
If pregabalin treatment 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 epileptic status and generalized seizures, may occur during treatment with pregabalin or shortly after discontinuation.
Data on long-term pregabalin treatment discontinuation suggest that the frequency and severity of withdrawal symptoms may depend on the dose.
Heart failure
Cases of heart failure have been reported in some patients taking pregabalin. This reaction was mostly observed during pregabalin treatment for 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., antispastic agents) required for managing this condition. This factor should be considered when prescribing pregabalin to such patients.
Respiratory depression
Cases of severe respiratory depression have been reported 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 higher risk of this serious adverse reaction. Dose adjustments may be required for these 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. Cases of suicidal thoughts and behavior have been observed in patients receiving pregabalin in 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 the same individual) demonstrated an increased risk of new-onset suicidal behavior and fatal outcomes due to suicide in patients receiving pregabalin.
Patients (and caregivers) should seek medical help if signs of suicidal thoughts or behavior occur.
Therefore, patients should be closely monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be initiated if such signs occur. Consideration should be given to discontinuing pregabalin treatment if suicidal thoughts or behavior emerge.
Lower gastrointestinal tract dysfunction
Events related to lower gastrointestinal tract dysfunction (intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use, particularly when used concomitantly with medications that may cause constipation, such as opioid analgesics. When pregabalin is used in combination with opioids, preventive measures for constipation should be implemented (especially in elderly patients and women).
Concomitant use with opioids
Pregabalin should be prescribed with caution when used 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, patients taking pregabalin with opioids had an increased risk of opioid-related death compared to those taking 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 high pregabalin doses (>300 mg, aOR 2.51 [95% CI, 1.24–5.06]).
Medication misuse, abuse, or dependence
Cases of medication misuse, abuse, and dependence have been reported. The drug should be prescribed with caution to patients with a history of substance abuse. Patients should be monitored for signs of misuse, abuse, or dependence on pregabalin (cases of dependence, dose escalation, and drug-seeking behavior have been reported).
Encephalopathy
Cases of encephalopathy occurred predominantly in patients with comorbid conditions that may predispose to encephalopathy.
Women of reproductive potential
Pregabalin use during the first trimester of pregnancy may cause serious congenital malformations (CM) in the unborn child. The medicinal product Ogranía**®** should not be used during pregnancy except in cases where the benefit to the mother clearly outweighs the potential risk to the fetus. Women of reproductive potential should use effective contraception during pregabalin treatment (see section "Pregnancy and breastfeeding").
Excipients
Ogranía**®** contains lactose monohydrate. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.
The 150 mg and 300 mg dosage forms contain azorubine and carmoisine (E 122), which may cause allergic reactions.
Use during pregnancy or breastfeeding.
Women of reproductive potential
Women of reproductive potential should use effective contraception during treatment.
Pregnancy
Animal studies have shown reproductive toxicity. Pregabalin crosses the placenta in rats.
Pregabalin may cross the human placenta.
Serious congenital malformations (CM)
Data from a Scandinavian observational study involving more than 2700 pregnant women exposed to pregabalin during the first trimester showed a higher prevalence of serious CM in children (live or stillborn) exposed to pregabalin in utero compared to the unexposed population (5.9% vs. 4.1%).
The risk of serious CM in children exposed to pregabalin during the first trimester of pregnancy was slightly higher compared to unexposed children (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96–1.35)) and compared to populations exposed to lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).
Analysis of specific CM types showed a higher risk for orofacial clefts and defects of the eye, nervous, or genitourinary systems, although the numbers were small and estimates imprecise.
Ogranía**®** should not be used during pregnancy, except in exceptional cases where the benefit to the pregnant woman clearly outweighs the potential risk to the fetus.
Breastfeeding
Pregabalin is excreted in breast milk (see section "Pharmacological properties"). The effect of pregabalin on newborns/infants is unknown. A decision should be made whether to discontinue breastfeeding or to discontinue pregabalin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Reproductive function
There are no clinical data on the effect of pregabalin on female reproductive function.
In a clinical study on the effect of pregabalin on sperm motility in healthy male volunteers, a dose of 600 mg/day of pregabalin was administered. After 3 months of treatment, no effect on sperm motility was observed.
Fertility studies demonstrated a negative effect on reproductive function in female rats and a negative effect on reproductive function and development in male rats. The clinical relevance of these findings is unknown.
Effect on ability to drive and use machines.
Ogranía**®** may have a slight or moderate influence on the ability to drive and use machines. The product may also cause dizziness and somnolence, which may affect the ability to drive vehicles and operate machinery. Patients should therefore be advised to refrain from driving, operating complex machinery, or engaging in other potentially hazardous activities until they know how this medicinal product affects their ability to perform such activities.
Method of administration and dosage.
Method of administration
Ogranía**®** can be taken independently of food intake.
Ogranía**®** is intended exclusively for oral administration.
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 in individual patients, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, up 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 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 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 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 of treatment. 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, pregabalin treatment should be discontinued gradually over at least one week, regardless of the indication (see sections «Special instructions» and «Adverse reactions»).
Patients with renal impairment
Pregabalin is eliminated from systemic circulation unchanged, primarily via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (see section «Pharmacokinetics»), dosage reduction in patients with impaired renal function should be individualized as indicated in Table 1, based on creatinine clearance (CLcr) calculated using the appropriate 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, an extra 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 |
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 |
|
* Divide the total daily dose (mg/day) by the number of doses according to the dosing regimen to obtain the mg/dose.
Fibromyalgia
The usual dose of the drug for most patients is 300–450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg/day) and may be increased, depending on efficacy and tolerability, to 150 mg twice daily (300 mg/day) within one week. For patients in whom a dose of 300 mg/day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg/day). If necessary, the dose may be further increased after one week to a maximum of 600 mg/day. There is no evidence that administration of this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Due to dose-dependent adverse reactions, doses above 450 mg/day are not recommended. Since pregabalin is primarily eliminated by the kidneys, dosage adjustment should be made in patients with renal impairment.
Patients with hepatic impairment
Dosage adjustment is not required for patients with hepatic impairment (see section "Pharmacokinetics").
Use in elderly patients (aged 65 years and older)
In elderly patients, dosage reduction of pregabalin may be required due to impaired renal function (see section "Special precautions").
Children.
The safety and efficacy of Ogranía**®** in children (under 18 years of age) have not been established. Available information to date is presented in the section "Adverse reactions" as well as in the sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosage 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. Rare cases of coma have been reported.
Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis.
Adverse reactions
In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 participants in double-blind, placebo-controlled studies. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally of mild or moderate severity. In all controlled studies, 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 in the pregabalin group were dizziness and somnolence.
Adverse reactions are listed by system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).
Within each frequency category, adverse reactions are listed in order of decreasing severity.
The listed 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 incidence of adverse reactions, CNS-related adverse reactions, and particularly somnolence, was increased (see section "Special warnings and precautions for use").
Additional adverse reactions reported post-marketing are listed below and indicated in italics.
Table 2
| System organ class |
Adverse drug reactions |
| Infections and infestations |
|
| Common |
Nasopharyngitis |
| Blood and lymphatic system disorders |
|
| Uncommon |
Neutropenia |
| Immune system disorders |
|
| Uncommon |
Hypersensitivity |
| Rare |
Angioedema, allergic reaction, anaphylactoid reactions |
| Metabolism and nutrition disorders |
|
| Common |
Increased appetite |
| Uncommon |
Loss of appetite, hypoglycemia |
| Psychiatric disorders |
|
| Common |
Euphoric mood, confusion, irritability, decreased libido, disorientation, insomnia |
| Uncommon |
Hallucinations, panic attacks, agitation, restlessness, depression, depressed mood, elevated mood, aggression, mood swings, depersonalization, difficulty in word finding, pathological dreams, increased libido, anorgasmia, apathy |
| Rare |
Disinhibition, suicidal ideation, suicidal behavior |
| Nervous system disorders |
|
| Very common |
Dizziness, somnolence, headache |
| Common |
Ataxia, coordination disorder, tremor, dysarthria, memory impairment, attention disturbance, paresthesia, sedation, balance disorder, lethargy, amnesia, hypesthesia |
| Uncommon |
Loss of consciousness, syncope, stupor, myoclonus, psychomotor hyperactivity, ageusia, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, speech disorders, hyporeflexia, hyperesthesia, burning sensation, perioral paresthesia, myoclonus, psychiatric disturbance, malaise, apathy |
| Rare |
Hypokinesia, parosmia, dysgraphia, dependence, manic reactions, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain–Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders, hypalgesia, convulsions, parkinsonism |
| Eye disorders |
|
| Common |
Blurred vision, diplopia, conjunctivitis |
| Uncommon |
Visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, dry eyes, increased lacrimation, accommodation disorder, blepharitis, ocular hemorrhage, photophobia, retinal edema, photopsia, peripheral vision loss, eye irritation |
| Rare |
Loss of vision, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulceration, exophthalmos, extraocular muscle 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 |
Sinus tachycardia, sinus arrhythmia, prolonged QT interval |
| Vascular disorders |
|
| Uncommon |
Flushing, hot flushes, arterial hypotension, arterial hypertension, cold sensation in extremities |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
Pharyngolaryngeal pain |
| Uncommon |
Dyspnea, dryness of nasal mucosa, epistaxis, cough, nasal congestion, snoring, rhinitis |
| Rare |
Pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning |
| Frequency unknown |
Respiratory depression |
| Gastrointestinal disorders |
|
| Common |
Vomiting, nausea, dry mouth, constipation, flatulence, gastroenteritis, abdominal distension, diarrhea |
| Uncommon |
Gastroesophageal reflux disease, excessive salivation, oral hypesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, rectal bleeding |
| Rare |
Ascites, pancreatitis, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscesses, tongue swelling |
| Hepatobiliary disorders |
|
| Uncommon |
Elevated liver enzymes (increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) |
| Rare |
Jaundice |
| Very rare |
Liver failure, hepatitis |
| Skin and subcutaneous tissue disorders |
|
| Common |
Pressure ulcers |
| Uncommon |
Papular rash, hyperhidrosis, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash, pruritus, urticaria |
| Rare |
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, toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders |
|
| Common |
Muscle spasms, arthralgia, back pain, limb pain, neck muscle spasms |
| Uncommon |
Myoclonic jerks, joint swelling, myalgia, muscle rigidity, neck pain |
| Rare |
Rhabdomyolysis |
| Renal and urinary disorders |
|
| Uncommon |
Urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis |
| Rare |
Renal failure, oliguria, acute renal failure, glomerulonephritis, pyelonephritis, urinary retention |
| Reproductive system and breast disorders |
|
| Common |
Erectile dysfunction, impotence |
| Uncommon |
Ejaculation delayed, sexual dysfunction, leukorrhea, menorrhagia, metrorrhagia, dysmenorrhea, breast pain |
| Rare |
Amenorrhea, galactorrhea, breast enlargement, cervicitis, balanitis, epididymitis, gynecomastia |
| General disorders and administration site conditions |
|
| Common |
Gait disturbance, feeling drunk, increased fatigue, peripheral edema, edema, unusual sensations, falls |
| Uncommon |
Chest tightness, general weakness, thirst, pain, malaise, chills, abscess, photosensitivity reactions, generalized edema, facial swelling, panniculitis |
| Rare |
Granuloma, self-harm, retroperitoneal fibrosis, shock |
| Investigations |
|
| Common |
Weight increased |
| Uncommon |
Elevated blood creatine phosphokinase, decreased platelet count, elevated blood glucose, decreased blood potassium, weight decreased, elevated blood creatinine |
| Rare |
Decreased blood leukocyte count |
In some patients, withdrawal symptoms have been observed after discontinuation of short- or long-term pregabalin treatment. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to the patient prior to initiating treatment.
Regarding discontinuation of long-term pregabalin therapy, available data indicate that the frequency and severity of withdrawal symptoms may be dose-dependent.
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 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and two open-label 1-year safety studies, n=54 and n=431) was similar to that observed in adult epilepsy studies. The most commonly reported adverse reactions in the 12-week pregabalin treatment 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 treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections “Pharmacodynamics”, “Pharmacokinetics”, and “Dosage and administration”).
Reporting suspected adverse reactions. Reporting of suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product.
Shelf life. 3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions. Store in the original packaging at a temperature not exceeding 25°C.
Keep out of the reach and sight of children.
Packaging. 75 mg capsules: 7 capsules per blister; 2 blisters per carton.
150 mg and 300 mg capsules: 10 capsules per blister; 3 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Farmak".
Manufacturer's name and address of the place of business.
74 Kyrylivska Street, Kyiv, 04080, Ukraine