Nervica 25/Nervica 75/Nervica 150

Nervica 25: White powder in opaque white/white capsule no. 4 with printed "25" and "PRE" in black color (interchangeable printing on cap and body).
Nervica 75: Opaque red/white capsule no. 4 with printed "75" and "PRE" in black color (interchangeable printing on cap and body).
Nervica 150: Opaque white/white capsule no. 2 with printed "150" and "PRE" in black color (interchangeable printing on cap and body).

Anticonvulsants.
Pharmacology: Pregabalin binds to an auxiliary submit (α₂-δ protein) of voltage-gated calcium channels in the central nervous system.
Pharmacokinetics: Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.
Absorption: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of Pregabalin absorption is decreased when given with food resulting in a decrease in C_max by approximately 25-30% and a delay in t_max to approximately 2.5 hours. However, administration of Pregabalin with food has no clinically significant effect on the extent of Pregabalin absorption.
Distribution: In preclinical studies, Pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of Pregabalin following oral administration is approximately 0.56 L/Kg. Pregabalin is not bound to plasma proteins.
Biotransformation: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled Pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged Pregabalin. The N-methylated derivative of Pregabalin, the major metabolite of Pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemization of Pregabalin S-enantiomer to the R-enantiomer.
Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance.
Dose adjustment in patients with reduced renal function or undergoing hemodialysis is necessary.
Linearity/non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for Pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of Pregabalin.
Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of Pregabalin.
Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, Pregabalin is effectively removed from plasma by hemodialysis (following a 4 hour hemodialysis treatment plasma Pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dose reduction in patients with renal impairment and dose supplementation following hemodialysis is necessary.
Hepatic impairment: No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since Pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter Pregabalin plasma concentrations.
Pediatric population: Pregabalin pharmacokinetics were evaluated in pediatric patients with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at dose levels of 2.5, 5, 10 and 15 mg/Kg/day in a pharmacokinetic and tolerability study.
After oral administration of Pregabalin in pediatric patients in the fasted state, in general, time to reach peak plasma concentration was similar across the entire age group and occurred 0.5 hours to 2 hours postdose.
Pregabalin C_max and AUC parameters increased in a linear manner with increasing dose within each age group. The AUC was lower by 30% in pediatric patients below a weight of 30 Kg due to an increased body weight adjusted clearance of 43% for these patients in comparison to patients weighing ≥30 Kg.
Pregabalin terminal half-life averaged about 3 to 4 hours in pediatric patients up to 6 years of age, and 4 to 6 hours in those 7 years of age and older.
Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate of Pregabalin oral clearance, body weight was a significant covariate of Pregabalin apparent oral volume of distribution, and these relationships were similar in pediatric and adult patients.
Pregabalin pharmacokinetics in patients younger than 3 months old have not been studied.
Elderly: Pregabalin clearance tends to decrease with increasing age. This decrease in Pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of Pregabalin dose may be required in patients who have age related compromised renal function.
Breastfeeding mothers: The pharmacokinetics of 150 mg Pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little to no influence on Pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated infant dose from breast milk (assuming mean milk consumption of 150 mL/Kg/day) of women receiving 300 mg/day or the maximum dose of 600 mg/day would be 0.31 or 0.62 mg/Kg/day, respectively. These estimated doses are approximately 7% of the total daily maternal dose on a mg/Kg basis.

Neuropathic pain: Pregabalin is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy: Pregabalin is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalization.
Generalized anxiety disorder: Pregabalin is indicated for the treatment of Generalized Anxiety Disorder (GAD) in adults.

Oral: Posology: The dose range is 150 to 600 mg per day given in either two or three divided doses.
Neuropathic pain: Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.
Epilepsy: Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.
Generalized anxiety disorder: The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment should be reassessed regularly.
Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. Following an additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day may be achieved after an additional week.
Discontinuation of Pregabalin: In accordance with current clinical practice, if Pregabalin has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week independent of the indication.
Renal impairment: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As Pregabalin clearance is directly proportional to creatinine clearance, dose reduction in patients with compromised renal function must be individualized according to creatinine clearance (CL_cr), as indicated in Table 1 determined using the following formula: see equation.

Click on icon to see table/diagram/image

Pregabalin is removed effectively from plasma by hemodialysis (50% of drug in 4 hours). For patients receiving hemodialysis, the Pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4 hour hemodialysis treatment (see Table 1).

Click on icon to see table/diagram/image

Hepatic impairment: No dose adjustment is required for patients with hepatic impairment.
Pediatric population: The safety and efficacy of Pregabalin in children below the age of 12 years and in adolescents (12-17 years of age) have not been established.
Elderly: Elderly patients may require a dose reduction of Pregabalin due to a decreased renal function.
Method of administration: Pregabalin may be taken with or without food.

In the postmarketing experience, the most commonly reported adverse reactions observed when Pregabalin was taken in overdose included somnolence, confusional state, agitation, and restlessness. Seizures were also reported.
In rare occasions, cases of coma have been reported.
Treatment of Pregabalin overdose should include general supportive measures and may include hemodialysis if necessary.

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

Diabetic patients: In accordance with current clinical practice, some diabetic patients who gain weight on Pregabalin treatment may need to adjust hypoglycemic medicinal products.
Hypersensitivity reactions: There have been reports in the postmarketing experience of hypersensitivity reactions, including cases of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.
Dizziness, somnolence, loss of consciousness, confusion and mental impairment: Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been postmarketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicinal product.
Vision-related effects: In controlled trials, a higher proportion of patients treated with Pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in Pregabalin-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients.
In the postmarketing experience, visual adverse reactions have also been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of Pregabalin may result in resolution or improvement of these visual symptoms.
Renal failure: Cases of renal failure have been reported and in some cases discontinuation of Pregabalin did show reversibility of this adverse reaction.
Withdrawal of concomitant anti-epileptic medicinal products: There are insufficient data for the withdrawal of concomitant anti-epileptic medicinal products, once seizure control with Pregabalin in the add-on situation has been reached, in order to reach monotherapy on Pregabalin.
Withdrawal symptoms: After discontinuation of short-term and long-term treatment with Pregabalin, withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, diarrhea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during Pregabalin use or shortly after discontinuing Pregabalin.
Concerning discontinuation of long-term treatment of Pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.
Congestive heart failure: There have been postmarketing reports of congestive heart failure in some patients receiving Pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during Pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these patients. Discontinuation of Pregabalin may resolve the reaction.
Treatment of central neuropathic pain due to spinal cord injury: In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, central nervous system adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing Pregabalin in this condition.
Suicidal ideation and behavior: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomized placebo controlled studies of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Pregabalin.
Therefore, patients should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.
Reduced lower gastrointestinal tract function: There are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) when Pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. When Pregabalin and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).
Concomitant use with opioids: Caution is advised when prescribing Pregabalin concomitantly with opioids due to risk of CNS depression. In a case-control study of opioid users, those patients who took Pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19-2.36]). This increased risk was observed at low doses of Pregabalin (≤300 mg, aOR 1.52 [95% CI, 1.04-2.22]) and there was a trend for a greater risk at high doses of Pregabalin (>300 mg, aOR 2.51 [95% CI 1.24-5.06]).
Misuse, abuse potential or dependence: Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of Pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug-seeking behavior have been reported).
Encephalopathy: Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.
Effects on Ability to Drive and Use Machines: Pregabalin may have minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.

Women of childbearing potential/Contraception in males and females: As the potential risk for humans is unknown, effective contraception must be used in women of childbearing potential.
Pregnancy: There are no adequate data from the use of Pregabalin in pregnant women.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus).
Breastfeeding: Pregabalin is excreted into human milk. The effect of Pregabalin on newborns/infants is unknown. A decision must 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.
Fertility: There are no clinical data on the effects of Pregabalin on female fertility.
In a clinical trial to assess the effect of Pregabalin on sperm motility, healthy male subjects were exposed to Pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on sperm motility.
A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects. The clinical relevance of these findings is unknown.

The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for patients receiving Pregabalin and 5% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from Pregabalin treatment groups were dizziness and somnolence.
All adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Additional reactions reported from postmarketing experience are included in italics in the list as follows. (See Table 2.)

Click on icon to see table/diagram/image

After discontinuation of short-term and long-term treatment with Pregabalin withdrawal symptoms have been observed in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety, diarrhea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of Pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.
Pediatric population: The Pregabalin safety profile observed in three pediatric studies in patients with partial seizures with or without secondary generalization (12-week efficacy and safety study in patients with partial onset seizures, n=295; pharmacokinetic and tolerability study, n=65; and 1 year open label follow on safety study, n=54) was similar to that observed in the adult studies of patients with epilepsy. The most common adverse events observed in the 12-week study with Pregabalin treatment were somnolence, pyrexia, upper respiratory tract infection, increased appetite, weight increased, and nasopharyngitis.
Seek medical attention immediately at the first sign of any adverse drug reaction.

Since Pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.
In vivo studies and population pharmacokinetic analysis: Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between Pregabalin and Phenytoin, Carbamazepine, Valproic acid, Lamotrigine, Gabapentin, Lorazepam, Oxycodone or Ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, Phenobarbital, Tiagabine and Topiramate had no clinically significant effect on Pregabalin clearance.
Oral contraceptives, Norethisterone and/or Ethinyl estradiol: Co-administration of Pregabalin with the oral contraceptives Norethisterone and/or Ethinyl estradiol does not influence the steady-state pharmacokinetics of either substance.
Central nervous system influencing medical products: Pregabalin may potentiate the effects of Ethanol and Lorazepam.
In the postmarketing experience, there are reports of respiratory failure and coma in patients taking Pregabalin and other central nervous system (CNS) depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by Oxycodone.
Interactions and the elderly: No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

Store at temperatures not exceeding 30°C.

Anticonvulsants / Drugs for Neuropathic Pain

N02BF02 - pregabalin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

Rx