Indications:
Treatment of neuropathic pain in adults.
Supportive treatment of partial seizures, with or without secondary generalized epilepsy in adults.
Treatment of generalized anxiety disorder (GAD) in adults.
Administration & dosage:
Administration:
To be taken orally, with or without food.
Dosage:
Doses of 150 – 600 mg daily are divided into two or three times.
Neuropathic pain:
Initial dose is 150 mg daily, divided into two or three times. Depending on individual patient response and tolerability, dose may be increased to 300 mg daily at intervals of 3 – 7 days, if necessary, to maximum dose of 600 mg daily approximately 7 days later.
Partial seizures:
Initial dose is 150 mg daily, divided into two or three times. Depending on individual patient response and tolerability, dose may be increased to 300 mg daily after 1 week of treatment. Dose may be increased to maximum 600 mg daily 1 week later.
GAD:
Doses from 150 – 600 mg daily are divided to two or three times. The need for treatment should be reassessed regularly.
Initial dose is 150 mg daily. Depending on individual patient response and tolerability, dose may be increased to 300 mg daily after 1 week of treatment. Continue treatment for 1 week with increased dose of 450 mg daily. Dose may be increased to maximum 600 mg daily 1 week later.
Pregabalin discontinuation:
If pregabalin must be discontinued, the dose should be reduced gradually over a minimum of 1 week, depending on indication.
Special populations:
Renal impairment:
Pregabalin is eliminated from the systemic circulation mainly by renal excretion as unchanged form. Because pregabalin clearance is proportional to creatinine clearance (see pharmacokinetics), dose reduction in patients with renal impairment should be based on individual patient’s creatinine clearance (Clcr), shown in table 1, use the following formula:
| Clcr (mL/min) = | 1.23 x {140 – age (year)} x weight (kg)
Serum creatinine (µmol/l) |
(x 0.85 for female patients) |
Pregabalin is effectively eliminated from plasma by hemodialysis (50% in 4 hours). In patients require hemodialysis, daily dose of pregabalin should be adjusted depending on renal function. In addition to daily dose, an additional dose should be administered immediately after every 4 hours of hemodialysis (see table 1):
Table 1. Pregabalin dose adjustment according to renal function:
| Creatinine clearance (CLcr) (mL/min) | Total daily dose of pregabalin (mg/day)* | Dosage regimen | |
| Initial dose | Maximum dose | ||
| ≥ 60 | 150 | 600 | BID or TID |
| ≥ 30 – < 60 | 75 | 300 | BID or TID |
| ≥ 15 – < 30 | 25 – 50 | 150 | QD or BID |
| < 15 | 25 | 75 | QD |
| Additional dose immediately after hemodialysis (mg) | |||
| 25 | 100 | QD** | |
TID = Divide into 3 times daily.
BID = Divide into 2 times daily.
QD = Single dose daily.
* Total daily dose (mg/day) should be divided by dosage regimen above to provide mg/dose.
** Additional dose is single dose.
Liver impairment:
No dose adjustment is required in patients with liver impairment (see Pharmacokinetics).
Children:
The safety and effectiveness of pregabalin for children under 12 years of age and adolescents (12 to 17 years of age) have not been established.
Not recommended for use in children.
Elderly:
Elderly patients may require reduction in pregabalin dose due to impaired renal function.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Hypersensitivity to pregabalin and/or to any excipients of this medicine.
Warnings and precautions for use:
Diabetic patients:
Some diabetic patients who experience weight gain on pregabalin treatment require adjustment in the use of hypoglycemic drugs.
Hypersensitivity reactions:
There have been reports of hypersensitivity reactions, including angioedema, pregabalin immediate discontinuation is required if symptoms of angioedema, such as facial, perioral, or upper respiratory tract edema are present.
Dizziness, drowsiness, unconsciousness, confusion and metal decline:
Dizziness and drowsiness usually occur in pregabalin treatment, increasing risk of traumatic accidents (falls) in the elderly. There have been reports of unconsciousness, confusion and metal decline. Therefore, patients must be instructed to exercise caution until familiar with the possible effects of the drug.
Visual effects:
In controlled studies, patients treated with pregabalin had a higher incidence of blurred vision compared with the placebo group. In clinical studies at the ophthalmic trial site, patients treated with pregabalin had a higher incifence of decreased visual acuity and visual field changes compared with the placebo group.
There have been reports of undesirable effects on visual including lost of vision, blurred vision or other changes in vision, most of which are transient. Pregabalin discontinuation may improve and resolve visual symptoms.
Renal impairment:
There have been reports of renal impairment cases and in some cases, reversible upon discontinuation of pregabalin.
Withdrawal of concomitant use with antiepileptic drugs:
There are insufficient data for the withdrawal of concomitant antiepileptic drugs, therefore, once seizures have been controlled with pregabalin in combination therapy, consideration should be paid to pregabalin monotherapy.
Withdrawal symptoms:
In short-term and long-term pregabalin treatment, after discontinuation, withdrawal syndrome has been observed in some patients, including symptoms: Insomnia, headache, nausea, anxiety, diarrhea, flu syndrome, stress, depression, pain, convulsions, increased sweating and dizziness. Therefore, patients should be informed of these undesirable effects before starting treatment.
Congestive heart failure:
There have been reports of congestive heart failure in some patients taking pregabalin. Occurs mainly in cardiovascular compromised elderly patients during pregabalin treatment for neuropathic indications. Pregabalin should be given with caution in these patients. Pregabalin discontinuation may result in remission of this condition.
Treatment of central nervous system (CNS) pain due to spinal cord injury:
During treatment of central nervous system pain due to spinal cord injury, the incidence of general undesirable effects and CNS undesirable effects, especially drowsiness, is increased. This may be due to cumulative effect of taking multiple medicines (such as antispasmodics). Pregabalin should be indicated with caution in this case.
Suicidal ideation and behavior:
Sucidal ideation and behavior have been recorded in patients treated with antiepileptic drugs for certain indications. In a meta-analysis of the results of randomized placebo-controlled studies of antiepileptic drugs, there was a significant increase in the risk of suicidal ideation and behavior. The mechanism of this risk is unknown and the available data do not exclude the possibility of this increased risk caused by pregabalin. Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment measures should be considered. Patients (and caregivers) should be counseled about signs of suicidal ideation and behavior.
Decreased lower gastrointestinal function:
Intestinal obstruction, paralytic ileus, and constipation may occur when pregabalin is used concurrently with drugs with the potential to cause constipation, such as opioid analgesics. When pregabalin is indicated concomitantly with opioids, precautions should be taken to prevent constipation (especially in female and elderly patients).
Improper use, potential risk of drug abuse or dependence:
Caution should be exercised in patients with a history of drug abuse and patients should be monitored for symptoms of pregabalin abuse (such as drug resistance, tendency to increase dose, or drug-seeking behavior).
Encephalopathy:
Cases of encephalopathy have been reported, mainly in patients with underlying diseases that can cause encephalopathy.
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase enzyme deficiency or glucose-galactose malabsorption should not take this medication.
Pregnancy and lactation:
Pregnancy:
Studies in pregnant animals (rats, rabbits) were administered pregabalin at doses that produced pregabalin plasma concentrations (AUC) 5 times or more than 5 times than those observed in humans at maximum recommended dose of 600 mg daily, showed increased rate of fetal malformations and toxic manifestations on fetal development, including: Mortality, growth retardation, impaired nervous system and reproductive system function in the fetus.
There are no adequate and well-controlled studies in pregnant women. The drug should only be used when the potential benefit to the mother outweighs the potential risk to the fetus.
Women of childbearing potential or using birth control methods should consult their doctor carefully before taking this medicine.
There is no information on fetal toxicity.
Lactation:
It is not known whether the drug passes into breast milk. The drug should be used with caution in lactating women. Studies in rats have shown that pregabalin passes into milk.
Effects on ability to drive and use machines:
There is no evidence of effect on ability to drive or use machines of the drug. However, patients should be careful when driving and operating machinery because the drug may cause drowsiness, dizziness, and may impair both physical and mental health.
Interaction, incompatibilities of medicine:
Interaction with other medicinal products and other forms of interaction:
Because pregabalin is eliminated mainly in the urine as unchanged form, the amount of drug metabolism is negligible (< 2% of dose have been found in urine as metabolites), does not cause in vitro inhibition of drug metabolism, and not bound to plasma proteins, so that pregabalin causes or is subject to pharmacokinetic interactions.
In vivo study and pharmacokinetic analysis in groups of subjects:
In in vivo studies, no clinical pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Pharmacokinetic analysis in each group of subject shown that oral antidiabetic drugs, diuretics, insulin, phenobarbital, tiagabin and topiramate have no significantly clinical effects on pregabalin clearance.
Oral contraceptives, norethisterone and/or ethinyl estradiol:
Concomitant administration of pregabalin with oral contraceptives, norethisterone and/or ethinyl estradiol have no effects on pharmacokinetic stability of either drug.
Effects on the central nervous system:
Pregabalin may interfere with the effects of ethanol and lorazepam. In controlled clinical studies, multiple doses of oral pregabin in combination with oxyxodone, lorazepam or ethanol did not have any clinically important effects on respiratory performance. There have been reports of respiratory depression and coma in patients taking pregabalin and other central nervous system (CNS) medicinal products. Pregabalin seems to increase the disturbances in cognition and overall motor function caused by oxycodone.
Elderly:
No specific pharmacodynamic interaction studies have been performed in elderly volunteers.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”.
Undesirable effects listed below may be related to underlying diseases and/or concomitant medications.
Undesirable effects occuring in clinical study:
| Affected body tissue | Undesirable effects |
| Bacterial and parasitic infections | |
| Common | Nasopharyngitis |
| Blood and lymphatic system disorders | |
| Uncommon | Neutropenia |
| Immune system disorders | |
| Uncommon | Hypersensitivity |
| Rare | Angioedema, allergic reactions |
| Nutritional and metabolic disorders | |
| Common | Increase appetite |
| Rare | Anorexia, hypoglycemia |
| Mental disorders | |
| Common | Mania, confusion, irritability, disorientation, insomnia, decreased libido |
| Uncommon | Hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, mania, aggression, mood swings, depersonalization disorder, difficulty verbalizing, daydreaming, increased libido, insensitivity, apathy |
| Rare | Loss of conditioned reflex |
| Nervous system disorders | |
| Very common | Dizziness, drowsiness, headache |
| Common | Ataxia, abnormal coordination, tremor, dysarthria, amnesia and memory impairment, distraction, paresthesia, hypoesthesia, sedation, balance disorder, lethargy |
| Uncommon | Syncope, stupor, myoclonus, unconsciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, voluntary tremor, nystagmus, cognitive disorders, mental impairment, language disorders, decreased reflexes, increased sensation, burning sentation, loss of taste, discomfort |
| Rare | Convulsion, olfactory disturbances, decreased muscle movement, dyslexia |
| Eye disorders | |
| Common | Blurred eyes, double vision |
| Uncommon | Loss of vision, visual disturbances, eye swelling, visual field loss, visual decreasing, eye pain, dizziness, dry eyes, increased tearing, eye irritation |
| Rare | Loss of vision, keratitis, fluctuations in vision, change perception of visual depth, strabismus, bright vision |
| Ear and labyrinth disorders | |
| Common | Dizziness |
| Uncommon | Increased hearing |
| Heart disorders | |
| Uncommon | Tachycardia, first-degree atrioventricular (AV) block, sinus bradycardia, congestive heart failure |
| Rare | Prolonged QT interval, sinus tachycardia, sinus arrhythmia |
| Vascular disorder | |
| Uncommon | Hypotension, hypertension, burning, flashing, cold limbs |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon | Dyspnoea, epistaxis, cough, stuffy nose, rhinitis, snoring, dry nose |
| Rare | Pulmonary edema, sore throat |
| Gastrointestinal disorders | |
| Common | Vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth |
| Uncommon | Esophageal reflux, increased salivation, decreased tactile sensation in the mouth |
| Rare | Ascites, pancreatitis, tongue swelling, difficulty swallowing |
| Hepatobiliary disorders | |
| Uncommon | Increase liver enzymes* |
| Rare | Jaundice |
| Very rare | Liver failure, hepatitis |
| Skin and subcutaneous tissue disorders | |
| Uncommon | Erythema nodosum, urticaria, excessive sweating, itching |
| Rare | Stevens Johnson syndrome, cold sweats |
| Musculoskeletal and connective tissue disorders | |
| Common | Cramps, joint pain, back pain, limb pain, cervical spasms |
| Uncommon | Joint swelling, muscle pain, muscle tremors, muscle stiffness |
| Rare | Rhabdomyolysis |
| Renal and urinary tract disorders | |
| Uncommon | Urinary incontinence, urinary retention |
| Rare | Renal failure, oliguria, urinary retention |
| Mammary gland and reproductive system disorders | |
| Common | Erectile dysfunction |
| Uncommon | Sexual dysfunction, delayed ejaculation, dysmenorrhea, breast pain |
| Rare | Amenorrhea, breast discharge, breast enlargement, breast enlargement in men |
| General disorders and administration site conditions | |
| Common | Peripheral edema, edema, abnormal gait, falls, intoxicated feeling, unusual feeling, fatigue |
| Uncommon | Generalized edema, facial edema, chest tightness, pain, fever, thirst, chills, weakness |
| Investigations | |
| Common | Weight gain |
| Uncommon | Increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, reduce blood potassium, lose weight |
| Rare | Leukopenia |
* Increase alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
In short-term and long-term treatment with pregabalin, after drug discontinuation, withdrawal syndrome has been observed in some patients. Including symptoms: Insomnia, headache, nausea, anxiety, diarrhea, flu syndrome, stress, depression, pain, convulsion, increased sweating and dizziness. Therefore, patients should be informed of these undesirable effects before starting treatment.
Regarding discontinuation of long-term treatment with pregabalin, data suggest that the frequency and severity of withdrawal symptoms may be dose-related.
Children:
The safety of pregabalin observed in three pediatric studies in patients with partial epilepsy with or without secondary generalization (12-week safety and efficacy study in patients with partial-onset epilepsy, n = 295; pharmacokinetic and tolerability study, n = 65; and 1-year open study on safety, n = 54) was similar to that observed in studies in adults with epilepsy. The most common undesirable effects were observed in 12-week study with pregabalin treatment including: drowsiness, vomiting, upper respiratory tract infection, increased appetite, weight gain and nasopharyngitis.
Guidance on handling ADR:
Some ADRs cause patients to discontinue their medication. 4% of patients experienced dizziness or drowsiness and stopped treatment. Most of the cases of blurred vision resolved on their own with continued treatment, less than 1% of patients had to stop treatment. If visual disturbance persists, eye examination is required.
The drug must be discontinued in the presence of myopathy, or when serum CPK concentration is elevated at least 3 times upper limit of normal. The drug must be discontinued when there is weight gain, peripheral edema in patients with pre-existing heart disease.
Angioedema is rare but usually occurs at the start of pregabalin treatment; therefore, before administering pregabalin to patient, thorough hypersensitivity history should be sought and appropriate emergency care should be prepared.
In addition, patients and families should be informed of the potential risk of suicide when taking antiepileptic drugs. Attention must be paid to signaling symptoms such as anxiety, struggle, aggression, attacking, opposition, mania, insomnia, and depression. Family needs to closely monitor the patient.
When discontinuing the drug, avoid abrupt discontinuation, reduce the dose gradually over at least a week.
Overdose and management:
Overdose:
Experience with pregabalin overdose is limited. The highest reported pregabalin dose of 800 mg was not clinically significant.
Management:
There is no specific antidote. If indicated, induce vomiting or gastric lavage, maintain airway if necessary. Symptomatic and supportive treatment. Hemodialysis if indicated (remove approximately 50% of pregabalin in 4 hours).
Closely monitor for timely remedial measures.
Pharmacodynamics:
Pharmacotherapeutic group: Nervous system – Antiepileptics – Pregabalin.
ATC code: N03AX16
Pregabalin is an anticonvulsant and analgesic. Pregabalin has the similar structure with central nervous system (CNS) depressant GABA, but does not bind directly to GABAA, GABAB receptors, or benzodiazepine receptors, dose not increase GABAA response in cultured neurons, nor alter GABA concentration in rat brain, nor affect GABA uptake or degradation. In cultured neurons, long-term use of pregabalin increases the density of transport proteins and increases the rate of GABA transport. Pregabalin binds to CNS tissues with high affinity at the α2-δ site (a subunit of a voltage-dependent calcium channel). Although the exact mechanism of pregabalin has not been fully known, binding to the α2-δ subunit may be involved in the analgesic and anticonvulsant effects of pregabalin.
In vitro, pregabalin reduces realease of calcium-dependent neurotransmitters such as glutamate, norepinephirine, calcitonin-regulating gene peptide, and substance P, possibly through regulation of calcium channel function.
Pharmacokinetics:
The steady-state pharmacokinetics of pregabalin were similar in healthy volunteers, epileptic patients receiving antiepileptic drugs and patients with chronic pain.
Absorption:
Pregabalin is rapidly absorbed after oral administration in fasted state, peak plasma concentration occurring 1 hour after single and multiple dosing.
Oral bioavailability of pregabalin is ≥ 90% and is dose dependent. With repeated dosing, steady state is reached in 24 – 48 hours. Absorption rate of pregabalin is decreased when taken with food, leading to decrease in Cmax of about 25 – 30% and a prolongation of tmax after about 2.5 hours. However, taking pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.
Distribution:
In preclinical studies, pregabalin readily crossed the blood-brain barrier in mice, rats, and monkeys. Pregabalin crosses the rat placenta and is present in rat milk. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins.
Metabolism:
Pregabalin is metabolised insignificantly in human body. Following administration, the radiolebelled radioisotope of pregabalin, about 98% found in urine is pregabalin in unchanged form. N-methylate derivative of pregabalin, main metabolite of pregabalin found in urine, approximately 0.9% of dose. In preclinical studies, there were no indications of pregabalin conversion from sinister isomer to rectus isomer.
Elimination:
Pregabalin is eliminated from systemic circulation mainly by renal elimination as unchanged form.
Average half life of pregabalin is 6.3 hours. Pregabalin plasma clearance and renal clearance are proportional to creatinine clearance,
Dose adjustment in patients with renal impairment or hemodialysis is necessary.
Linear/non-linear:
Pregabalin pharmacokinetics are linear over single daily dose.
Pregabalin pharmacokinetics variability range is low (< 20%). Pharmacokinetics properties of multiple doses can be predicted from single dose data.
Gender:
Clinical studies have shown that gender has no clinically significant effect on pregabalin plasma concentration.
Pharmacokinetics in special populations:
Renal impairment:
Pregabalin clearance is proportional to crearinine clearance. In addition, pregabalin is effectively eliminated from plasma by hemodialysis (pregabalin plasma concentration is reduced approximately 50% by hemodialysis after 4 hours). Because renal elimination is main route of elimination, dose reduction in patients with renal impairment and additional dosing in patients on hemodialysis is necessary.
Liver impairment:
No specific studies have been performed in patients with hepatic impairment. Because pregabalin is insignificantly metabolized and eliminated mainly in urine as unchanged form, patients with hepatic impairment do not experience significant changes in plasma concentration.
Children:
Pregabalin pharmacokinetics evaluated in pediatric patients with epilepsy (Age groups: From 1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at doses of 2.5 mg, 5 mg, 10 mg and 15 mg/kg/day in a pharmacokinetics and tolerability study.
Pediatric patients at the fasted state after taking pregabalin, time to reach peak plasma concentration was similar across entire age groups and occurred 0.5 to 2 hours after oral administration.
Pregabalin Cmax and AUC increased linearly with increased dose in each age group. In pediatric patients weigh below 30 kg, AUC below 30% because increased body weight has adjusted clearance 43% in these patients compared to patients weigh ≥ 30 kg.
Average final half life of pregabalin about 3 to 4 hours in pediatric patients less than 6 years and 4 to 6 hours in pediatric patients more than 7 years.
Pharmacokinetic analysis showed that creatinine clearance is important parameter of oral pregabalin clearance, body weight is important parameter of oral pregabalin distribution volume, and these relationships are similar in children and adults.
Pregabalin pharmacokinetics in patients less than 3 months old has not been studied.
Elderly:
Pregabalin clearance tends to decrease with increasing age. The decrease in oral pregabalin clearance is consistent with the decrease in creatinine clearance with increasing age. Pregabalin dose reduction is required in patients with renal function impairment due to advanced age.
Latation:
Pharmacokinetics of pregabalin 150 mg administered every 12 hours (300 mg daily dose) were investigated in 10 lactating women who were in postpartum period for at least 12 weeks. Lactation has little or no effect on the pharmacokinetics of pregabalin. Pregabalin is excreted into milk with average steady-state concentration approximately 76% of maternal plasma concentration. Estimated infant pregabalin intake from breastmilk (assuming average milk consumption is 150 mL/kg/day) in women taking 300 mg/day and maximum dose of 600 mg/day was 0.31 and 0.62 mg/kg/day, respectively, which is about 7% compared with maternal dose in mg/kg.
