Pregabalin

159.22600

159.23

604-639-1

55JG375S6M

2782

DTXSID1045950

C64625

White to off-white crystalline solid

N03AX16|QN03AX16|N - Nervous system

2915900090

63.32000

1.78240

Solid

0.997 g/cm3

195 °C (decomp) @ Solvent: Isopropanol

274ºC at 760 mmHg

119.5ºC

1.464

deionized water: ≥10mg/mL

Store at 25 deg C (77 deg F); excursions permitted to 15 to 30 deg C (59 to 86 deg F).

0.00153mmHg at 25°C

Specific optical rotation = +10.52 deg/D (c = 1.00 in water)

Henry's Law constant = 6.89X10-11 atm-cu m/mol at 25 °C (est)

pKa1 = 4.2; pKa2 = 10.6

The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is -1.35|Hydroxyl radical reaction rate constant = 4.1X10-11 cu cm/molec-sec at 25 °C (est)

UN1230 - class 3 - PG 2 - Methanol, solution

3

63-48/22-39/23/24/25-23/24/25-11

22-36/37-45-16-7

Xn,T,F

P280-P305 + P351 + P338

H318-H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pregabalin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule V includes pregabalin, DEA Code #2782; Drug class: Depressants.

|Danger|H318 (79.06%): Causes serious eye damage [Danger Serious eye damage/eye irritation]|P201, P202, P260, P280, P281, P305+P351+P338, P308+P313, P310, P314, P405, and P501|Aggregated GHS information provided by 192 companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation. The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures. Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway). Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Limited data is available on the hepatotoxicity of pregabalin. In prelicensure clinical trials in diabetic neuropathy and epilepsy, therapy with pregabalin was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Since its approval and more wide scale use, however, pregabalin has been linked to rare instances of clinically apparent liver injury. Most cases were mild and frequently without jaundice. The latency to onset of injury was short, symptoms of liver injury arising within 3 to 14 days. Both cholestatic and hepatocellular patterns of injury have been reported. Signs of hypersensitivity (fever, rash, eosinophilia) and autoimmunity were not present. Some cases have been severe and associated with marked jaundice and prolongation of the prothrombin time, but all cases ultimately resolved after the medication was stopped without evidence of residual injury.

Patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines should be informed that they may experience additive CNS side effects, such as somnolence.|The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration... Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.|Pregabalin coadministration had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 mug, respectively) in healthy subjects.|Multiple-dose administration of pregabalin in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam had no effect on the steady-state pharmacokinetics of pregabalin.|For more Interactions (Complete) data for PREGABALIN (8 total), please visit the HSDB record page.

Advise diabetic patients to watch for skin damage while receiving pregabalin therapy, since increased risk of skin ulcerations associated with pregabalin therapy has been observed in animal studies.|Because there are limited data regarding use of pregabalin in patients with New York Heart Association (NYHA) class III or IV congestive heart failure, the drug should be used with caution in these patients.

Pregabalin is not plasma protein bound.

While data specific to pregabalin were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older.|FDA Label|Neuropathic painLyrica is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyLyrica is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised anxiety disorderLyrica is indicated for the treatment of generalised anxiety disorder (GAD) in adults.|EpilepsyPregabalin Mylan Pharma is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Mylan Pharma is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Neuropathic painPregabalin Mylan is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyPregabalin Mylan is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Mylan is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Neuropathic painPregabalin Pfizer is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyPregabalin Pfizer is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Pfizer is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Neuropathic painPregabalin Zentiva k.s. is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyPregabalin Zentiva k.s. is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised anxiety disorderPregabalin Zentiva k.s. is indicated for the treatment of generalised anxiety disorder (GAD) in adults.|EpilepsyPregabalin Accord is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Accord is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Neuropathic painPregabalin Zentiva is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyPregabalin Zentiva is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised anxiety disorderPregabalin Zentiva is indicated for the treatment of generalised anxiety disorder (GAD) in adults.|EpilepsyPregabalin Sandoz GmbH is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Sandoz GmbH is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Neuropathic painPregabalin Sandoz is indicated for the treatment of peripheral and central neuropathic pain in adults.EpilepsyPregabalin Sandoz is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.Generalised Anxiety DisorderPregabalin Sandoz is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.|Alleviation of acute anxiety and fear associated with transportation and veterinary visits.

Pregabalin is an inhibitor of neuronal activity used for therapy of painful neuropathy and as an anticonvulsant. Therapy with pregabalin is not associated with serum aminotransferase elevations, and clinically apparent liver injury from pregabalin has been reported but appears to be quite rare.

Anticonvulsants

Pregabalin is indicated for management of post-herpetic neuralgia. /Included in US product label/|Pregabalin is indicated for management of neuropathic pain associated with diabetic peripheral neuropathy. /Included in US product labe/|Pregabalin is indicated as an adjunctive therapy for adult patients with partial onset seizures. /Included in US product label/|The U.S. Food and Drug Administration ... has approved Lyrica (pregabalin), the first drug to treat fibromyalgia, a disorder characterized by pain, fatigue and sleep problems.

Known hypersensitivity to pregabalin or any ingredient in the formulation.|Because of the possibility of increased seizure frequency, anticonvulsant drugs, including pregabalin, should be withdrawn gradually and dosage reduced slowly over at least 1 week. Abrupt discontinuance of pregabalin has been associated with insomnia, nausea, headache, and diarrhea.|In controlled studies, blurred vision, which was reported in 6 or 2% of patients receiving pregabalin or placebo, respectively, resolved in the majority of cases with continued dosing; less than 1% of patients required discontinuance of the drug. In addition, decreased visual acuity was reported in 7 or 5% of patients receiving pregabalin or placebo, respectively, while visual field changes were detected in 13 or 12% of patients receiving the drug or placebo, respectively, and funduscopic changes were observed in 2% of patients receiving pregabalin or placebo. The clinical importance of these ophthalmologic findings has not been elucidated. If visual disturbance persists, further ocular assessment should be considered, while more frequent assessment is recommended in patients who already are monitored for ocular conditions.|Weight gain, which was related to dosage and duration of exposure to pregabalin, has been reported in patients receiving pregabalin. Weight gain did not appear to be associated with baseline body mass index (BMI), gender, or age and was not limited to patients with edema.|For more Drug Warnings (Complete) data for PREGABALIN (20 total), please visit the HSDB record page.

In controlled clinical studies, 4 or 1% of patients receiving pregabalin or placebo, respectively, reported euphoria as an adverse event, although in some patient populations studied, this rate of euphoria was higher and ranged from 1-12%. In clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, or diarrhea, suggestive of physical dependence.|Pregabalin is not known to be active at receptor sites associated with drugs of abuse. However, the Drug Enforcement Administration (DEA) has placed pregabalin into schedule V of the Federal Controlled Substances Act (CSA) of 1970 subsequent to a recommendation for control from the Department of Health and Human Services (DHHS).

Although the structure of pregabalin is similar to gamma-aminobutyric acid (GABA), it does not bind to GABA receptors. Instead, it binds the alpha2-delta subunit of presynaptic voltage-gated calcium channels in the central nervous system. Pregabalin does not modulate dopamine receptors, serotonin receptors, opiate receptors, sodium channels or cyclooxygenase activity.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here. (See all compounds classified as Anti-Anxiety Agents.)|Compounds capable of relieving pain without the loss of CONSCIOUSNESS. (See all compounds classified as Analgesics.)|Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)|A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)

After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional. Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.|Pregabalin is almost exclusively eliminated in the urine. Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body.|After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg. Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB. In rat models, pregabalin has been shown to cross the placenta.|In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved.|Pregabalin is well absorbed after oral administration ...|Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is >/=90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (C max ) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.|The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.|Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.|For more Absorption, Distribution and Excretion (Complete) data for PREGABALIN (8 total), please visit the HSDB record page.

Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the urine.|Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as 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, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.

The elimination half life of pregabalin is 6.3 hours.|Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function.

Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models. By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors.|Pregabalin is an anticonvulsant that is structurally related to the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA). Pregabalin also has demonstrated analgesic activity. Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA-A, GABA-B, or benzodiazepine receptors; does not augment GABA-A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.|Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues. ... In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, including glutamate, norepinephrine, and substance P, possibly by modulation of calcium channel function.|Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.|Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system that exhibits potent anticonvulsant, analgesic, and anxiolytic activity in a range of animal models. ... Potent binding to the alpha-2-delta site reduces depolarization-induced calcium influx with a consequential modulation in excitatory neurotransmitter release. Pregabalin has no demonstrated effects on GABAergic mechanisms. ...|For more Mechanism of Action (Complete) data for PREGABALIN (6 total), please visit the HSDB record page.

There is no known antidote for pregabalin. Treatment is generally symptomatic and supportive. ... To enhance elimination- Hemodialysis indicated by the patients clinical state; patients with significant renal impairment may increase clearance of pregabalin approximately 50% in 4 hours. Monitoring of vital signs and observation of clinical status of the patient. Supportive care- Contacting a certified poison control center for up-to-date information on management of overdose with pregabalin.|Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat stupor and coma if they occur. Protect the patient from self-injury caused by ataxia. Treat agitation and delirium if they occur. Monitor asymptomatic patients for a minimum of 4-6 hours. Admit symptomatic patients for at least 24 hours after lamotrigine, felbamate, topiramate, or zonisamide ingestions. ... Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Anticonvulsants, Newer/

/HUMAN EXPOSURE STUDIES/ In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.|/CASE REPORTS/ /Investigators/ present a patient who, after unintended rapid up-titration of pregabalin, experienced psychotic symptoms associated with rhythmic EEG-changes resolving completely after discontinuation of pregabalin and benzodiazepine administration.|/CASE REPORTS/ /Investigators/ report two patients with refractory epilepsy who developed unilateral painful gynecomastia and lower extremity pain (one of them localized and the other one diffuse), shortly after receiving Pregabalin (PGB). Neither of them had previous endocrinologic problems or complaints about pain on their medical history. PGB was stopped in one patient and reduced in the other one, with complete disparition of the symptoms in the following weeks in both patients.|/CASE REPORTS/ /Investigators/ present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy.|For more Human Toxicity Excerpts (Complete) data for PREGABALIN (7 total), please visit the HSDB record page.

(R-)-3-isobutyl GABA

Pregabalin|Lyrica|2782|Schedule V - Substances in the DEA Schedule V have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.|No

Lyrica

Human drugs -> Lyrica -> EMA Drug Category|Antiepileptics, Other antiepileptics -> Human pharmacotherapeutic group|Human drugs -> Pregabalin Mylan Pharma -> EMA Drug Category|Antiepileptics -> Human pharmacotherapeutic group|Human drugs -> Pregabalin Mylan -> EMA Drug Category|Human drugs -> Pregabalin Pfizer -> EMA Drug Category|Human drugs -> Pregabalin Zentiva k.s. -> EMA Drug Category|Human drugs -> Pregabalin Accord -> EMA Drug Category|Human drugs -> Pregabalin Zentiva -> EMA Drug Category|Human drugs -> Pregabalin Sandoz GmbH -> EMA Drug Category|Human drugs -> Pregabalin Sandoz -> EMA Drug Category|Veterinary drugs -> Bonqat -> EMA Drug Category|Antiepileptics -> Veterinary pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients