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PREGABALIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pregabalin (3-isobutyl gamma-aminobutyric acid (GABA)) is a GABA analogue with structural similarity and actions similar to gabapentin. Like gabapentin, pregabalin has antiepileptic, analgesic, and anxiolytic activity.

Specific Substances

    1) CI-1008
    2) Isobutyl GABA
    3) PD-144723
    4) Pregabalina
    5) (S)-3-(Aminomethyl)-5-methylhexanoic acid
    6) Molecular Formula: C8-H17-N-O2
    7) CAS 148553-50-8
    1.2.1) MOLECULAR FORMULA
    1) C8H17NO2

Available Forms Sources

    A) FORMS
    1) Pregabalin is available as 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules and 20 mg/mL oral solution (Prod Info LYRICA oral capsules, oral solution, 2013).
    B) USES
    1) Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for adults with partial onset seizures (Prod Info LYRICA oral capsules, oral solution, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for adults with partial onset seizures.
    B) PHARMACOLOGY: The mechanism of action in humans is unknown; however, pregabalin possibly modulates calcium channel function by reducing the calcium-dependent release of several neurotransmitters in vitro and binds with high affinity to the alpha(2)-delta site in central nervous system tissues, which may lead to antiseizure and antinociceptive effects.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness and somnolence, ataxia, tremor, amnesia, speech disturbances, myoclonus, neuropathy, confusion, euphoria, incoordination, abnormal gait, nervousness, twitching, headache. LESS COMMON: Peripheral edema, a mildly prolonged PR interval, decreased platelet count, and increased creatine kinase, rhabdomyolysis and blurred vision.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. During clinical trials, the highest reported accidental overdose of pregabalin was 8000 mg; no notable consequences were observed. During clinical studies, some patients took as much as 2400 mg/day. Adverse events in patients exposed to doses greater than or equal to 900 mg were not clinically different from those of patients who received recommended doses of pregabalin.
    2) SEVERE TOXICITY: An adult intentionally ingested 8.4 g of pregabalin and developed CNS depression and coma approximately 3 hours after exposure. The patient required intubation and mechanical ventilation for 26 hours. No permanent sequelae occurred.
    0.2.20) REPRODUCTIVE
    A) There are no adequate and well-controlled studies of pregabalin in pregnant women. However, animal reproduction studies of the drug's administration during organogenesis demonstrated increased incidences of fetal structural abnormalities and signs of developmental toxicity including skeletal malformations, retarded ossification, and decreased fetal body weights. Advise pregnant women of the potential for fetal harm if pregabalin is used during pregnancy. Advise men taking pregabalin who plan to father a child of the potential risk to the fetus. Pregabalin is excreted in human milk. Because of the potential risk of tumorigenicity in breastfed infants, advise women to avoid breastfeeding during pregabalin therapy.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of pregabalin.

Laboratory Monitoring

    A) Monitor ECG for PR prolongation and CBC for decreased platelets.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) In patients with muscle pain, weakness or tenderness, monitor CK for rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment of pregabalin exposure is largely supportive in nature with careful attention to airway protection in severe cases. Hypotension is usually mild responding to intravenous fluid boluses. If hypotension persists, administer dopamine or norepinephrine. Admit all severely symptomatic patients. Treat seizures with IV benzodiazepines or barbiturates.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital GI decontamination is generally not necessary.
    2) HOSPITAL: Consider activated charcoal if ingestion was recent, substantial and patient can protect airway.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation will be necessary in patients with significant CNS or respiratory depression.
    E) ANTIDOTE
    1) None.
    F) SEIZURES
    1) Treat seizures with IV benzodiazepines, barbiturates.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis has been used in a hemodialysis dependent patient following inadvertent pregabalin exposure. The manufacturer has suggested that hemodialysis might be useful in patients with severe toxicity or those with significant renal impairment. Standard hemodialysis results in pregabalin clearance of approximately 50% in 4 hours. Hemodialysis is rarely necessary as most patients do well with supportive care
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with inadvertent ingestions who are not symptomatic may be observed at home with telephone follow up.
    2) OBSERVATION CRITERIA: Observe all patients who are symptomatic for 4 to 6 hours. When patients are asymptomatic they may be discharged home.
    3) ADMISSION CRITERIA: Admit all moderately to severely symptomatic patients, especially if there is a concern for falls, inability to care for self, or risk of worsening central nervous system depression.
    4) CONSULT CRITERIA: Involve a toxicologist or poison center with any patient with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Overtreatment is the primary risk as severe toxicity is rare. Consider the possibility that other anticonvulsants or psychiatric medications may have been involved in the ingestion.
    J) PHARMACOKINETICS
    1) Oral bioavailability is approximately 90% and is independent of dose. Pregabalin is not bound to plasma proteins. Approximately 90% is recovered in the urine as unchanged drug. The mean elimination half-life is 6.3 hours in patients with normal renal function
    K) DIFFERENTIAL DIAGNOSIS
    1) Other anticonvulsants, ethanol, benzodiazepines, and lithium.

Range Of Toxicity

    A) TOXICITY: During clinical development, the highest reported accidental overdose of pregabalin was 8000 mg; no notable consequences were observed. An adult intentionally ingested 8.4 g of pregabalin and developed CNS depression and coma requiring mechanical ventilation for 26 hours; neurologic status gradually improved with no permanent sequelae. During clinical studies, some patients took as much as 2400 mg/day. Adverse events in patients exposed to doses greater than or equal to 900 mg were not clinically different from those of patients who received the recommended dose.
    B) THERAPEUTIC DOSE: ADULT: Initial dose: 150 mg/day. Maximum dose: 600 mg/day. PEDIATRIC: The safety and efficacy of pregabalin have not been determined in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, postherpetic neuralgia, fibromyalgia, and as adjunctive therapy for adults with partial onset seizures.
    B) PHARMACOLOGY: The mechanism of action in humans is unknown; however, pregabalin possibly modulates calcium channel function by reducing the calcium-dependent release of several neurotransmitters in vitro and binds with high affinity to the alpha(2)-delta site in central nervous system tissues, which may lead to antiseizure and antinociceptive effects.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness and somnolence, ataxia, tremor, amnesia, speech disturbances, myoclonus, neuropathy, confusion, euphoria, incoordination, abnormal gait, nervousness, twitching, headache. LESS COMMON: Peripheral edema, a mildly prolonged PR interval, decreased platelet count, and increased creatine kinase, rhabdomyolysis and blurred vision.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. During clinical trials, the highest reported accidental overdose of pregabalin was 8000 mg; no notable consequences were observed. During clinical studies, some patients took as much as 2400 mg/day. Adverse events in patients exposed to doses greater than or equal to 900 mg were not clinically different from those of patients who received recommended doses of pregabalin.
    2) SEVERE TOXICITY: An adult intentionally ingested 8.4 g of pregabalin and developed CNS depression and coma approximately 3 hours after exposure. The patient required intubation and mechanical ventilation for 26 hours. No permanent sequelae occurred.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurry vision and other unspecified visual symptoms have been described during therapy (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema was observed in 9% of 979 patients taking pregabalin, compared with 2% of 459 patients taking placebo in trials of patients with neuropathic pain associated with diabetic peripheral neuropathy. In a trial of patients with neuropathic pain associated with postherpetic neuralgia, peripheral edema was reported in 12% of 852 pregabalin-treated patients, compared with 4% of 398 patients taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) PROLONGED PR INTERVAL
    1) WITH THERAPEUTIC USE
    a) A mildly prolonged PR interval has been associated with pregabalin treatment. The mean PR interval increase was 3 to 6 msec at doses greater than or equal to 300 mg/day. This mean change was not associated with an increased risk of adverse events of second or third degree AV block.
    1) Subgroup analyses did not identify an increased risk of PR prolongation in patients taking other PR prolonging medications or patients with baseline PR prolongation. These analyses, however, cannot be considered definitive because of the limited number of patients in these categories (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    C) ATRIOVENTRICULAR BLOCK
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 65-year-old woman, who was taking pregabalin 300 mg daily for 8 months, presented with dizziness and syncope. She had a medical history of diabetes mellitus, lumbar spondylosis, diabetic nephropathy, chronic renal failure, and anemia of chronic disease. An ECG showed complete atrioventricular (AV) block and right bundle-brunch block with a heart rate of 39 beats/min. An echocardiography showed normal left ventricular dimensions, systolic functions (ejection fraction of 60%), and heart valves. Laboratory results revealed serum creatinine of 1.8 mg/dL and creatinine clearance of 50 mL/min. Following the discontinuation of pregabalin and supportive care, the complete AV block resolved spontaneously to Mobitz type II block on day 4, and to sinus rhythm with right bundle-brunch block 7 days postadmission. Of note, the authors suggested that 150 mg daily of pregabalin would have been the corrected dose for this patient based on her chronic renal failure (Aksakal et al, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and somnolence are the most frequent adverse effects associated with pregabalin, are dose-related and usually mild or moderate in severity (Prod Info LYRICA(R) oral capsules, oral solution, 2009; Abou-Khalil et al, 1999; Anon, 2001; Bailer et al, 2001; Nicholson & Leach, 2001).
    b) In clinical trials, dizziness was reported in 21% to 32% of pregabalin-treated patients, compared with 5% to 11% taking placebo. Somnolence was reported in 12% to 22% of pregabalin-treated patients, compared with 3% to 11% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    c) In one study, the median duration of dizziness and somnolence was 11 to 14 days and 64 days, respectively. Dizziness occurred in 9.1% to 42% of patients taking pregabalin, compared with 9% of patients taking placebo (dose range 50 mg/day to 600 mg/day). Pregabalin was associated with somnolence in 10.2% to 28.1% of patients, compared with 11% of patients taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    d) Dizziness (6%), ataxia (4%) and somnolence (3%) were the adverse events that most frequently lead to withdrawal from controlled studies (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) DROWSY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 59-year-old woman intentionally ingested an unknown amount of pregabalin and was seen in the ED one hour later. Mild drowsiness was the only symptom observed. Initial vital signs and laboratory studies were normal. Serum and urine screenings for drugs of abuse were negative. The patient remained drowsy for approximately 8 to 10 hours, but otherwise asymptomatic. The patient was discharged the following day for further mental health care (Spiller et al, 2008).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) A 54-year-old man intentionally ingested 8.4 g of pregabalin (serum concentration 66.5 mg/L) and developed CNS depression and coma approximately 3 hours after exposure. The patient was admitted to the Intensive Care Unit and intubated and mechanically ventilated for 26 hours when his neurological status gradually improved. He was extubated without difficulty. The patient did develop aspiration pneumonia during his admission, that was treated successfully with intravenous antibiotics. Following psychiatric review, the patient was deemed capable and refused any further treatment (Wood et al, 2010).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, patients with neuropathic pain associated with diabetic peripheral neuropathy (n=979) were treated with pregabalin 75 mg/day, 150 mg/day, 300 mg/day, or 600 mg/day vs placebo (n=459). In other clinical trials, patients with postherpetic neuralgia (n=852) or epilepsy (n=670) were treated pregabalin (same doses as above) or placebo (n=398 or n=294). In these trials, ataxia was reported in up to 15% of pregabalin-treated patients, compared with up to 4% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) In clinical trials, patients with neuropathic pain associated with diabetic peripheral neuropathy (n=979) were treated with pregabalin 75 mg/day, 150 mg/day, 300 mg/day, or 600 mg/day vs placebo (n=459). In other clinical trials, patients with postherpetic neuralgia (n=852) or epilepsy (n=670) were treated with pregabalin (same doses as above) or placebo (n=398 or n=294). In these trials, tremor was reported in up to 8% of pregabalin-treated patients, compared with up to 4% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    F) DISTURBANCE IN THINKING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, patients with neuropathic pain associated with diabetic peripheral neuropathy (n=979) were treated with pregabalin 75 mg/day, 150 mg/day, 300 mg/day, or 600 mg/day vs placebo (n=459). In other clinical trials, patients with postherpetic neuralgia (n=852) or epilepsy (n=670) were treated pregabalin (same doses as above) or placebo (n=398 or n=294). In these trials, difficulty with concentration/attention, language problems, and slowed thinking were reported in up to 8% of pregabalin-treated patients, compared with up to 2% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    G) AMNESIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials, patients with neuropathic pain associated with diabetic peripheral neuropathy (n=979) were treated with pregabalin 75 mg/day, 150 mg/day, 300 mg/day, or 600 mg/day vs placebo (n=459). In other clinical trials, patients with postherpetic neuralgia (n=852) or epilepsy (n=670) were treated pregabalin (same doses as above) or placebo (n=398 or n=294). In these trials, amnesia was reported in up to 5% of pregabalin-treated patients, compared with up to 2% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    H) DISTURBANCE IN SPEECH
    1) WITH THERAPEUTIC USE
    a) In clinical trials, patients with neuropathic pain associated with diabetic peripheral neuropathy (n=979) were treated with pregabalin 75 mg/day, 150 mg/day, 300 mg/day, or 600 mg/day vs placebo (n=459). In other clinical trials, patients with postherpetic neuralgia (n=852) or epilepsy (n=670) were treated pregabalin (same doses as above) or placebo (n=398 or n=294). In these trials, speech disorder was reported in up to 7% of pregabalin-treated patients, compared with up to 1% taking placebo (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    I) MYOCLONUS
    1) WITH THERAPEUTIC USE
    a) Myoclonus, usually multifocal, has been observed during pregabalin therapy. In 2 series of epileptic patients, myoclonus developed in 6 of 25 patients (24%) treated with 50 to 600 mg daily for periods of 1 to 45 days as add-on therapy to other antiepileptic agents (carbamazepine alone or combined with lamotrigine, phenytoin, tiagabine, clobazam or phenobarbital) (Asconape et al, 1999; Huppertz et al, 2001). The highest frequency of myoclonic jerks occurred in a patient receiving rapid upward dose titration (to 600 mg); the frequency and intensity decreased upon dose reduction (from 600 mg to 450 mg daily) (Huppertz et al, 2001) .
    1) In another 5 patients, intensity was not severe and therapy was continued with persistent myoclonus. The mechanism is unclear. Five patients in these case reports were receiving concomitant carbamazepine therapy, which has been associated with myoclonic jerking. However, all cases of myoclonus were new-onset, with no evidence of myoclonic symptoms prior to addition of pregabalin. One patient was receiving only concomitant phenytoin/lamotrigine.
    b) The occurrence of myoclonus during therapy is not an absolute indication to discontinue the drug; many patients with low- or moderate-intensity myoclonus have continued therapy without further worsening, even with dose increases (Huppertz et al, 2001).
    c) CASE REPORT: A 58-year-old, hemodialysis-dependent woman with multiple myeloma was treated with pregabalin 75 mg/day for arthritis of the knees. After five days of once-daily dosing, she developed muscle spasms, myoclonus, ataxia, and dysarthria. All symptoms promptly resolved following discontinuation of pregabalin and performing 2 sessions of hemodialysis (Homs et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 30 year-old hemodialysis-dependent woman with a history of bladder cancer and obstructive uropathy developed severe myoclonus after inadvertently receiving 75 mg of pregabalin every 8 hours (previous dose 50 mg/day) for approximately 3 days. Severe myoclonus of the arms and legs was temporally related to pregabalin and therapy was discontinued. Symptoms improved after the first session of hemodialysis with complete resolution of myoclonus following the second session of hemodialysis (Yoo et al, 2009).
    J) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, the following adverse events were reported pregabalin-treated patients: neuropathy, confusion, euphoria, incoordination, abnormal gait, nervousness, and twitching (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    b) In other studies, the adverse CNS effects have included asthenia (5.7% to 10%), ataxia (3.4% to 10.1%) headache (5.6% to 9.3%), blurred vision (3.4% to 10.1%), tremor (3.4% to 11.2%), and incoordination (2.3% to 10.1%) (French et al, 2003; French et al, 1999; Abou-Khalil et al, 1999; Bailer et al, 2001; Nicholson & Leach, 2001; Willmore, 2000; Czuczwar & Patsalos, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported with therapeutic use of pregabalin (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth has been reported with therapeutic use, and has been more frequently associated with higher doses (600 mg/day) (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    C) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting has been reported infrequently with therapy (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    b) Vomiting was reported frequently after 300 mg single doses in post-dental surgery patients in 1 study, although a specific incidence was not provided (Hill et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ACQUIRED PLATELET DISORDER
    1) WITH THERAPEUTIC USE
    a) A mean maximal decrease in platelet count of 20 x 10(3)/mcL was observed in pregabalin-treated patients, compared with 11 x 10(3)/mcL in placebo patients. Overall, 3% of pregabalin and 2% of placebo patients experienced clinically significant decreases in platelets, defined as 20% below baseline value and less than 150 x 10(3)/mcL (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) During clinical trials, 3 pregabalin-treated patients developed rhabdomyolysis (Prod Info Lyrica, 2005).
    1) In clinical trials, mean changes in creatine kinase were 60 Units/L from baseline for pregabalin-treated patients and 28 Units/L for patients taking placebo. In all trials across multiple patient populations, a value at least 3 times the upper limit of normal was observed in 2% of the pregabalin-treated patients and 1% of placebo patients (Prod Info Lyrica, 2005).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of angioedema in patients during initial and chronic therapy with pregabalin. Symptoms have included swelling of the face, lips, tongue and neck (throat and larynx). Emergency care has been required in some cases due to severe respiratory compromise (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity (skin redness blisters, hives, rash, dyspnea and wheezing) has been observed in some patients following the initiation of pregabalin therapy (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate and well-controlled studies of pregabalin in pregnant women. However, animal reproduction studies of the drug's administration during organogenesis demonstrated increased incidences of fetal structural abnormalities and signs of developmental toxicity including skeletal malformations, retarded ossification, and decreased fetal body weights. Advise pregnant women of the potential for fetal harm if pregabalin is used during pregnancy. Advise men taking pregabalin who plan to father a child of the potential risk to the fetus. Pregabalin is excreted in human milk. Because of the potential risk of tumorigenicity in breastfed infants, advise women to avoid breastfeeding during pregabalin therapy.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) In animal studies, pregabalin was associated with an increased risk of male-mediated teratogenicity (Prod Info LYRICA oral capsules, oral solution, 2016).
    B) MAJOR BIRTH DEFECTS
    1) A multicenter observational prospective cohort study compared pregnancy outcomes in 164 women exposed to pregabalin and 656 matched controls. After the exclusion of chromosomal aberration syndromes as well as an analysis of cases of first-trimester pregabalin exposure, a significantly higher rate of major birth defects was observed in the pregabalin exposure group. Although definitive conclusions cannot be drawn due to several study limitations, the study's findings suggest that pregabalin should be prescribed to women of childbearing potential only after a thorough risk-benefit analysis is performed and that enhanced fetal monitoring may be required in cases of pregabalin exposure during pregnancy (Winterfeld et al, 2016).
    C) ANIMAL STUDIES
    1) The administration of oral pregabalin during organ formation led to an increased incidence of specific skull alterations attributed to abnormally advanced ossification at higher doses and increased incidences of retarded ossification and skeletal variations at all doses. The low dose was associated with a plasma exposure (AUC) approximately 17 times the maximum recommended human dose (Prod Info LYRICA oral capsules, oral solution, 2016).
    2) Pregabalin administration during gestation and lactation resulted in reduced offspring growth, decreased offspring survival, and even 100% mortality. Testing of adult offspring showed neurobehavioral abnormalities and reproductive impairments. The lowest dose was associated with a plasma exposure approximately 2 times the maximum recommended human dose. A prenatal-postnatal study in rats showed that pregabalin prolonged gestation and induced dystocia at doses greater than or equal to 50 times the mean human exposure (AUC) (Prod Info LYRICA oral capsules, oral solution, 2016).
    3) The administration of oral pregabalin during organogenesis resulted in decreased fetal body weight and increased incidences of skeletal malformations, retarded ossification, and visceral variations. No developmental toxicity was noted at a plasma exposure approximately 16 times the maximum recommended dose (Prod Info LYRICA oral capsules, oral solution, 2016).
    4) Pregabalin administration during pregnancy at doses that produced plasma exposures 5 times or more the maximum recommended human dose showed higher rates of fetal structural abnormalities and developmental toxicities, including lethality, growth retardation, and nervous and reproductive system functional impairments (Prod Info LYRICA oral capsules, oral solution, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Advise pregnant women of the potential for fetal harm if pregabalin is used during pregnancy. Advise men taking pregabalin who plan to father a child of the potential risk to the fetus (Prod Info LYRICA oral capsules, oral solution, 2016).
    B) PREGNANCY REGISTRY
    1) The North American Antiepileptic Drug Pregnancy Registry monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. Physicians are advised to encourage pregnant patients taking pregabalin to enroll in the registry by calling 1-888-233-2334. Patients may also obtain information on the NAAED on the website: www.aedpregnancyregistry.org/ (Prod Info LYRICA oral capsules, oral solution, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Small amounts of pregabalin have been detected in human milk at concentrations approximately 76% of maternal plasma concentrations. It has not been evaluated whether pregabalin therapy affects milk production or has effects on the breastfed infant. Because of the potential risk of tumorigenicity in breastfed infants, advise women to avoid breastfeeding during pregabalin therapy (Prod Info LYRICA oral capsules, oral solution, 2016).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) In a double-blind, placebo-controlled trial, 30 healthy men were exposed to pregabalin at 600 mg/day. After 3 months, neither group had a mean change in sperm motility of more than 2% from baseline. Other male reproductive effects in humans have not been adequately studied (Prod Info Lyrica(R) oral capsules, 2009; Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) ANIMAL STUDIES
    1) Decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size and weights, and increased fetal abnormalities were observed when oral pregabalin was administered to males before and during mating with untreated females. Effects on sperm and fertility were reversible in studies of 3 to 4 months of duration. The no-effect dose for male reproductive toxicity was associated with a plasma pregabalin exposure of approximately 3 times the maximum recommended human exposure (Prod Info LYRICA oral capsules, oral solution, 2016).
    2) Adverse effects on the testes and epididymides were observed histopathologically in males exposed to pregabalin for 4 weeks or more. The no-effect dose for male reproductive organ histopathology was associated with a plasma exposure approximately 8 times the maximum recommended human dose (Prod Info LYRICA oral capsules, oral solution, 2016).
    3) Disruptions in the estrous cycle led to more days to mating when oral doses were given to females before and during mating and early gestation. Embryo death occurred at the highest dose. A no-effect dose for female reproductive toxicity was not established; at the lowest dose, plasma exposure was approximately 9 times the maximum recommended dose (Prod Info LYRICA oral capsules, oral solution, 2016).
    4) In animal studies, pregabalin was associated with an increased risk of male-mediated teratogenicity. Advise men taking pregabalin who plan to father a child of the potential risk to the fetus (Prod Info LYRICA oral capsules, oral solution, 2016).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS148553-50-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of pregabalin.
    3.21.4) ANIMAL STUDIES
    A) HEMANGIOSARCOMA
    1) MICE: There was evidence of a dose-dependent increase in hemangiosarcomas when 2 strains of mice were given oral pregabalin at doses of 200, 1000, or 5000 mg/kg for 2 years. The lowest dose at which an increased frequency of hemangiosarcomas occurred in these mice was approximately equal to the human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose in mice was not established (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) LACK OF EFFECT
    1) RATS: There was no evidence of carcinogenicity in 2 rat studies in which male and female rats were given pregabalin at doses of 50, 150, or 450 mg/kg (14 times the maximum recommended human dose (MRHD) of 600 mg/day) and 100, 300, or 900 mg/kg (24 times the MRHD), respectively, for 2 years (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Genotoxicity

    A) There was no evidence of mutagenicity or clastogenicity of pregabalin in the following tests: unscheduled DNA synthesis in rat or mouse hepatocytes, mammalian systems in vitro and in vivo, or bacterial or mammalian cells in vitro (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor ECG for PR prolongation and CBC for decreased platelets.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) In patients with muscle pain, weakness or tenderness, monitor CK for rhabdomyolysis.
    4.1.2) SERUM/BLOOD
    A) Monitor ECG for PR prolongation, and CBC for decreased platelets. Monitor serum electrolytes in patients with significant vomiting. In patients with muscle pain, weakness or tenderness, monitor CK for rhabdomyolysis.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit all moderately to severely symptomatic patients, especially if there is a concern for falls, inability to care for self, or risk of worsening central nervous system depression.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with inadvertent ingestions who are not symptomatic may be observed at home with telephone follow up.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Involve a toxicologist or poison center with any patient with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Observe all patients who are symptomatic for 4 to 6 hours. When patients are asymptomatic they may be discharged home.

Monitoring

    A) Monitor ECG for PR prolongation and CBC for decreased platelets.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) In patients with muscle pain, weakness or tenderness, monitor CK for rhabdomyolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is SYMPTOMATIC and SUPPORTIVE. Intubation and mechanical ventilation may be necessary in patients who develop significant CNS depression.
    B) MONITORING OF PATIENT
    1) Monitor ECG for mild PR prolongation, and CBC for decreased platelets.
    2) Monitor fluid and electrolytes in patients with significant vomiting.
    3) In patients with muscle pain, weakness or tenderness, monitor CK for rhabdomyolysis.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis has been used in a hemodialysis-dependent patient following inadvertent pregabalin exposure (Yoo et al, 2009). The manufacturer has suggested that hemodialysis might be useful in patients with severe toxicity or those with significant renal impairment. Standard hemodialysis results in pregabalin clearance of approximately 50% in 4 hours (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    2) CASE REPORT: A 30 year-old hemodialysis-dependent woman with a history of bladder cancer and obstructive uropathy developed pregabalin toxicity, which was successfully treated with hemodialysis. The patient had been receiving pregabalin therapy (50 mg daily) for neuropathic pain, which was inadvertently increased to 75 mg every 8 hours for approximately 3 days. Severe myoclonus of the arms and legs was temporally related to pregabalin and therapy was discontinued. Pregabalin concentration predialysis was 13 mcg/mL (therapeutic: up to 9.5 mcg/mL) and postdialysis serum concentrations were 6.5 mcg/mL (2-hour session on day 7) and 2.0 mcg/mL (4-hour session on day 8). Symptoms improved after the first session with complete resolution of myoclonus following the second session of hemodialysis (Yoo et al, 2009). The authors report a pregabalin clearance of 88.8 mL/min with hemodialysis with complete resolution of symptoms, which is consistent with the pharmacokinetic properties (ie, low molecular weight, low volume of distribution) of pregabalin.

Range Of Toxicity

Summary

    A) TOXICITY: During clinical development, the highest reported accidental overdose of pregabalin was 8000 mg; no notable consequences were observed. An adult intentionally ingested 8.4 g of pregabalin and developed CNS depression and coma requiring mechanical ventilation for 26 hours; neurologic status gradually improved with no permanent sequelae. During clinical studies, some patients took as much as 2400 mg/day. Adverse events in patients exposed to doses greater than or equal to 900 mg were not clinically different from those of patients who received the recommended dose.
    B) THERAPEUTIC DOSE: ADULT: Initial dose: 150 mg/day. Maximum dose: 600 mg/day. PEDIATRIC: The safety and efficacy of pregabalin have not been determined in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) DIABETIC PERIPHERAL NEUROPATHY PAIN
    1) The recommended initial dose is 50 mg 3 times per day (150 mg/day), which may be increased to 100 mg 3 times per day (300 mg/day) within 1 week based on efficacy and tolerability. MAXIMUM DOSE: 300 mg/day (Prod Info LYRICA oral capsules, oral solution, 2012).
    B) FIBROMYALGIA
    1) The recommended initial dose is 75 mg twice daily (150 mg/day), which may be increased to 150 mg twice daily (300 mg/day) within 1 week based on efficacy and tolerability. MAXIMUM DOSE: 450 mg/day (Prod Info LYRICA oral capsules, oral solution, 2012).
    C) PARTIAL ONSET SEIZURE, ADJUNCT
    1) The recommended initial dose is no greater than 75 mg twice daily or 50 mg 3 times per day (150 mg/day), which may be increased to 600 mg/day in 2 or 3 divided doses based on efficacy and tolerability. MAXIMUM DOSE: 600 mg/day (Prod Info LYRICA oral capsules, oral solution, 2012).
    D) POSTHERPETIC NEURALGIA
    1) The recommended initial dose is 75 mg twice daily or 50 mg 3 times per day (150 mg/day), which may be increased to 300 mg/day within 1 week based on efficacy and tolerability. MAXIMUM DOSE: 600 mg/day (Prod Info LYRICA oral capsules, oral solution, 2012).
    E) SPINAL CORD INJURY NEUROPATHIC PAIN
    1) The recommended initial dose is 75 mg 2 times per day (150 mg/day), which may be increased to 300 mg/day within 1 week based on efficacy and tolerability. MAXIMUM DOSE: 600 mg/day (Prod Info LYRICA oral capsules, oral solution, 2012).
    F) NOTE: When discontinuing pregabalin, therapy should be tapered gradually over a minimum of 1 week (Prod Info LYRICA oral capsules, oral solution, 2012).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of pregabalin have not been established in pediatric patients (Prod Info LYRICA oral capsules, oral solution, 2012).

Maximum Tolerated Exposure

    A) SUMMARY
    1) During clinical development, the highest reported accidental overdose of pregabalin was 8000 mg; no notable consequences were observed. During clinical studies, some patients took as much as 2400 mg/day. Adverse events in patients exposed to doses greater than or equal to 900 mg were not clinically different from those of patients who received recommended doses of pregabalin (Prod Info Lyrica(R) oral capsules, 2009).
    B) CASE REPORT
    1) A 54-year-old man intentionally ingested 8.4 g of pregabalin (serum concentration 66.5 mg/L) and developed CNS depression and coma approximately 3 hours after exposure. The patient was admitted to the Intensive Care Unit and intubated and mechanically ventilated for 26 hours when his neurological status gradually improved. He was extubated without difficulty. The patient did develop aspiration pneumonia during his admission, that was treated successfully with intravenous antibiotics. Following psychiatric review, the patient was deemed capable and refused any further treatment (Wood et al, 2010).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 54-year-old man intentionally ingested 8.4 g of pregabalin and developed significant CNS depression and coma approximately 3 hours after exposure. A serum concentration of 66.5 mg/L (highest level reported to date) was obtained at the time the patient became comatose. The patient improved neurologically over the next 26 hours with supportive care (intubation and mechanical ventilation). No permanent sequelae was observed (Wood et al, 2010).
    2) CASE REPORT: A 59-year-old woman had a pregabalin serum concentration of 29 mcg/mL approximately 9 hours after an intentional ingestion of an unknown amount. Mild drowsiness was the only symptom observed (Spiller et al, 2008).
    3) CASE REPORT: A 30 year-old hemodialysis-dependent woman developed severe myoclonus after inadvertently receiving 75 mg of pregabalin every 8 hours for approximately 3 days. The pregabalin concentration predialysis was 13 mcg/mL (therapeutic: up to 9.5 mcg/mL) and postdialysis serum concentrations were 6.5 mcg/mL (2-hour session) and 2.0 mcg/mL (4-hour session). Symptoms resolved completely after the second session of hemodialysis (Yoo et al, 2009).

Workplace Standards

    A) ACGIH TLV Values for CAS148553-50-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS148553-50-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS148553-50-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS148553-50-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pregabalin binds with high affinity to the alpha(2)-delta site in central nervous system tissues. The mechanism of action is unknown; however, results with genetically altered mice and with compounds structurally related to pregabalin suggest that binding to the alpha(2)-delta subunit may be involved in pregabalin's antiseizure and antinociceptive effects in animal models. Pregabalin reduces the calcium-dependent release of several neurotransmitters in vitro, possibly by modulation of calcium channel function (Prod Info LYRICA(R) oral capsules, oral solution, 2009).
    B) Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA); however, it does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation; does not bind directly to GABA(A), GABA(B), or benzodiazepine receptors; and does not augment GABA(A) responses in cultured neurons. In cultured neurons, repeated application of pregabalin increases the rate of functional GABA transport and increases the density of GABA transporter protein. Pregabalin is not active at opiate receptors, does not alter cyclooxygenase enzyme activity, and does not block sodium channels (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Physicochemical

Physical Characteristics

    A) Pregabalin is an off-white to white crystalline solid that is freely soluble in water and both basic and acidic aqueous solutions (Prod Info LYRICA(R) oral capsules, oral solution, 2009).

Molecular Weight

    A) 159.23 (Prod Info LYRICA(R) oral capsules, oral solution, 2009)

References

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