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GABAPENTIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gabapentin is an amino acid structurally related to gamma-aminobutyric acid (GABA), but is able to cross the blood-brain barrier due to a cyclohexane structure that confers a lipophilic property to the drug. It does not interact with GABA receptors and it is not an inhibitor of GABA uptake or degradation. It is used for the treatment of seizures and postherpetic neuralgia.

Specific Substances

    1) Gabapentin enacarbil
    2) GOE-3450
    3) 1-(Aminomethyl) cyclohexaneacetic acid
    4) CI 945
    5) CI-945
    6) CAS 60142-96-3
    1.2.1) MOLECULAR FORMULA
    1) C9H17NO2

Available Forms Sources

    A) FORMS
    1) Gabapentin is available in the United States as 100 mg, 300 mg, and 400 mg capsules, 100 mg, 300 mg, 400 mg, 600 mg, and 800 mg tablets, and 250 mg/5 mL oral solution, and 300 mg and 600 mg oral extended-release tablets (Prod Info HORIZANT(R) oral extended-release tablets, 2013; Prod Info Neurontin(R) oral capsules, tablets, solution, 2009; Prod Info gabapentin oral tablets, 2006).
    B) USES
    1) Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in epileptic patients older than 12 years of age, and as adjunctive therapy in the treatment of partial seizures in patients 3 to 12 years of age (Prod Info Neurontin(R) oral capsules, tablets, solution, 2009).
    2) Gabapentin is indicated for the treatment of postherpetic neuralgia in adults (Prod Info Neurontin(R) oral capsules, tablets, solution, 2009).
    3) Gabapentin enacarbil extended-release is indicated in adult patients for the management of postherpetic neuralgia and moderate-to-severe primary restless legs syndrome (RLS)(Prod Info HORIZANT(R) oral extended-release tablets, 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: Gabapentin is approved by the US Food and Drug Administration (FDA) for the treatment of partial seizures (with and without secondary generalization) and postherpetic neuralgia. Gabapentin is also used for the treatment of diabetic peripheral neuropathy, migraines, pain disorders, and various mood and movement disorders (non-FDA labeled indications).
    B) PHARMACOLOGY: Gabapentin is a highly lipophilic amino acid structurally similar to GABA, but does not bind GABA receptors or alter levels in the brain. Gabapentin’s mechanism of action is unclear.
    C) TOXICOLOGY: Although gabapentin’s mechanism of action is unclear, its sedating effects are likely secondary to its lipophilic configuration and structural similarity to the inhibitory neurotransmitter GABA.
    D) EPIDEMIOLOGY: Gabapentin overdose is uncommon and manifestations are usually not severe.
    E) WITH THERAPEUTIC USE
    1) Following therapeutic use, sedation, ataxia, dizziness, fatigue, nystagmus, hypotension, and hypertension have occurred. Leukopenia has also been described with therapeutic use. Rhabdomyolysis is a rare adverse effect.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: In mild to moderate overdose, patients may present with sedation, ataxia, slurred speech, nystagmus, movement disorders, and gastrointestinal upset.
    2) SEVERE TOXICITY: In more severe cases, patients may present with mild hypotension and profound central nervous system depression requiring intubation.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hypertension has been reported following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Gabapentin and gabapentin enacarbil are classified as FDA pregnancy category C. There is evidence of placental transfer of gabapentin when administered during pregnancy and transfer to the nursing infant when administered to nursing mothers. In animal studies, rodents experienced developmental and fetal toxicity with gabapentin administration, and gabapentin enacarbil administration resulted in developmental toxicity, increased embryo-fetal mortality, and decreased fetal weight in rats and rabbits.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity was not directly assessed in human clinical trials. However, in clinical studies of gabapentin as adjunctive therapy in epilepsy, 10 patients were reported to develop new tumors, and 11 patients had preexisting tumors that worsened during treatment or up to 2 years following discontinuation of gabapentin.

Laboratory Monitoring

    A) Gabapentin serum concentrations are not readily available or useful in guiding therapy.
    B) Basic laboratory studies along with acetaminophen and salicylate levels can be ordered for severely symptomatic or self-harm patients. No studies are required for minimally symptomatic patients who have not attempted self-harm.
    C) Monitor mental status and vital signs in symptomatic patients.
    D) Monitor CK in patients with muscle pain, tenderness or weakness, and renal function and urine output in patients with rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment of gabapentin exposure is largely supportive with mild/moderate symptoms. An observation period of 4 to 6 hours is reasonable.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment of gabapentin 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: Activated charcoal may be utilized to limit adsorption in patients with large, recent ingestions; however, risk of aspiration should be considered prior to administration.
    D) AIRWAY MANAGEMENT
    1) In severely ill patients, airway management is paramount.
    E) ANTIDOTE
    1) None. In one case report, flumazenil was effectively used to treat gabapentin-induced coma in a hemodialysis-dependent man with end-stage renal disease.
    F) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    G) ENHANCED ELIMINATION
    1) Gabapentin can be removed by hemodialysis; it has a small volume of distribution and minimal protein binding. However, as toxicity is generally mild, hemodialysis is rarely indicated. Hemodialysis may be useful in patients with renal insufficiency who are severely symptomatic.
    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 with any questions or concerns.
    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) Time to peak concentration is 1.5 to 4 hours after therapeutic use. Approximately 50% to 60% is absorbed from the gastrointestinal tract. Volume of distribution is 50 to 60 L; protein binding is less than 3%, and elimination half-life is 5 to 7 hours after therapeutic use.
    K) PREDISPOSING CONDITIONS
    1) Patients with renal insufficiency are predisposed to toxicity.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other anticonvulsants, ethanol, benzodiazepines, and lithium.

Range Of Toxicity

    A) TOXICITY: Overdoses of 35 g or less have been associated with mild toxicity in adults. Doses of 40 g or more have been associated with moderate toxicity in adults. A woman ingested 90 g of immediate release gabapentin and developed only mild symptoms that did not require any clinical intervention. An adult ingested more than 100 g and recovered with supportive care.
    B) THERAPEUTIC DOSE: ADULT: 900 to 3600 mg divided into three doses daily orally. PEDIATRIC: 10 mg/kg to 40 mg/kg in 3 divided doses daily.

Clinical Effects

Summary Of Exposure

    A) USES: Gabapentin is approved by the US Food and Drug Administration (FDA) for the treatment of partial seizures (with and without secondary generalization) and postherpetic neuralgia. Gabapentin is also used for the treatment of diabetic peripheral neuropathy, migraines, pain disorders, and various mood and movement disorders (non-FDA labeled indications).
    B) PHARMACOLOGY: Gabapentin is a highly lipophilic amino acid structurally similar to GABA, but does not bind GABA receptors or alter levels in the brain. Gabapentin’s mechanism of action is unclear.
    C) TOXICOLOGY: Although gabapentin’s mechanism of action is unclear, its sedating effects are likely secondary to its lipophilic configuration and structural similarity to the inhibitory neurotransmitter GABA.
    D) EPIDEMIOLOGY: Gabapentin overdose is uncommon and manifestations are usually not severe.
    E) WITH THERAPEUTIC USE
    1) Following therapeutic use, sedation, ataxia, dizziness, fatigue, nystagmus, hypotension, and hypertension have occurred. Leukopenia has also been described with therapeutic use. Rhabdomyolysis is a rare adverse effect.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: In mild to moderate overdose, patients may present with sedation, ataxia, slurred speech, nystagmus, movement disorders, and gastrointestinal upset.
    2) SEVERE TOXICITY: In more severe cases, patients may present with mild hypotension and profound central nervous system depression requiring intubation.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypertension has been reported following therapeutic doses.
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) It may be advisable to monitor blood pressure in overdoses, as hypertension has been reported following therapeutic doses of gabapentin (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision, diplopia and nystagmus have occasionally been reported following therapeutic doses of gabapentin (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    B) WITH POISONING/EXPOSURE
    1) Overdoses have been associated with diplopia (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Rhinitis, coughing and pharyngitis have been associated with gabapentin therapy (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) SUFFOCATING
    1) WITH POISONING/EXPOSURE
    a) Theoretically, aspiration can occur in a lethargic or comatose patient. Somnolence has frequently been reported following gabapentin overdose (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    B) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Gabapentin therapy was associated with hypoventilation, hypercapnia, and respiratory failure in a 69-year-old man under treatment for chronic obstructive pulmonary disease (COPD), insomnia, and anxiety disorder (Batoon et al, 2001).
    b) CASE REPORT: After taking multiple doses of gabapentin over two days, without intervening hemodialysis, a 46-year-old woman with endstage renal disease became hypoxic and somnolent. Her oxygen saturation was 80% on room air and she was subsequently intubated. She had a Glasgow Coma Scale score of 8 and a gabapentin level of 22.6 mcg/mL. Following hemodialysis her mental status rapidly improved and she was extubated. This gabapentin level is less than previous literature reports of toxicity. The authors suggested that gabapentin toxicity should be considered when patients receiving gabapentin with endstage renal disease show signs of impaired mental functioning (Jones et al, 2002).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Following therapeutic doses of gabapentin, the most common adverse effects reported have been somnolence, dizziness, and fatigue. Other less common adverse effects have been tremors, slurred speech, impaired concentration, and headache (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    b) CASE REPORT: A 57-year-old woman with diabetes mellitus and uremia on regular hemodialysis (three times a week) presented with dizziness and vomiting two hours after taking a single recommended dose of gabapentin (half a tablet). She developed altered consciousness with lethargy four hours later. Following a session of hemodialysis, she recovered completely and was discharged after 24 hours of observation (Hung et al, 2008).
    c) CASE REPORT: A 75-year-old woman with mild renal impairment (baseline, serum creatinine 1.3 mg/dL; urea 60.8 mg/dL; estimated glomerular filtration rate 43 mL/min/1.73 m(2)) developed significant drowsiness two days after taking gabapentin 300 mg 3 times daily for pain. Her condition worsened over the next several days and gabapentin toxicity was suspected. Following the discontinuation of gabapentin and supportive care, including 5 days of continuous venovenous hemofiltration, she recovered completely (Miller & Price, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a prospective, observational study, drowsiness was commonly reported following gabapentin exposure. Most symptoms developed in less than 5 hours (Klein-Schwartz et al, 2003).
    b) CASE REPORT: Fischer et al (1994) report the case of a 16-year-old female who experienced somnolence and dizziness following the ingestion of 48.9 grams gabapentin.
    c) CASE REPORT: Somnolence and slurred speech, which resolved over 12 hours, were reported in a 31-year-old man approximately 1 to 2 hours following an overdose of gabapentin (108 g), valproic acid (54 g) and beer (Fernandez et al, 1995).
    d) Following acute overdoses of up to 49 g, the major adverse events reported were drowsiness, lethargy and slurred speech (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    e) CASE REPORT: A 17-year-old female was reported to experience somnolence, dysarthria, ataxia, and lethargy following an overdose of gabapentin (12,000 mg) and lamotrigine (2,000 mg). She fully recovered following supportive care (Stopforth, 1997).
    B) COMA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 83-year-old man, with end-stage renal disease on chronic hemodialysis who was hospitalized for an above the knee amputation, developed profound mental deterioration and coma 4 hours after receiving a 200 mg dose of gabapentin for ongoing pain. The patient was initially treated with flumazenil and his mental status improved, which was followed by a trial of hemodialysis. Within 30 minutes of dialysis the patient was fully awake and the drug concentration declined; no permanent sequelae occurred (Butler et al, 2003a).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 61-year-old woman developed coma (responsive to pain only) after ingesting an estimated 54 g (180 capsules of 300 mg) gabapentin. She was believed to have also ingested quetiapine, which likely contributed to her CNS depression (Spiller et al, 2002). Ten hours after presentation she was awake and could recognize staff.
    C) NYSTAGMUS
    1) WITH THERAPEUTIC USE
    a) Nystagmus and diplopia have been reported following overdoses as well as therapeutic doses of gabapentin (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) An increase in frequency of partial seizures has been observed infrequently following therapeutic doses of gabapentin (Anon, 1990).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 30-year-old woman with dialysis dependent renal failure developed chronic gabapentin intoxication (tremors and cognitive impairment) while receiving 600 mg of gabapentin 3 times daily. Her serum gabapentin level was 85 mcg/mL (reference level, 2-15 mcg/mL). Following a dose reduction (600 mg 3 times weekly after each dialysis), her serum level returned to normal; however, the tremor and encephalopathy persisted until phenytoin was added to her therapy and valproate discontinued (Verma et al, 1999).
    F) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old man presented with painful sensory polyneuropathy (constant burning sensation in his lower extremities extending to his hips) and pruritic rash approximately 5 months following initiation of gabapentin therapy (maximum dose, 2400 mg/day) for treatment of neuropathic pain syndrome. Symptoms were exacerbated for approximately 2 months following discontinuation of gabapentin (Gould, 1998).
    G) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 26-year-old man, with a prior history of IV drug abuse, took a recreational single 1600 mg dose of gabapentin and approximately one hour later developed head rotation to the left and a clenched jaw, with visible intermittent involuntary spasmodic contractions of the neck and jaw musculature. Symptoms resolved completely after being treated with a single IV dose of procyclidine 10 mg. Based on the current literature, the authors report that the mechanism of how gabapentin causes dystonic reactions remains unknown (Rohman & Hebron, 2014).
    H) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Two men developed generalized dyskinetic movements of the face and limbs 3 days after receiving gabapentin 900 mg or 1200 mg per day, respectively. The men were being treated for anxiety. Withdrawal of the drug resulted in resolution of abnormal movements within 1.5 to 3 days, respectively (Norton & Quarles, 2001).
    I) NEUROTOXICITY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 75-year-old man with renal dysfunction (creatinine clearance 26 mL/min; BUN 74 mg/dL [8 to 23 mg/dL]) developed neurologic toxicity (episodes of multifocal myoclonus, altered mental status, ataxia, and tremors) after taking gabapentin 800 mg 4 times/day for postherpetic neuralgia. On hospital day 1, his gabapentin dose was stopped and the patient's symptoms resolved following supportive care (Bookwalter & Gitlin, 2005).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) Acute animal exposures of as high as 8000 mg/kg produced signs including ataxia, labored breathing, ptosis, somnolence, hypoactivity, or excitation (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Nausea, gastric upset, and vomiting have been reported infrequently following therapeutic doses (Sivenius et al, 1991; Anon, 1990; Crawford et al, 1987).
    b) CASE REPORT: Vomiting and altered consciousness developed in a 57-year-old woman with diabetes mellitus and uremia on regular hemodialysis (three times per week), two hours after taking a single recommended dose of gabapentin (half a tablet). Following a session of hemodialysis, she recovered completely and was discharged after 24 hours of observation (Hung et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) Acute overdoses of as high as 49 grams have produced minimal effects, but abdominal pain and diarrhea appear to be major effects (Fischer et al, 1994; Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTASIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 50-year-old diabetic man with peripheral neuropathy was treated with a titrated dose of gabapentin (300 mg daily on day 1; 300 mg twice daily on day 2; and 300 mg three times daily thereafter) for 2 weeks and developed signs and symptoms of cholestasis. Liver function tests were elevated; screening for hepatitis was negative. Laboratory studies and symptoms improved with drug cessation (Richardson et al, 2002).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) Impotence has been reported in 1.5% of patients treated with therapeutic doses of gabapentin (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    B) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) Weight gain and painful gynecomastia were reported in a 64-year-old man with terminal cancer, 3 months after starting therapy with gabapentin (2100 mg/day). The authors suggested a mechanism of selective hypothalamic insufficiency of the gonadotropin-releasing hormone axis by gabapentin (Zylicz & Mudde, 2000).
    C) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Two cases of increased serum creatinine after starting gabapentin have been reported. Both patients had a history of chronic renal insufficiency (Silvia & Spitznas, 2007) .
    1) The first patient was a 59-year-old woman who received lithium for 25 years and her baseline serum creatinine when lithium was discontinued was 2.3 mg/dL. Gabapentin was commenced less than 1 week after lithium discontinuation and was titrated to a dose of 3200 mg/day over 2 months. Her serum creatinine continued to increase and peaked at 3.4 mg/dL approximately 5 months after gabapentin therapy was initiated. Despite this 47.8% increase in serum creatinine, gabapentin was continued due to the clinical benefit seen (Silvia & Spitznas, 2007).
    2) The second patient was a 49-year-old man who had been treated with lithium for 3 years, and when the drug was discontinued the patient's serum creatinine was 4 mg/dL. Gabapentin was not started until 10 months after the lithium was stopped, and the dose of gabapentin was titrated to 300 mg/day over 1 month. His serum creatinine continued to increase and plateaued at a peak of 5.2 mg/dL 10 months after starting gabapentin (30% increase). The patient saw clinical benefit with gabapentin, so therapy was continued with appropriate dose reductions (Silvia & Spitznas, 2007).
    D) RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Patients with impaired renal function may develop gabapentin toxicity at therapeutic doses
    b) CASE REPORT: A 75-year-old female presented drowsy and vague after falling at home. Two weeks prior, she had seen her physician for hip pain. She had been maintained on a combination of diclofenac, tramadol and dihydrocodeine for congenital hip dislocation and hemiarthroplasty. Her physician prescribed gabapentin as an analgesic adjunct, although no record of a neuropathic element to the patient's hip pain existed. The gabapentin dose at presentation was 300 mg three times daily.
    1) Along with the patient's lethargy, lab results revealed renal impairment (creatinine 1.56 mg/dL, GFR 34 mL/min) and abnormal liver enzymes. CT showed evidence of dilated common bile duct and bilateral renal cysts. The patient's status declined over the next week, requiring ICU care. A review of her medications on day 10 prompted care givers to discontinue the gabapentin and start CVVH to clear accumulated drug and assist the persistent renal failure (creatinine 1.93 mg/dL). Within 12 hours of initiating CVVH, the patient was markedly more lucid, and she was discharged to floor status after 5 days of renal supportive care (Miller & Price, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in approximately 1% of gabapentin-treated patients as compared with 0.5% of a placebo-controlled group (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes, pruritus, acne or eczema have been occasionally associated with gabapentin therapy (Crawford et al, 1987; Anon, 1990; Sivenius et al, 1991; Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005). Discontinuance of therapy due to a maculopapular skin rash has been reported (Anon, 1990).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens Johnson syndrome has been reported as an adverse effect following therapeutic use. Gonzalez-Sicilia et al (1998) report the onset of facial erythema spreading caudally, pruritus, and epidermal necrosis, later diagnosed as Stevens Johnson syndrome, on the third day of gabapentin therapy in a woman with a history of HIV infection. Discontinuation of gabapentin resulted in resolution of the skin disorder.
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Acute alopecia has been described as an adverse event following gabapentin therapy (Picard et al, 1997).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: In a single case report, the administration of gabapentin appeared to induce rhabdomyolysis in a 63-year-old diabetic woman. The patient had a history of type 2 diabetes mellitus, hypertension, and dyslipidemia. She was taking multiple insulin injections daily, irbesartan 150 mg daily, and gabapentin 300 mg thrice daily, of which gabapentin was prescribed three weeks earlier for diabetic neuropathy. Prior to initiation of gabapentin, her creatinine was 1.2 mg/dL, CPK was 142 units/L, AST was 26 units/L, ALT was 21 units/L, and microalbuminuria was 170 mg/day. On admission, the patient presented with muscle weakness of her lower extremities, muscle pain, fatigue along with decreased urine output, and discolored urine. Physical examination revealed proximal muscle tenderness and weakness, absence of angle jerk reflexes, and decreased vibration sensation. Laboratory testing revealed elevated creatinine level of 7.9 mg/dL, CPK of 75,680 units/L, AST of 1451 units/L, ALT of 453 units/L, LDH of 1847 units/L, potassium level of 6.3 mmol/L, and positive for myoglobin in urine; indicative of acute renal failure and myopathy. Both thyroid hormones and troponin-I were in normal ranges. Muscle biopsy concluded the diagnosis of rhabdomyolysis. Hemodialysis was initiated to remedy hyperkalemia and anuria. Gabapentin was discontinued and parenteral fluids along with furosemide were initiated to induce diuresis, with the patient showing gradual renal improvement. Six months following hospital discharge, the patient was asymptomatic, and her renal function and muscle enzymes were normalized (Bilgir et al, 2009).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses have occasionally been associated with arthralgias(Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Hypoglycemia has been reported in both diabetic and nondiabetic patients receiving gabapentin. It has been suggested that hypoglycemia can occur possibly through GABA(A) receptor activation or binding to the alpha2-gamma2 subunit of pancreatic voltage-gated calcium channels (Scholl et al, 2015).
    b) CASE REPORTS: In one case, a woman with a history of a complex regional pain syndrome was admitted with syncope. Her blood sugar on admission was 1.6 mmol/L (28.8 mg/dL) and she was treated with IV glucose. She had started on gabapentin (1800 mg/day) one month prior to admission and pyridostigmine (180 mg/day) 2 weeks prior to admission to treat her chronic pain syndrome. Gabapentin was reduced and pyridostigmine was discontinued. The patient recovered without sequelae. In another case, a 54-year-old nondiabetic woman was hospitalized for hypoglycemia (minimum blood glucose value 1.3 mmol/L; 23.4 mg/dL) 3 weeks after starting gabapentin for chronic cervical pain. She improved with IV glucose and the discontinuation of gabapentin; no other medications were reported (Scholl et al, 2015).
    B) THYROIDITIS
    1) WITH THERAPEUTIC USE
    a) A case of possible gabapentin-induced thyroiditis has been reported. During a clinical trial, a 28-year-old female developed physical symptoms of hyperthyroidism after receiving gabapentin (4800 mg/day) for several weeks. A normal sized, homogeneous gland with low uptake (1% at 24 hr) was seen on an I-123 uptake scan. Prompt resolution of symptoms occurred following discontinuation of gabapentin (Frye et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Gabapentin and gabapentin enacarbil are classified as FDA pregnancy category C. There is evidence of placental transfer of gabapentin when administered during pregnancy and transfer to the nursing infant when administered to nursing mothers. In animal studies, rodents experienced developmental and fetal toxicity with gabapentin administration, and gabapentin enacarbil administration resulted in developmental toxicity, increased embryo-fetal mortality, and decreased fetal weight in rats and rabbits.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALIES
    1) There was no significantly increased risk of major congenital malformations with first trimester maternal use of gabapentin-monotherapy. According to several pregnancy registries, major congenital malformations were reported in 1.7% of infants with first trimester gabapentin monotherapy exposure compared to 1.6% to 2.2% reported in the general population. Major congenital malformations included: ventricular septal defect, congenital heart disease, endocardial fibroelastosis, tethered spinal cord and hydronephrosis (Guttuso et al, 2014).
    2) No significantly increased incidence of major malformations was found with prenatal gabapentin exposure compared with unexposed infants in one prospective, multicenter study. However, infants with prenatal gabapentin exposure (n=223) experienced significantly more preterm births (10.5% with gabapentin vs 3.9% without gabapentin; p = 0.019), postnatal care in the neonatal intensive care unit (NICU) or special care nursery (SCN) (38% with gabapentin exposure in late pregnancy vs 2.9% without gabapentin; less than 0.001), and low birth weights (below 2500 g; 10.5% with gabapentin vs 4.4% without gabapentin; p = 0.033) compared with infants with no gabapentin exposure (n=223). Indications for NICU or SCN care included arrhythmia, low heart rate, jaundice, hypotonia, hypoglycemia, respiratory distress, jitteriness, diarrhea, and fever, although some institutions observed all neonates with known prenatal exposure to psychotropic drugs, regardless of symptoms. All indications were self-limiting and resolved in up to a week. Major malformations occurred in 4.1% of gabapentin-exposed infants (including ventricular septal defect; anencephaly; macrocephaly, micro retrognathism, and cutis marmorata; pyloric stenosis; bilateral varus clubfoot; and cryptorchidism) and 2.5% of unexposed infants. Among gabapentin-exposed infants with major malformations, daily doses of maternal concomitant gabapentin therapy (no monotherapy was reported) ranged from 600 to 2400 mg/day, with 5 of the 7 infants exposed throughout pregnancy (Fujii et al, 2013).
    3) The Gabapentin Pregnancy Registry has collected data on 39 women with 51 fetuses exposed to the drug. The following malformations were reported: hypospadia in a baby exposed to gabapentin and valproate, congenital solitary kidney in a baby exposed to gabapentin in the first trimester and thereafter phenobarbital, and minor malformation of the left external ear canal in an infant exposed to gabapentin and lamotrigine throughout gestation. The above birth statistics are similar to those reported in women with epilepsy and in the general population. The effects of gabapentin exposure cannot be fully elucidated from these results (Montouris, 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Gabapentin and gabapentin enacarbil have been classified as FDA pregnancy category C (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014; Prod Info HORIZANT(R) oral extended-release tablets, 2013a; Prod Info GRALISE(R) oral tablets, 2011).
    2) To provide data regarding the effects of in utero gabapentin exposure, pregnant patients receiving gabapentin therapy should be instructed to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334; enrollment must be completed by the patient. Further information regarding this pregnancy registry may be found at http://www.aedpregnancyregistry.org/ (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014; Prod Info GRALISE(R) oral tablets, 2011).
    3) Gabapentin or gabapentin enacarbil should only be used during pregnancy if the potential maternal benefit outweighs the potential fetal risk (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014; Prod Info HORIZANT(R) oral extended-release tablets, 2013a).
    B) FETAL AND MATERNAL TOXICITY
    1) The Gabapentin Pregnancy Registry has collected data on 39 women with 51 fetuses exposed to the drug. In the women, one case of hypertension, one case of oligohydramnios, and one case of eclampsia were reported during the pregnancies. There were 44 (86.3%) live births, 6 miscarriages and one elective abortion. Full-term babies accounted for 77.2% of the births. Preterm deliveries occurred between weeks 32 to 36. The time and length of gabapentin exposure in the above cases was not fully described. The above birth statistics are similar to those reported in women with epilepsy and in the general population. The effects of gabapentin exposure cannot be fully elucidated from these results (Montouris, 2003).
    C) PLACENTAL BARRIER
    1) Data from a limited study of 6 women who were administered gabapentin during pregnancy and lactation demonstrated fetal accumulation of gabapentin. The women were given gabapentin doses ranging from 900 to 3200 mg/day. While 1 woman had a premature delivery at week 33, the remaining deliveries were uneventful and resulted in healthy children. At the time of delivery, the mean umbilical-to-maternal gabapentin plasma concentration ratio was 1.74. The study investigators conclude that this ratio is indicative of an active transplacental transport of gabapentin (Ohman et al, 2005).
    D) PRETERM BIRTH, INCREASED NICU RISK, AND LOW BIRTH WEIGHT
    1) No significantly increased incidence of major malformations was found with prenatal gabapentin exposure compared with unexposed infants in one prospective, multicenter study. However, infants with prenatal gabapentin exposure (n=223) experienced significantly more preterm births (10.5% with gabapentin vs 3.9% without gabapentin; p = 0.019), postnatal care in the neonatal intensive care unit (NICU) or special care nursery (SCN) (38% with gabapentin exposure in late pregnancy vs 2.9% without gabapentin; less than 0.001), and low birth weights (below 2500 g; 10.5% with gabapentin vs 4.4% without gabapentin; p = 0.033) compared with infants with no gabapentin exposure (n=223). Indications for NICU or SCN care included arrhythmia, low heart rate, jaundice, hypotonia, hypoglycemia, respiratory distress, jitteriness, diarrhea, and fever, although some institutions observed all neonates with known prenatal exposure to psychotropic drugs, regardless of symptoms. All indications were self-limiting and resolved in up to a week. Major malformations occurred in 4.1% of gabapentin-exposed infants (including ventricular septal defect; anencephaly; macrocephaly, micro retrognathism, and cutis marmorata; pyloric stenosis; bilateral varus clubfoot; and cryptorchidism) and 2.5% of unexposed infants. Among gabapentin-exposed infants with major malformations, daily doses of maternal concomitant gabapentin therapy (no monotherapy was reported) ranged from 600 to 2400 mg/day, with 5 of the 7 infants exposed throughout pregnancy (Fujii et al, 2013).
    E) NEONATAL WITHDRAWAL SYNDROME
    1) CASE REPORT: A newborn female born at 35 6/7 weeks (2250 g) to a 31-year-old mother with paraplegia and a history of a C6-7 incomplete transection injury to the spinal cord. Maternal medications included baclofen, gabapentin and oxybutynin; no drugs of abuse were found. The infant was initially treated for hypoglycemia and apnea with desaturations that required moderate stimulation. She was a poor feeder and had a poorly coordinated suck with oral feeds. During the first 24 hours the infant began to demonstrate signs and symptoms of drug withdrawal that included sneezing, irritability, jitteriness and loose stools; seizures or hyperthermia were not present. Gabapentin withdrawal was diagnosed following the exclusion of baclofen or oxybutynin. The newborn was treated with gabapentin at 2.5 mg/kg every 12 hours on day 6 and then increased to 5 mg/kg every 12 hours. Her Finnegan scores (used to evaluate neonatal abstinence) gradually declined with gabapentin therapy and clinical symptoms improved. Over the next few weeks of life, the infant was able to tolerate all enteral feedings by day 24 of life with the help of speech therapy and ongoing gabapentin therapy. By day 48, gabapentin was discontinued after gradually weaning (Carrasco et al, 2015).
    F) ANIMAL STUDIES
    1) GABAPENTIN
    a) MICE: Embryo-fetal toxicity (increased rate of skeletal variations) was observed in mice administered oral 1000 mg/kg/day (approximately equal to the maximum recommended human dose, based on mg/m(2)) or higher doses during organogenesis. A marked decrease in neuronal synapse formation in brains was observed in mice administered 400 mg/kg/day doses via intraperitoneal injection during the first postnatal week (the period of synaptogenesis in rodents, corresponding to the last trimester of pregnancy in humans). Abnormal neuronal synapse formation was observed in a mouse model of synaptic repair (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    b) RABBITS: An increase in embryo-fetal mortality was observed in rabbits administered doses of 60 mg/kg or greater during organogenesis (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    c) RATS: Adverse effects on offspring development (higher rates of hydroureter and/or hydronephrosis) were reported in the offspring of pregnant rats administered oral doses between 500 to 2000 mg/kg/day during pregnancy (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014)
    2) GABAPENTIN ENACARBIL
    a) RABBITS: Embryo-fetal mortality and decreased fetal weight were reported in rabbits administered oral 2500 mg/kg/day doses during organogenesis (Prod Info HORIZANT(R) oral extended-release tablets, 2013a).
    b) RATS: Embryo-fetal mortality was reported in rats administered oral 1000 or 5000 mg/kg/day doses during organogenesis. Additionally, decreased fetal weight was reported with the 5000 mg/kg/day dose. Decreased offspring growth and survival were reported in female rats administered oral 1000 or 5000 mg/kg/day during pregnancy and lactation (Prod Info HORIZANT(R) oral extended-release tablets, 2013a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Gabapentin is secreted into human milk (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014; Prod Info HORIZANT(R) oral extended-release tablets, 2013a), with a maximum potential exposure of approximately 1 mg/kg/day (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014). This drug should only be used in women who are breastfeeding if the benefit outweighs the risk (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014) and a decision should be made to either discontinue nursing or the drug, while taking into account the importance of the drug to the mother (Prod Info HORIZANT(R) oral extended-release tablets, 2013a).
    2) SMALL STUDY: Data from a limited study of 6 women who were administered gabapentin during pregnancy and lactation demonstrated extensive transfer of gabapentin to breast milk but low serum concentrations in the nursed infant. The women were given gabapentin doses ranging from 900 to 3200 mg/day. At the time of delivery, the mean umbilical-to-maternal gabapentin plasma concentration ratio was 1.74. At 24 hours postpartum, the mean gabapentin plasma concentrations in the infants were 27% of the cord plasma levels (range, 12% to 36%) with an estimated elimination half-life in the neonates of approximately 14 hours. Sampling of the breast milk was conducted before maternal intake of the morning dose of gabapentin, approximately 10 to 15 hours following the last gabapentin dose. Based on data from 5 of the mother-infant pairs, mean milk/maternal plasma gabapentin ratio was 1 (range 0.7 to 1.3) after 2 weeks to 3 months from delivery and the relative infant gabapentin dose was approximated to be 0.2 to 1.3 mg/kg/day, which was equivalent to 1.3% to 3.8% of the weight normalized dose administered to the mother. No adverse effects were observed in the infants (Ohman et al, 2005).
    3) CASE REPORT: Gabapentin was transferred into the breast milk of a lactating woman who was administered gabapentin for chronic back pain. The 34-year-old woman had been taking gabapentin 600 mg 3 times daily (36.7 mg/kg/day) for 6 weeks. The woman and her 1.6-month-old male infant, weighing 3.1 kg, were studied over a 24-hour period at steady state to determine the milk-plasma ratio and relative infant dose of gabapentin. The milk-plasma ratio was 0.86 and the relative infant dose was 2.34% of the weight-adjusted maternal dose. The absolute infant dose was 0.86 mg/kg/day, which is approximately 3% of a child's dose of 25 to 35 mg/kg/day. The gabapentin plasma concentration in the infant was 0.4 mg/L, which was approximately 6% of the mother's average drug plasma concentration of 6.7 mg/L. No adverse effects were noted in the infant (Kristensen et al, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) GABAPENTIN
    a) RATS: No adverse effects on fertility or reproduction were observed in rats administered doses up to 2000 mg/kg (approximately 8 or 11 times the maximum recommended human dose, based on AUC or mg/m(2), respectively) (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014; Prod Info GRALISE(R) oral tablets, 2011).
    2) GABAPENTIN ENACARBIL
    a) RATS: No adverse effects on fertility were noted in male and female rats administered oral doses up to 5000 mg/kg/day (approximately 39 times the maximum recommended human dose (MRHD), based on AUC) prior to and throughout mating, with continued dosing in females up to day 7 of gestation (Prod Info HORIZANT(R) oral extended-release tablets, 2013a).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity was not directly assessed in human clinical trials. However, in clinical studies of gabapentin as adjunctive therapy in epilepsy, 10 patients were reported to develop new tumors, and 11 patients had preexisting tumors that worsened during treatment or up to 2 years following discontinuation of gabapentin.
    3.21.3) HUMAN STUDIES
    A) TUMORIGENIC POTENTIAL
    1) The potential for gabapentin to induce tumors in humans was not directly assessed in clinical trials. However, in clinical studies of gabapentin as adjunctive therapy in epilepsy that represented 2085 patient-years of exposure in those older than 12 years of age, 10 patients were reported to develop new tumors (2 breast, 3 brain, 2 lung, 1 adrenal, a non-Hodgkin lymphoma, and 1 endometrial carcinoma in situ), and 11 patients had preexisting tumors that worsened (9 brain, 1 breast, and 1 prostate) during treatment or up to 2 years following discontinuation of gabapentin. It is impossible to know whether or not this incidence was affected by gabapentin treatment, as the incidence and recurrence in a similar population not treated with gabapentin is not definitively known (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    3.21.4) ANIMAL STUDIES
    A) GASTRIC CARCINOMA
    1) Mice treated with gabapentin up to 2000 mg/kg/day (up to approximately 2 times the human dose of 3600 mg/day) for 2 years did not show signs of carcinogenicity. However, a statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was seen in male rats receiving gabapentin at a dose of 2000 mg/kg/day (approximately 10 times the human dose of 3600 mg/day based on exposure) over a 2-year period but not at doses of 250 or 1000 mg/kg/day (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    2) An increased incidence of pancreatic acinar adenomas and carcinomas were seen in male and female rats receiving gabapentin enacarbil at doses of 2000 or 5000 mg/kg/day (approximately 17 and 37 times the human AUC for 1200 mg/day dose) over a period of 90 to 104 weeks (Prod Info HORIZANT(R) oral extended-release tablets, 2012).

Genotoxicity

    A) Gabapentin did not show mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. It was not mutagenic in the Ames test; it was negative in the in vitro hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) forward mutation assay in Chinese hamster lung cells, the in vivo chromosomal aberration assay, the in vivo micronucleus test in Chinese hamster bone marrow, and the in vivo mouse micronucleus assay. It did not cause significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats administered gabapentin (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    B) Gabapentin enacarbil caused increased chromosomal aberrations in an in vitro human lymphocyte assay. This was attributed to the release of acetaldehyde by hydrolysis during incubation. The small amount of acetaldehyde formed in vivo is rapidly cleared by normal metabolic activity. Gabapentin enacarbil did not show mutagenic potential in the Ames test and the in vivo rat micronucleus assays (Prod Info HORIZANT(R) oral extended-release tablets, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported as a frequent adverse event following therapeutic doses of gabapentin. Less frequently reported have been vasodilation and peripheral edema (Prod Info NEURONTIN(R) oral tablets, oral capsules, oral solution, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: No ECG changes were evident in a 16-year-old female after the ingestion of 48.9 grams gabapentin (Fischer et al, 1994). Her vital signs were all within normal limits.
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hypotension (70/40 mmHg), refractory to crystalloid and pressor infusions, was reported in a 31-year-old male following the ingestion of gabapentin (54 grams) and valproic acid (105 grams). Concurrent hemoperfusion and hemodialysis in series was used to decrease serum valproic acid and gabapentin levels. The refractory hypotension was most likely a result of the valproic acid overdose in this case (Fernandez et al, 1996).
    b) CASE REPORT: A 61-year-old woman developed hypotension (68/40 mmHg) after ingesting an estimated 54 grams (180 capsules of 300 mg) gabapentin. She was believed to have also ingested quetiapine, which was likely responsible for the hypotension (Spiller et al, 2002). Hypotension responded to dopamine infusion, and the patient recovered.
    c) Mild hypotension that resolved without therapy developed in two of 20 cases of gabapentin only overdose (Klein-Schwartz et al, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Gabapentin serum concentrations are not readily available or useful in guiding therapy.
    B) Basic laboratory studies along with acetaminophen and salicylate levels can be ordered for severely symptomatic or self-harm patients. No studies are required for minimally symptomatic patients who have not attempted self-harm.
    C) Monitor mental status and vital signs in symptomatic patients.
    D) Monitor CK in patients with muscle pain, tenderness or weakness, and renal function and urine output in patients with rhabdomyolysis.

Methods

    A) CHROMATOGRAPHY
    1) A quantitative high-performance liquid chromatographic assay method for gabapentin measurements in serum is described in one study. Solid-phase sorbents are used to isolate gabapentin before derivatization, thus minimizing co-derivatization of potentially interfering endogenous compounds (Lensmeyer et al, 1995).
    2) One study described a method of high-performance liquid chromatography and pre-column labelling for ultraviolet detection of gabapentin in plasma and urine. This method is based on the detection of amino acids by pre-column derivatization with 2,4,6-trinitrobenzenesulphonic acid (TNBS) utilising UV photometric detection (Hengy & Kolle, 1985).
    3) Another study described a method of determining gabapentin in plasma and urine using capillary column gas chromatography. A cation-exchange resin is used to remove the amino acids from deproteinized plasma followed by formation of the methyl ester and N-trifluoroacetyl derivatives for capillary column gas chromatography (Hooper et al, 1990).

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 with any questions or concerns.
    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) Gabapentin serum concentrations are not readily available or useful in guiding therapy.
    B) Basic laboratory studies along with acetaminophen and salicylate levels can be ordered for severely symptomatic or self-harm patients. No studies are required for minimally symptomatic patients who have not attempted self-harm.
    C) Monitor mental status and vital signs in symptomatic patients.
    D) Monitor CK in patients with muscle pain, tenderness or weakness, and renal function and urine output in patients with 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) MONITORING OF PATIENT
    1) Gabapentin serum concentrations are not readily available or useful in guiding therapy.
    2) Basic laboratory studies along with acetaminophen and salicylate levels can be ordered for severely symptomatic or self-harm patients. No studies are required for minimally symptomatic patients who have not attempted self-harm.
    3) Monitor mental status and vital signs in symptomatic patients.
    4) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    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).
    D) FLUMAZENIL
    1) CASE REPORT: Flumazenil was effectively used to treat gabapentin toxicity in an 83-year-old, hemodialysis-dependent man with end-stage renal disease. Two weeks following surgery for above-the-knee amputation, gabapentin 200 mg was ordered after each dialysis treatment for phantom limb pain. Approximately 4 hours after ingesting the first dose of gabapentin, the patient became comatose. Spontaneous limb movement returned after he was treated with a trial dose of flumazenil 0.2 mg IV. A second infusion of flumazenil 0.3 mg IV was administered and within 15 minutes the patient was responsive and speaking clearly (Butler et al, 2003).
    E) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Gabapentin clearance is dependent on renal function. Gabapentin may be removed by hemodialysis; however since toxicity after acute overdose is generally mild it is unlikely to be necessary. Hemodialysis may be indicated by the patient's clinical status or in patients with significant renal impairment (Prod Info Neurontin(R), gabapentin, 1999).
    2) In patients with uremia without hemodialysis, the average elimination half-life of gabapentin is 132 hours, which shortens to 4 hours during hemodialysis (Hung et al, 2008).
    a) CASE REPORT - A 57-year-old woman with diabetes mellitus and uremia on regular hemodialysis (three times a week) presented with dizziness and vomiting two hours after taking a single recommended dose of gabapentin (half a tablet). She developed altered consciousness with lethargy four hours later. Following a session of hemodialysis, she recovered completely and was discharged after 24 hours of observation (Hung et al, 2008).
    3) CASE REPORT - Concurrent in series hemoperfusion and hemodialysis were used to treat a 31-year-old with valproic acid and gabapentin overdose (Fernandez et al, 1996). Gabapentin clearance ranged from 19.2 to 64.5 milliliters/minute and was NOT substantially greater than reported values for intrinsic clearance in volunteers (1.3 to 1.9 milliliters/kilogram/minute).
    B) CONTINUOUS VENOVENOUS HEMOFILTRATION
    1) CASE REPORT: A 75-year-old woman with mild renal impairment (baseline, serum creatinine 1.3 mg/dL; urea 60.8 mg/dL; estimated glomerular filtration rate 43 mL/min/1.73 m(2)) developed significant drowsiness two days after taking gabapentin 300 mg three times daily for pain. Her condition worsened over the next several days and gabapentin toxicity was suspected. Following the discontinuation of gabapentin and supportive care, including 5 days of continuous venovenous hemofiltration, she recovered completely (Miller & Price, 2009).

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS
    a) Fischer et al (1994) report the case of a 16-year-old female who reported to the ED 8 hours after ingestion of 48.9 grams of gabapentin with dizziness, lethargy and diarrhea. The patient admitted to inhaling cocaine approximately 12 hours prior to the gabapentin overdose. Vital signs were stable and no abnormalities were found on physical examination. Her ECG was normal. Serum electrolytes, liver and kidney function tests, CBC, and urinalysis were all within normal limits.
    1) Decontamination was performed with gastric lavage with normal saline followed by activated charcoal and sorbitol. Her initial gabapentin plasma concentration at 8.5 hours post-ingestion was 62 mcg/mL. Eighteen hours post-ingestion the patient was alert with no further complaints of somnolence or dizziness. Laboratory studies at 3 and 6 weeks were normal.

Range Of Toxicity

Summary

    A) TOXICITY: Overdoses of 35 g or less have been associated with mild toxicity in adults. Doses of 40 g or more have been associated with moderate toxicity in adults. A woman ingested 90 g of immediate release gabapentin and developed only mild symptoms that did not require any clinical intervention. An adult ingested more than 100 g and recovered with supportive care.
    B) THERAPEUTIC DOSE: ADULT: 900 to 3600 mg divided into three doses daily orally. PEDIATRIC: 10 mg/kg to 40 mg/kg in 3 divided doses daily.

Therapeutic Dose

    7.2.1) ADULT
    A) SEIZURES
    1) GABAPENTIN: The recommended dose is 300 mg orally 3 times a day; may increase up to 1800 mg/day (divided into 3 doses). Dosages up to 2400 mg/day have been well-tolerated and doses of 3600 mg/day have been administered to a small number of patients for a relatively short duration (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    B) POSTHERPETIC NEURALGIA
    1) GABAPENTIN: The recommended dose is 300 mg orally on Day 1, 300 mg twice a day on Day 2, and 300 mg 3 times a day on Day 3; may increase dosage up to 1800 mg/day (divided into 3 doses) (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    2) GABAPENTIN, ONCE-DAILY FORMULATION: The recommended dose is 300 mg on Day 1, 600 mg on Day 2, 900 mg on Days 3 to 6, 1200 mg on Days 7 to 10, 1500 mg on Days 11 to 14, and 1800 mg on Day 15 and thereafter (Prod Info GRALISE(TM) oral tablets, 2011).
    3) GABAPENTIN ENACARBIL (EXTENDED RELEASE): The recommended dose is 600 mg orally once daily in the morning for 3 days, then 600 mg orally twice daily beginning on day 4 (Prod Info HORIZANT(R) oral extended-release tablets, 2013).
    C) RESTLESS LEGS SYNDROME
    1) GABAPENTIN ENACARBIL (EXTENDED RELEASE): The recommended dose is 600 mg orally once daily at about 5 pm (Prod Info HORIZANT(R) oral extended-release tablets, 2013).
    7.2.2) PEDIATRIC
    A) GABAPENTIN, IMMEDIATE-RELEASE
    1) SEIZURES
    a) AGE 3 TO 12 YEARS: INITIAL: 10 to 15 mg/kg/day orally in 3 divided doses (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    b) AGE 3 TO 4 YEARS: MAINTENANCE: Titrate upwards over 3 days to 40 mg/kg/day orally in 3 divided doses (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    c) AGE 5 TO 11 YEARS: MAINTENANCE: Titrate upwards over 3 days to 25 to 35 mg/kg/day orally in 3 divided doses (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    d) 12 YEARS AND OLDER: 300 mg orally 3 times a day; may increase up to 1800 mg/day (divided into 3 doses). Dosages up to 2400 mg/day have been well-tolerated and doses of 3600 mg/day have been administered to a small number of patients for a relatively short duration (Prod Info NEURONTIN(R) oral capsules, oral tablets, oral solution, 2014).
    B) GABAPENTIN, ONCE-DAILY FORMULATION
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info GRALISE(TM) oral tablets, 2011).
    C) GABAPENTIN ENACARBIL, EXTENDED RELEASE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info HORIZANT(R) oral extended-release tablets, 2013).

Minimum Lethal Exposure

    A) SUMMARY
    1) Minimum toxic levels of gabapentin have not yet been established for humans.
    B) CASE REPORT
    1) A 62-year-old woman with a long history of depression was found dead in a hotel room after a gabapentin overdose; total dose unknown. A prescription for gabapentin (150 capsules of 300 mg gabapentin) was filled one day prior to being found. Postmortem findings were consistent with gabapentin toxicity (blood concentration 88 mcg/mL (therapeutic: 2.6 mcg/mL)); other drug analyses (eg, clonazepam) were normal (Middleton, 2011).
    C) ANIMAL DATA
    1) Single oral doses of 8000 mg/kg in mice and rats have produced signs of acute toxicity, including ataxia, dyspnea, ptosis, lethargy, hypoactivity, or excitation. A lethal dose in animals has not yet been identified (Prod Info Neurontin(R), gabapentin, 1999).

Maximum Tolerated Exposure

    A) ACUTE EXPOSURE
    1) CASE REPORTS
    a) A 26-year-old man, with a prior history of IV drug abuse, took a recreational single 1600 mg dose of gabapentin and approximately one hour later developed head rotation to the left and a clenched jaw, with visible intermittent involuntary spasmodic contractions of the neck and jaw musculature. Dystonic symptoms resolved completely after being treated with a single IV dose of procyclidine 10 mg. Based on the current literature, the authors report that the mechanism of how gabapentin causes dystonic reactions remains unknown (Rohman & Hebron, 2014).
    b) A 59-year-old woman, with a history of depression and anxiety, intentionally ingested up to 300 (90 g) immediate release capsules of gabapentin and 4 hydrocodone/acetaminophen (5/325 mg tablets) approximately 1 hour prior to admission. She had filled a prescription for 1080 capsules earlier that day and the pill count was verified by EMS and the prescription refill date was verified by an electronic dispensing system, as well as corroboration by her spouse. She was admitted with mild sedation and nausea. Her initial assessment included an ECG and laboratory studies that were all normal. A toxicology screen was negative and no other drugs or ethanol were detected. Her gabapentin level was later reported as 72.8 mcg/mL (therapeutic 2 to 20 mcg/mL). The patient remained asymptomatic but was admitted for cardiac monitoring and observation for 24 hours. The following day the patient remained clinically stable and was transferred to an inpatient psychiatric care setting (Schauer & Varney, 2013).
    c) A 61-year-old woman ingested approximately 54 g of gabapentin (blood concentration 104.5 mcg/mL; therapeutic 4 to 8.5 mcg/mL), and was found unarousable. Upon admission the patient was responsive to pain only requiring intubation, and hypotensive (BP 68/40). A urine drug screen was negative. A qualitative serum drug screen was positive for tricyclic antidepressants (the patient's routine medications included quetiapine). The patient had a complete recovery (Spiller et al, 2002).
    d) An acute overdose of 49 g was reported in an adult. Signs of toxicity included diplopia, slurred speech, drowsiness, lethargy and diarrhea (Prod Info Neurontin(R), gabapentin, 1999)
    e) A 16-year-old girl ingested 48.9 g of gabapentin, and 6 hours later she complained of dizziness, lethargy, and diarrhea (Fischer et al, 1994).
    f) The only clinical effects in a 31-year-old man, following an overdose of gabapentin (108 g), valproic acid (54 g) and ethanol, were slurred speech and somnolence, which resolved over 12 hours (Fernandez et al, 1995).
    g) Coma and refractory hypotension (most likely due to valproic acid) were reported in a 31-year-old man following the ingestion of 54 g gabapentin and 105 g valproic acid (Fernandez et al, 1996).
    2) CASE SERIES
    a) In a small observational study of gabapentin only exposures (n=20), doses ranging from 50 mg to 35 g were associated with minimal toxicity. Drowsiness/lethargy and dizziness were the most common findings, with hypotension being reported in 2 patients. Symptoms were most likely to occur in less than 5 hours. Based on the small number of cases and lack of laboratory confirmation, further study is indicated to determine a dose response relationship (Klein-Schwartz et al, 2003).
    3) CHRONIC EXPOSURE
    a) A 34-year-old healthy man, with chronic back pain who was taking 8000 mg (self-titrated dose) of gabapentin daily for 9 months, developed withdrawal seizures following a 2 day absence of gabapentin. The patient recovered with no neurological deficits (Barrueto et al, 2002).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Therapeutic serum levels have not been established. Normal values have included levels of approximately 2 mcg/mL or slightly greater, in 67% of patients treated with 1200 mg daily (Sivenius et al, 1991).
    2) Fernandez et al (1995) have reported therapeutic serum concentrations of gabapentin to range from 2.0 to 8.0 mcg/mL (Fernandez et al, 1995).
    3) Verma et al (1999) reported a reference range for therapeutic gabapentin serum level of 2 to 15 mcg/mL (Verma et al, 1999).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) A 62-year-old woman with a long history of depression was found dead after a gabapentin overdose; total dose unknown. A prescription for gabapentin (150 capsules of 300 mg gabapentin) was filled one day prior to being found. Postmortem findings were consistent with gabapentin toxicity (blood concentration 88 mcg/mL (therapeutic: 2.6 mcg/mL)); other drug analyses (eg, clonazepam) were normal (Middleton, 2011).
    b) At 8.5 hours following the ingestion of 48.9 g gabapentin, plasma concentration was reported to be 62 mcg/mL in a 16-year-old female (Fischer et al, 1994).
    c) Serum levels of gabapentin (GBP) in a 31-year-old man, following an overdose of at least 108 g, was reported to be (Fernandez et al, 1995):
    Hr after ingestionGBP (mcg/mL)
    1.0044.5
    4.7522.8
    13.0016.4

    d) Gabapentin (GBP) serum levels of 60 mcg/mL were reported following an overdose of 54 g GBP and 105 g valproic acid in a 31-year-old man (Fernandez et al, 1996).
    e) A chronic renal failure patient on hemodialysis was started on gabapentin 600 mg 3 times daily. Three weeks later she was reported to have a gabapentin serum level of 85 mcg/mL (reference level 2-15 mcg/mL). The patient was reported to be tremulous and had difficulty with cognition. Following a gabapentin dose reduction, the patient's serum level returned to normal (Verma et al, 1999).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Gabapentin is an amino acid structurally related to gamma-aminobutyric acid (GABA), but is able to cross the blood-brain barrier due to a cyclohexane structure that confers a lipophilic property to the drug. It does not interact with GABA receptors and it is not an inhibitor of GABA uptake or degradation. It is used as an add-on anticonvulsant agent in the treatment of refractory partial seizures. It also appears effective in generalized seizures (Crawford et al, 1987; Sivenius et al, 1991).
    B) Animal studies have demonstrated the anticonvulsant activity of gabapentin, particularly in seizures caused by interference with GABAergic transmission or provoked by excitatory amino acids (Crawford et al, 1987; Anon, 1990). Although gabapentin appears to possess GABA-mimetic properties (Crawford et al, 1987), its precise mechanism of action remains unclear. The drug has not altered whole brain GABA levels and has no significant effect on GABA transaminase activity; it does not bind to GABA or benzodiazepine receptors or influence the neural uptake of GABA when given in pharmacologically active doses (Crawford et al, 1987; Sivenius et al, 1991). An effect of gabapentin on central serotonin metabolism has been postulated by some investigators (Rao et al, 1988).
    1) GABA is the major inhibitory neurotransmitter in the central nervous system, and impairment of GABAergic transmission is involved in the pathogenesis of epilepsy (Gram, 1988; AMA, 1991).

Physicochemical

Physical Characteristics

    A) Gabapentin is a white to off-white crystalline solid, which is freely soluble in water and in both acidic and basic solutions. The pKa1 is 3.7 and the pKa2 is 10.7 (Prod Info GRALISE(R) oral tablets, 2011).

Molecular Weight

    A) 171.24 (Prod Info GRALISE(R) oral tablets, 2011)

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