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Gabapentin

Pronunciation

Pronunciation

(GA ba pen tin)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Neurontin: 100 mg, 300 mg, 400 mg

Generic: 100 mg, 300 mg, 400 mg

Cream, External:

Neuraptine: 10% (30 mL) [contains cetyl alcohol]

Miscellaneous, Oral:

Gralise Starter: 300 & 600 mg (78 ea) [contains soybean lecithin]

Solution, Oral:

Neurontin: 250 mg/5 mL (470 mL) [strawberry anise flavor]

Generic: 250 mg/5 mL (5 mL, 470 mL, 473 mL); 300 mg/6 mL (6 mL)

Suspension, Oral:

Fanatrex FusePaq: 25 mg/mL (420 mL) [contains saccharin sodium, sodium benzoate]

Tablet, Oral:

Gralise: 300 mg [contains soybean lecithin]

Gralise: 600 mg

Neurontin: 600 mg, 800 mg [scored]

Generic: 600 mg, 800 mg

Brand Names: U.S.

  • Fanatrex FusePaq
  • Gralise
  • Gralise Starter
  • Neuraptine
  • Neurontin

Pharmacologic Category

  • Anticonvulsant, Miscellaneous
  • GABA Analog

Pharmacology

Gabapentin is structurally related to GABA. However, it does not bind to GABAA or GABAB receptors, and it does not appear to influence synthesis or uptake of GABA. High affinity gabapentin binding sites have been located throughout the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. This channel appears to be located presynaptically, and may modulate the release of excitatory neurotransmitters which participate in epileptogenesis and nociception.

Absorption

Variable, from proximal small bowel by L-amino transport system; saturable process; dose-dependent

Distribution

Vd: 58 ± 6 L; CSF concentrations are ~20% of plasma concentrations

Metabolism

Not metabolized

Excretion

Proportional to renal function; urine (as unchanged drug)

Clearance: Apparent oral clearance is directly proportional to CrCl: Clearance in infants is highly variable; oral clearance (per kg) in children <5 years of age is higher than in children ≥5 years of age

Time to Peak

Immediate release: Infants 1 month to Children 12 years: 2 to 3 hours; Adults: 2 to 4 hours; Gralise: 8 hours

Half-Life Elimination

Infants 1 month to Children 12 years: 4.7 hours

Adults, normal: 5 to 7 hours; increased half-life with decreased renal function; anuric adult patients: 132 hours; adults during hemodialysis: 3.8 hours

Protein Binding

<3%

Special Populations: Renal Function Impairment

In CrCl less than 30 mL/minute, half-life is approximately 52 hours (immediate release). In moderate and severe renal impairment, Cl was decreased to 3 and 1 L/hour, respectively, compared with 5 to 7 L/hour in nonrenal impairment patients (ER).

Hemodialysis

The half-life in anuric patients is approximately 132 hours on nondialysis days; during dialysis, half-life is reduced to 3.8 hours (immediate release). Gabapentin is significantly removed by hemodialysis.

Use: Labeled Indications

Postherpetic neuralgia: Management of postherpetic neuralgia (PHN) in adults.

Seizures, partial onset (excluding Gralise): As adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and pediatric patients 3 years and older with epilepsy.

Off Label Uses

Alcohol dependence

Data from randomized, double-blind, placebo-controlled studies supports the use of gabapentin in the maintenance of abstinence in patients with alcohol dependence [Brower 2008], [Furieri 2007], [Mason 2014]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Based on the VA/DoD clinical practice guideline for the management of substance use disorders, gabapentin given for moderate to severe alcohol use disorder is effective and suggested when first-line pharmacotherapy is contraindicated or ineffective [VA/DoD 2015].

Alcohol withdrawal

Data from a randomized, double-blind, active-controlled study supports the use of gabapentin in the treatment of alcohol withdrawal [Myrick 2009]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Based on the VA/DoD clinical practice guideline for the management of substance use disorders, gabapentin given for mild to moderate alcohol withdrawal is effective and suggested when the risk of benzodiazepines outweigh the benefits (ie, inadequate monitoring available, abuse liability, contraindication, adverse reaction) [VA/DoD 2015].

Brachioradial pruritus

Data from a limited number of patients suggest that gabapentin may be beneficial for the treatment of brachioradial pruritus [Bueller 1999], [Carvalho 2015], [Kanitakis 2006], [Winhoven 2004], [Yilmaz 2010]. Additional data may be necessary to further define the role of gabapentin in this condition.

Based on European Dermatology Forum and European Academy of Dermatology and Venerology guidelines for the treatment of chronic pruritus, gabapentin is recommended for chronic pruritus of neuropathic origin. Evidence for brachioradial pruritus in based on anecdotal (case report) data [EDF/EADV [Weisshaar 2012]].

Cough, chronic (refractory)

Data from a small, randomized, double-blind, placebo-controlled trial showed that gabapentin significantly improved cough-specific quality of life in patients with refractory chronic cough compared to placebo. Participants with central sensitization of the cough reflex exhibited a greater response to gabapentin treatment compared to participants without central sensitization [Ryan 2012]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Based on the American College of Chest Physicians guidelines for the treatment of unexplained chronic cough, gabapentin, on a therapeutic trial basis, is suggested in patients with unexplained chronic cough as long as the potential side-effects and risk-benefit profile are discussed prior to use, and there is reassessment at 6 months prior to continuation of treatment [ACCP [Gibson 2016]].

Diabetic neuropathy

Gabapentin has been evaluated in the management of diabetic neuropathy in several controlled trials. Results were conflicting; gabapentin demonstrated no or little benefit in some trials and comparable activity to amitriptyline or tramadol with acetaminophen in other trials. Guideline recommendations also vary. Gabapentin is considered first-line therapy supported by strong evidence in guidelines by the American Association of Clinical Endocrinologists, American Diabetes Association/Toronto Diabetic Neuropathy Expert Group, and European Federation of Neurological Societies. In contrast, guidelines from the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation state that gabapentin is probably effective and should be considered alternative treatment for painful diabetic neuropathy based on limited benefit in controlled trials.

Fibromyalgia syndrome

Data from a randomized, double-blind, placebo-controlled study supports the use of gabapentin in the treatment of pain and sleep disturbances associated with fibromyalgia [Arnold 2007]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Hot flashes

Data from controlled trials support the use of gabapentin for the treatment of hot flashes. However, most trials were of short duration (up to 12 weeks), and use of gabapentin may be limited by its adverse effect profile. Additional trials may be necessary to further define the role of gabapentin in this condition.

Evidence-based American and Canadian guidelines recommend gabapentin as an alternative to SSRIs/SSNRIs for the management of hot flashes in natural and medically induced menopause in women.

Neuropathic pain

In a meta-analysis of trials evaluating the treatment of peripheral neuropathy caused by multiple etiologies, including painful polyneuropathy, post-amputation pain, post-traumatic pain, complex regional pain syndrome type II, central post-stroke pain, spinal cord injury pain, multiple sclerosis-associated pain, cancer pain and radiculopathy, gabapentin was shown to be safe and effective [IASP [Finnerup 2015]].

Based on International Association for the Study of Pain (IASP), European Federation of Neurological Societies (EFNS) and Society of Critical Care Medicine (SCCM) guidelines, gabapentin is effective and recommended for the management of peripheral neuropathy.

Post-operative pain (adjunct)

Data from 3 meta-analyses supports the use of preemptive doses of gabapentin to decrease postoperative pain and opioid use [Doleman 2015], [Peng 2007], [Yu 2013]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Restless legs syndrome

Gabapentin in the management of RLS has been evaluated in small controlled trials, demonstrating benefits when compared with placebo. Additional trials may be necessary to further define the role of gabapentin in this condition.

The American Academy of Sleep Medicine guidelines regarding RLS management consider gabapentin effective based on low level evidence and noted that patients with pain symptoms appeared to benefit most. The benefit-risk ratio is unclear. The EFNS/ENS/ESRS task force guidelines consider gabapentin effective for short-term management and possibly effective for long-term management of RLS. Additional study is needed to establish optimal dosing.

Social anxiety disorder

Data from a limited number of patients studied in a double-blind, placebo-controlled trial suggest that gabapentin may be beneficial for the treatment of social anxiety disorder [Pande 1999]. Additional data may be necessary to further define the role of gabapentin in this condition.

Uremic pruritus

Data from randomized, blinded, controlled trials and a meta-analysis supports the use of gabapentin in the treatment of uremic pruritus unresponsive to previous therapy [Gunal 2004], [Naini 2007], [Nofal 2016], [Pongcharoen 2016], [Razeghi 2009]. Additional trials may be necessary to further define the role of gabapentin in this condition.

Based on the European Dermatology Forum and European Academy of Dermatology and Venerology guidelines for the management of chronic pruritus, gabapentin is recommended in the management of chronic kidney disease-associated pruritus [EDF/EADV [Weisshaar 2012]].

Contraindications

Hypersensitivity to gabapentin or any component of the formulation

Dosing: Adult

Postherpetic neuralgia: Oral:

Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times daily; dose may be titrated as needed for pain relief (range: 1,800 to 3,600 mg/day in divided doses, daily doses >1,800 mg do not generally show greater benefit)

Gralise only: Day 1: 300 mg, Day 2: 600 mg, Days 3 to 6: 900 mg once daily, Days 7 to 10: 1,200 mg once daily, Days 11 to 14: 1,500 mg once daily, Days ≥15: 1,800 mg once daily

Seizures, partial onset: Oral (excluding Gralise):

Initial: 300 mg 3 times daily; increase dosage based on response and tolerability; usual dosage: 900 to 1,800 mg/day administered in 3 divided doses; doses of up to 2,400 mg/day have been tolerated in long-term clinical studies; up to 3,600 mg/day has been tolerated in short-term studies

Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week.

Alcohol dependence (off-label use): Oral: Immediate release: 300 mg once daily on day 1, followed by dosage escalation, based on response and tolerability, in increments of 300 mg/day up to a target dose of 1,800 mg/day in 3 divided doses (Brower 2008; Mason 2014; VA/DoD 2015).

Alcohol withdrawal (off-label use): Oral: Immediate release: 300 to 400 mg 3 times daily on days 1 through 3, then 300 to 400 mg twice daily on day 4, then discontinue. For breakthrough symptoms during days 1 through 4, consider providing single doses of 100 mg administered up to 3 times daily and a 300 mg dose reserved for the evening (Myrick 2009).

Brachioradial pruritus (off-label use): Oral: Immediate release: Initial: 100 mg 3 times daily; increase dose based on response and tolerability up to 1,800 mg/day (Bueller 1999; Kanitakis 2006; Winhoven 2004; Yilmaz 2010). Additional data may be necessary to further define the role of gabapentin in this condition.

Cough, chronic (refractory) (off-label use): Oral: Immediate release: 300 mg once daily on day 1, followed by dosage escalation in increments of 300 mg/day until cough symptoms cease, side effects are intolerable, or a maximum tolerated dose of 1,800 mg/day given in 2 divided doses is reached (ACCP [Gibson 2016]; Ryan 2012). Additional data may be necessary to further define the role of gabapentin in this condition.

Diabetic neuropathy (off-label use): Oral: Immediate release: 900 to 3,600 mg/day (Bril 2011)

Fibromyalgia syndrome (off-label use): Oral: Immediate release: Initial: 300 mg once daily at bedtime, increase in increments of 300 to 600 mg/day every 1 to 2 weeks based on response and tolerability up to 2,400 mg/day in divided doses. Median dosage in clinical trial was 1,800 mg/day with a range of 1,200 to 2,400 mg/day (Arnold 2007).

Hot flashes (off-label use): Oral: Immediate release: 300 mg once daily at bedtime on day 1, then 300 mg twice daily on day 2, then 300 mg 3 times daily (Butt 2008).

Neuropathic pain (off-label use): Oral: Immediate release: 1,200 to 3,600 mg/day in 3 divided doses (IASP [Finnerup 2015]).

Critically ill patients: Oral: Immediate release: Initial: 100 mg 3 times daily in combination with IV opioids; maintenance: 300 to 1,200 mg 3 times daily; maximum dose: 3,600 mg daily (SCCM [Barr 2013])

Postoperative pain (adjunct) (off-label use): Oral: Immediate release: 300 to 1,200 mg given the night before, 1 to 2 hours prior to surgery or immediately following surgery (Doleman 2015; Peng 2007; Yu 2013)

Restless legs syndrome (RLS) (off-label use): Oral: Immediate release: Initial: 300 mg once daily 2 hours before bedtime. Doses ≥600 mg/day have been given in 2 divided doses (late afternoon and 2 hours before bedtime). Dose may be titrated every 2 weeks until symptom relief achieved (range: 300 to 1,800 mg/day). Suggested maintenance dosing schedule: One-third of total daily dose given at 12 pm, remaining two-thirds total daily dose given at 8 pm. (Garcia-Borreguero 2002; Happe 2003; Saletu 2010; Vignatelli 2006)

Social anxiety disorder (off-label use): Oral: Immediate release: Initial: 300 mg twice daily; increase dose based on response and tolerability in increments of no more than 300 mg/day up to a maximum of 3,600 mg/day given in 3 divided doses. Doses for responders ranged from 900 to 3,600 mg/day in the clinical trial (Pande 1999). Additional data may be necessary to further define the role of gabapentin in this condition.

Uremic pruritus (off-label use): Oral: Immediate release: Initial: 100 mg after dialysis on hemodialysis days; may increase dose based on response and tolerability up to 400 mg after dialysis on hemodialysis days (Gunal 2004; Naini 2007; Nofal 2016; Razeghi 2009).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Seizures, partial onset:

Children 3 to 4 years: Oral (excluding Gralise) Initial: 10 to 15 mg/kg/day in 3 divided doses; titrate to effective dose over ~3 days; increase dosage based on response and tolerability; usual dosage: 40 mg/kg/day in 3 divided doses; dosages of up to 50 mg/kg/day have been tolerated in clinical studies:

Children 5 to 11 years: Oral (excluding Gralise): Initial: 10 to 15 mg/kg/day in 3 divided doses; titrate to effective dose over ~3 days; increase dosage based on response and tolerability; usual dosage: 25 to 35 mg/kg/day in 3 divided doses; dosages of up to 50 mg/kg/day have been tolerated in clinical studies

Children ≥12 years: Refer to adult dosing.

Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week

Dosing: Renal Impairment

Children ≥12 years and Adults:

All products, excluding Gralise:

CrCl ≥60 mL/minute: 300 to 1,200 mg 3 times daily

CrCl >30 to 59 mL/minute: 200 to 700 mg twice daily

CrCl >15 to 29 mL/minute: 200 to 700 mg once daily

CrCl 15 mL/minute: 100 to 300 mg once daily

CrCl <15 mL/minute: Reduce daily dose in proportion to creatinine clearance based on dose for creatinine clearance of 15 mL/minute (eg, reduce dose by one-half [range: 50 to 150 mg/day] for CrCl 7.5 mL/minute)

ESRD requiring hemodialysis: Dose based on CrCl plus a single supplemental dose of 125 to 350 mg (given after each 4 hours of hemodialysis)

Gralise only: Note: Follow initial dose titration schedule if treatment-naive.

CrCl ≥60 mL/minute: 1,800 mg once daily

CrCl >30 to 59 mL/minute: 600 to 1,800 mg once daily; dependent on tolerability and clinical response

CrCl <30 mL/minute: Use is not recommended.

ESRD requiring hemodialysis: Use is not recommended.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, gabapentin is not hepatically metabolized.

Extemporaneously Prepared

Note: Commercial oral solution is available (50 mg/mL)

A 100 mg/mL suspension may be made with tablets (immediate release) and either a 1:1 mixture of Ora-Sweet® (100 mL) and Ora-Plus® (100 mL) or 1:1 mixture of methylcellulose 1% (100 mL) and Simple Syrup N.F. (100 mL). Crush sixty-seven 300 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 200 mL. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (preferred) or 56 days at room temperature.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Capsule, tablet (excluding Gralise), solution: May administer without regards to meals. Administer first dose on first day at bedtime to avoid somnolence and dizziness. Dosage must be adjusted for renal function; when given 3 times daily, the maximum time between doses should not exceed 12 hours.

Gralise: Take with evening meal. Swallow whole; do not chew, crush, or split.

Dietary Considerations

Gralise should be taken with food.

Storage

Capsules and tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Use scored 600 or 800 mg tablets that are broken in half within 28 days of breaking the tablet.

Oral solution: Store refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Antacids: May decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after antacid administration. Monitor patients closely for evidence of reduced response to gabapentin therapy when both of these drugs are being used. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Salts: May enhance the CNS depressant effect of Gabapentin. Specifically, high dose intravenous/epidural magnesium sulfate may enhance the CNS depressant effects of gabapentin. Magnesium Salts may decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after oral magnesium salts administration. Monitor patients closely for evidence of reduced response to gabapentin therapy. Monitor for CNS depression if high dose IV/epidural magnesium sulfate is used. Consider therapy modification

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Morphine (Systemic): Gabapentin may enhance the CNS depressant effect of Morphine (Systemic). Morphine (Systemic) may increase the serum concentration of Gabapentin. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

False positives have been reported with the Ames N-Multistix SG® dipstick test for urine protein

Adverse Reactions

As reported for immediate release (IR) formulations in patients >12 years of age, unless otherwise noted in children (3 to 12 years) or with use of Gralise

>10%:

Central nervous system: Dizziness (IR: 17% to 28%; children 3%; Gralise: 11%), drowsiness (IR: 19% to 21%; children 8%; Gralise: 5%), ataxia (1% to 13%), fatigue (11%; children 3%)

Infection: Viral infection (children 11%)

1% to 10%:

Cardiovascular: Peripheral edema (IR: 2% to 8%; Gralise: 4%), vasodilatation (1%)

Central nervous system: Hostility (children 5% to 8%), tremor (7%), emotional lability (children 4% to 6%), hyperkinesia (children 3% to 5%), headache (children and adolescents >2%), abnormality in thinking (2% to 3%; children 2%), abnormal gait (2%), amnesia (2%), depression (2%), nervousness (2%), pain (Gralise: 1% to 2%), hyperesthesia (1%), lethargy (Gralise: 1%), twitching (1%), vertigo (Gralise: 1%)

Dermatologic: Pruritus (1%), skin rash (1%)

Endocrine & metabolic: Weight gain (IR: Adults and children 2% to 3%; Gralise: 2%), hyperglycemia (1%)

Gastrointestinal: Diarrhea (IR: 6%), nausea and vomiting (3% to 4%; children 8%), xerostomia (IR: 2% to 5%; Gralise: 3%), constipation (IR: 1% to 4%; Gralise: 1%), abdominal pain (3%), dyspepsia (IR: 2%; Gralise: 1%), dry throat (2%), dental disease (2%), flatulence (2%), increased appetite (1%)

Genitourinary: Impotence (2%), urinary tract infection (Gralise: 2%)

Hematologic & oncologic: Decreased white blood cell count (1%), leukopenia (1%)

Infection: Infection (5%)

Neuromuscular & skeletal: Weakness (6%), back pain (IR: 2%; Gralise: 2%), dysarthria (2%), limb pain (Gralise: 2%), myalgia (2%), bone fracture (1%)

Ophthalmic: Nystagmus (8%), diplopia (1% to 6%), amblyopia (4%), blurred vision (3% to 4%), conjunctivitis (1%)

Otic: Otitis media (1%)

Respiratory: Rhinitis (4%), bronchitis (children 3%), nasopharyngitis (Gralise: 3%), respiratory tract infection (children 3%), pharyngitis (1% to 3%), cough (2%)

Miscellaneous: Fever (children 10%)

Postmarketing and case reports: Abnormal hepatic function, acute renal failure, agitation, altered serum glucose, anaphylaxis, anemia, angina pectoris, angioedema, aphasia, aspiration pneumonia, blindness, blood coagulation disorder, bradycardia, brain disease, breast hypertrophy, bronchospasm, cardiac arrhythmia (various), cerebrovascular accident, change in libido, cholestatic hepatitis, CNS neoplasm, colitis, confusion, Cushingoid appearance, DRESS syndrome, drug abuse, drug dependence, dyspnea, ejaculatory disorder, erythema multiforme, facial paralysis, falling, fecal incontinence, fulminant hepatitis, gastroenteritis, glaucoma, glycosuria, gynecomastia, hearing loss, heart block, hematemesis, hematuria, hemiplegia, hemorrhage, hepatitis, hepatomegaly, herpes zoster, hyperlipidemia, hypersensitivity reaction, hypertension, hyperthyroidism, hyperventilation, hypoglycemia, hyponatremia, hypotension, hypothyroidism, hypoventilation, increased creatine phosphokinase, increased liver enzymes, increased serum creatinine, jaundice, joint swelling, leukocytosis, loss of consciousness, lymphadenopathy, lymphocytosis, memory impairment, meningism, migraine, movement disorder, myocardial infarction, myoclonus (local), nephrolithiasis, nephrosis, nerve palsy, non-Hodgkin lymphoma, ovarian failure, palpitations, pancreatitis, paresthesia, peptic ulcer, pericardial effusion, pericardial rub, pericarditis, peripheral vascular disease, pneumonia, psychosis, pulmonary edema, pulmonary thromboembolism, purpura, retinopathy, rhabdomyolysis, seasonal allergy, sexual disorder, skin necrosis, status epilepticus, Stevens-Johnson syndrome, subdural hematoma, suicidal ideation, suicidal tendencies, syncope, tachycardia, thrombocytopenia, thrombophlebitis, tumor growth, withdrawal syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/angioedema: May occur after the first dose or at any time during treatment. Discontinue therapy and seek immediate medical care if signs or symptoms of anaphylaxis or angioedema occur.

• CNS depression: May cause CNS depression including somnolence and dizziness, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Multiorgan hypersensitivity: Potentially serious, sometimes fatal multiorgan hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) has been reported with some antiepileptic drugs, including gabapentin. Monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, cardiac, and/or hematologic systems; fever, rash, and eosinophilia may also be present. Discontinue immediately if suspected.

• Neuropsychiatric effects: Use in pediatric patients with epilepsy has been associated with the occurrence of CNS adverse effects of mild to moderate intensity. The most significant include emotional lability, hostility (eg, aggressive behaviors), changes in behavior and thinking (eg, concentration problems and changes in school performance), and hyperkinesia (primarily restlessness and hyperactivity).

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Renal impairment: Use with caution in patients with severe renal impairment; dose adjustment required.

• Seizure disorder: The safety and efficacy of Gralise has not been studied in patients with epilepsy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Product interchangeability: Gabapentin immediate release and Gralise products are not interchangeable with each other or with gabapentin enacarbil (Horizant) due to differences in formulations, indications, and pharmacokinetics.

Other warnings/precautions:

• Tumorigenic potential: Male rat studies demonstrated an association with pancreatic adenocarcinoma (clinical implication in humans is unknown).

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Gralise should be withdrawn over ≥1 week.

Monitoring Parameters

Periodic renal function, suicidality (eg, suicidal thoughts, depression, behavioral changes)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Gabapentin crosses the placenta. In a small study (n=6), the umbilical/maternal plasma concentration ratio was ~1.74. Neonatal concentrations declined quickly after delivery and at 24 hours of life were ~27% of the cord blood concentrations at birth (gabapentin neonatal half-life ~14 hours) (Ohman 2005). Outcome data following maternal use of gabapentin during pregnancy is limited (Holmes 2012).

Patients exposed to gabapentin during pregnancy are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, nausea, vomiting, diarrhea, or dry mouth. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), enlarged lymph nodes, memory impairment, vision changes, confusion, tremors, shortness of breath, excessive weight gain, swelling of arms or legs, severe loss of strength and energy, involuntary eye movements, twitching, seizures, bruising, bleeding, chills, pharyngitis, muscle pain, muscle weakness, change in balance, difficulty speaking, difficulty focusing, severe dizziness, passing out, agitation, irritability, panic attacks, or mood changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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