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Gabapentin

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Ingrezza

(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

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)

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.

  • Gralise
  • Gralise Starter
  • 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; Extended release: 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 <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).

Use: Labeled Indications

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

Seizures, partial onset (immediate release only): 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 use disorder, moderate to severe

Data from randomized, double-blind, placebo-controlled studies support the use of gabapentin in the maintenance of abstinence in patients with alcohol use disorder [Brower 2008], [Furieri 2007], [Mason 2014].

Based on the American Psychiatric Association guidelines for the pharmacological treatment of patients with alcohol use disorder, gabapentin is suggested for patients with alcohol use disorder (moderate to severe) who want to decrease or abstain from use of alcohol and either prefer gabapentin or are unable to tolerate or are unresponsive to naltrexone and acamprosate [APA [Reus 2018]]. 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, mild

Data from a randomized, double-blind, active-controlled study support the use of gabapentin in the treatment of alcohol withdrawal [Myrick 2009].

Based on the VA/DoD clinical practice guideline for the management of substance use disorders, gabapentin given for mild alcohol withdrawal is effective and suggested when the risk of benzodiazepines outweigh the benefits (eg, 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].

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

Data from a small, randomized, double-blind, placebo-controlled trial showed that gabapentin significantly improves 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].

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

Data from meta-analyses support the use of immediate-release gabapentin for reducing pain by more than 50% in diabetic neuropathy [Moore 2014], [Rudroju 2013]. Data from a limited number of clinical trials support the use of extended-release gabapentin in reducing pain by more than 50% and improving sleep in diabetic neuropathy [Sandercock 2009], [Sandercock 2012].

Based on guidelines from the European Federation of Neurological Societies, International Association for the Study of Pain (IASP), and National Institute for Health and Care Excellence, gabapentin is effective and recommended as first-line therapy, supported by strong evidence, in the management of diabetic neuropathy [EFNS [Attal 2010]], [IASP [Finnerup 2015]], [NICE 2013]. The IASP guidelines recommend both immediate- and extended-release gabapentin [IASP [Finnerup 2015]]. In contrast, a guideline from the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation states that gabapentin is probably effective and should be considered an alternative treatment for painful diabetic neuropathy based on limited benefit in 2 controlled trials [AAN [Bril 2011]]. Similarly, a position statement from the American Diabetes Association recommends gabapentin as a second-line option [ADA [Pop-Busui 2017]].

Fibromyalgia syndrome

Data from a randomized, double-blind, placebo-controlled study support the use of gabapentin in the treatment of pain and sleep disturbances associated with fibromyalgia [Arnold 2007].

Hiccups (singultus)

Data from a limited number of patients in case reports/series and a retrospective chart review suggest that gabapentin (monotherapy or as an adjunct to other agents such as baclofen, cisapride, omeprazole, haloperidol, and metoclopramide) may decrease the frequency and severity of persistent or intractable hiccups [Alonso-Navarro 2007], [Hernandez 2004], [Jatzko 2007], [Menon 2012], [Moretti 1999], [Moretti 2004], [Ong 2008], [Petroianu 2000], [Porzio 2003], [Porzio 2010], [Schuchmann 2007].

Neuropathic pain (other than postherpetic neuralgia)

In a meta-analysis of trials evaluating the treatment of neuropathic pain, including painful polyneuropathy and spinal cord injury pain, gabapentin was shown to be safe and effective [IASP [Finnerup 2015]].

Based on IASP, EFNS, and Society of Critical Care Medicine (SCCM) guidelines, gabapentin is effective and recommended for the management of peripheral neuropathy.

Paraneoplastic pruritus

Data from a limited number of patients studied suggest that gabapentin may be beneficial for the treatment of paraneoplastic pruritus [Demierre 2006], [Lee 2010].

Postoperative pain

Data from 3 meta-analyses support the use of preemptive doses of gabapentin to decrease postoperative pain and opioid use [Doleman 2015], [Peng 2007], [Yu 2013].

Based on the American Pain Society, American Society of Regional Anesthesia and Pain Medicine, and American Society of Anesthesiologists guidelines on the management of postoperative pain, gabapentin should be considered as part of a perioperative multimodal analgesia regimen.

Restless legs syndrome

Gabapentin in the management of restless legs syndrome (RLS) has been evaluated in small controlled trials, demonstrating benefits compared with placebo. Gabapentin enacarbil is FDA-approved for the treatment of RLS [Garcia-Borreguero 2002], [Saletu 2010].

The American Academy of Sleep Medicine (AASM) guidelines regarding RLS management consider gabapentin effective based on low-level evidence and note that patients with pain symptoms appeared to benefit most. The benefit-risk ratio is unclear. The European Federation of Neurological Societies/European Neurological Society/European Sleep Research Society (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. Based on the International Restless Legs Syndrome Study Group, European Restless Legs Syndrome Study Group, and RLS Foundation (IRLSSG/EURLSSG/RLS-F) guidelines for the prevention and treatment of dopaminergic augmentation in restless legs syndrome, α2δ ligands (eg, gabapentin) are effective and should be considered for the initial treatment of patients with RLS due to their minimal risk of augmentation. Additionally, patients who experience augmentation on dopaminergic agents may benefit from a switch to α2δ ligands (eg, gabapentin). However, the guidelines note that long-term studies are needed.

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].

Uremic pruritus

Data from randomized, blinded, controlled trials and a meta-analysis support the use of gabapentin in the treatment of uremic pruritus unresponsive to previous therapy [Gunal 2004], [Naini 2007], [Nofal 2016], [Pongcharoen 2016], [Razeghi 2009].

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]].

Vasomotor symptoms associated with menopause

Data from meta-analyses and an individual patient pooled analysis support the use of immediate-release gabapentin for decreasing the frequency and severity of hot flashes in postmenopausal women and breast cancer survivors [Toulis 2009], [Loprinzi 2009], [Li 2016]. Data from a randomized, double-blind, placebo-controlled study support the use of extended-release gabapentin for decreasing frequency and severity of hot flashes and associated sleep interference in postmenopausal women [Pinkerton 2014].

Based on the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) position statement on menopause, the Endocrine Society (ES) guideline on treatment of symptoms of menopause, and the North American Menopause Society (NAMS) statement on nonhormonal management of menopause-associated vasomotor symptoms, gabapentin is an effective and recommended alternative for the management of vasomotor symptoms associated with menopause in patients with contraindications to hormonal therapy or who prefer not to use hormonal therapy. Based on the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) breast cancer survivorship care guideline, gabapentin may be used to help mitigate vasomotor symptoms of premature menopause in women previously treated for breast cancer.

Contraindications

Hypersensitivity to gabapentin or any component of the formulation

Dosing: Adult

Alcohol use disorder, moderate to severe (alternative agent) (off-label use): Oral: Immediate release: Initial: 300 mg once daily; increase dose every 1 to 2 days 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). Note: Goals of therapy include abstinence or reduction of heavy drinking (VA/DoD 2015). Gabapentin may be misused by some patients with substance use disorders; evaluate for risk and signs of addiction and dependence (Mersfelder 2016).

Alcohol withdrawal, mild (alternative agent) (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, which may be administered up to 3 times daily and a 300 mg dose reserved for the evening (Myrick 2009; VA/DoD 2015). Note: Gabapentin should not be routinely used in patients with moderate or severe alcohol withdrawal (Hoffman 2018). Because withdrawal symptoms may progress at different rates, duration of treatment may need to be more flexible (Holt 2018).

Cough, chronic (alternative agent) (off-label use): Oral: Immediate release: Initial: 300 mg once daily; increase dose daily based on response and tolerability in 300 mg/day increments to a maximum dose of 1,800 mg/day given in 2 divided doses (ACCP [Gibson 2016]; Ryan 2012).

Fibromyalgia syndrome (alternative agent) (off-label use): Note: Generally, for patients who do not respond to or do not tolerate a tricyclic antidepressant (Goldenberg 2018). 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). Some experts recommend a starting dose of 100 mg at bedtime with titration as needed and based on tolerability (Goldenberg 2018).

Hiccups (singultus) (off-label use): Oral: Immediate release: Usual dose range: 300 to 1,200 mg daily in 3 to 4 divided doses. Some regimens have used short-term therapy (6 days) as needed and others have used continuous therapy (Hernández 2004; Jatzko 2007; Moretti 2004; Porzio 2010; Schuchmann 2007). Note: In patients with refractory hiccups, may use in combination with a proton pump inhibitor, baclofen, or metoclopramide (Kohse 2017).

Neuropathic pain (other than postherpetic neuralgia) (off-label use): Oral: Immediate release: Initial: 300 to 900 mg/day in 1 to 3 divided doses (Dolgun 2014; Mishra 2012); increase dose based on response and tolerability to a target dose of 1,200 to 3,600 mg/day in 3 divided doses (IASP [Finnerup 2015]). Note: An adequate trial with gabapentin may require 2 months or more (Bone 2002; Rosenquist 2018).

Diabetic neuropathy (alternative therapy):

Immediate release: Oral: Initial: 100 to 300 mg 1 to 3 times daily; target dose: 900 to 3,600 mg/day (AAN [Bril 2011]; ADA [Pop-Busui 2017]; EFNS [Attal 2010]; IASP [Finnerup 2015]). Note: Some experts recommend initiating with 300 to 600 mg 3 times daily (Backonja 1998; Feldman 2018).

Extended release: Oral: Initial: 300 mg at bedtime; increase dose based on efficacy and tolerability over 2 weeks to a target dose of 3,000 to 3,600 mg/day (IASP [Finnerup 2015]; Sandercock 2012)

Postherpetic neuralgia:

Immediate release: 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)

Extended release: Oral: 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

Postoperative pain (adjunct) (off-label use): Oral: Immediate release: 300 to 1,200 mg given 1 to 2 hours prior to surgery or immediately following surgery (Chou 2016; Doleman 2015; Peng 2007; Yu 2013)

Pruritus (alternative agent) (off-label use):

Brachioradial pruritus: Oral: Immediate release: Initial: 300 mg/day in 1 to 3 divided doses; increase dose based on response and tolerability up to 1,800 mg/day (Bueller 1999; Kanitakis 2006; Winhoven 2004; Yilmaz 2010).

Paraneoplastic pruritus: Oral: Immediate release: Initial: 300 mg/day in 1 to 3 divided doses; increase dose based on response and tolerability up to 3,600 mg/day (Demierre 2006; Lee 2010)

Uremic pruritus: 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).

Restless legs syndrome (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 is achieved (range: 300 to 2,400 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; IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]; Happe 2003; Saletu 2010; Vignatelli 2006).

Seizures, partial onset: Oral: Immediate release: 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. Some experts recommend a lower starting dose with titration as tolerated (Schachter 2018).

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).

Vasomotor symptoms associated with menopause (off-label use):

Immediate release: Oral: Initial: 300 to 400 mg once daily at bedtime; may initiate with 100 mg at bedtime if concerned about adverse reactions; increase over 3 to 12 days based on response and tolerability up to 600 to 2,400 mg/day in 2 to 3 divided doses (ACOG 2014; NAMS 2015; Reddy 2006, Toulis 2009).

Extended release: Oral: Target dose: 600 mg in the morning and 1,200 mg at bedtime; increase to target dose over 1 week (Pinkerton 2014).

Discontinuation of therapy: In patients receiving gabapentin chronically, unless safety concerns require a more rapid withdrawal, gabapentin should be withdrawn gradually over ≥1 week to minimize the potential of increased seizure frequency (in patients with epilepsy) or other withdrawal symptoms (eg, confusion, irritability, tachycardia, diaphoresis) (Norton 2001; Tran 2005).

Dosing: Geriatric

Restless legs syndrome (off-label use): Oral: Initial: 100 mg once daily (IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016])

Other indications: Refer to adult dosing.

Dosing: Pediatric

Seizures, partial onset: Immediate release:

Children 3 to 4 years: Oral: 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: 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 and Adolescents: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

Dosing: Renal Impairment

Note: Estimation of renal function for dosing adjustments should be done using the Cockcroft-Gault formula.

Children ≥12 years, Adolescents, and Adults:

Immediate release:

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)

Extended release: 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

Immediate release: 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.

Extended release: Administer with evening meal. Swallow whole; do not chew, crush, or split.

Dietary Considerations

Extended release tablet 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

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

Aluminum Hydroxide: May decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after administration of antacids containing aluminum hydroxide or magnesium hydroxide. 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

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

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

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

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

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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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 use of a magnesium-containing antacid. 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

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. 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

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

Tetrahydrocannabinol and Cannabidiol: 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

>10%:

Central nervous system: Dizziness (immediate release, adolescents and adults: 17% to 28%; extended release, adults: 11%; immediate release, children: 3%), drowsiness (immediate release, adolescents and adults: 19% to 21%; immediate release, children: 8%; extended release, adults: 5%), ataxia (immediate release, adolescents and adults: 1% to 13%), fatigue (immediate release, adolescents and adults: 11%; immediate release, children: 3%)

Infection: Viral infection (immediate release, children: 11%)

1% to 10%:

Cardiovascular: Peripheral edema (adolescents and adults: 2% to 8%), hypertension (extended release, adults: >1%), increased blood pressure (extended release, adults: >1%), vasodilatation (immediate release, adolescents and adults: 1%)

Central nervous system: Hostility (immediate release: 5% to 8%), emotional lability (immediate release: 4% to 6%), abnormality in thinking (immediate release: 2% to 3%), abnormal gait (immediate release, adults: 2%), amnesia (immediate release, adolescents and adults: 2%), depression (immediate release, adolescents and adults: 2%), status epilepticus (immediate release, adolescents and adults: 2%), confusion (extended release, adults: >1%), memory impairment (extended release, adults: >1%), lethargy (extended release, adults: 1%), pain (extended release, adults: 1%), vertigo (extended release, adults: 1%)

Dermatologic: Skin rash (extended release, adults: >1%), excoriation (immediate release, adolescents and adults: 1%)

Endocrine & metabolic: Weight gain (2% to 3%), hyperglycemia (immediate release, adults: 1%)

Gastrointestinal: Nausea (immediate release: ≤8%; extended release, adults: >1%), vomiting (immediate release: ≤8%), diarrhea (immediate release, adults: 6%), xerostomia (adolescents and adults: ≤5%;), constipation (adolescents and adults: 1% to 4%), dental disease (immediate release, adolescents and adults: 2%), dyspepsia (adolescents and adults: 1% to 2%), viral gastroenteritis (extended release, adults: >1)

Genitourinary: Impotence (immediate release, adolescents and adults: 2%), urinary tract infection (extended release, adults: 2%)

Hypersensitivity: Seasonal allergy (extended release, adults: >1%)

Infection: Infection (immediate release, adults: 5%), herpes zoster infection (extended release, adults: >1%)

Neuromuscular & skeletal: Tremor (immediate release, adolescents and adults: 7%), asthenia (immediate release, adults: 6%), hyperkinesia (immediate release: 3% to 5%), back pain (adolescents and adults: 2%), dysarthria (immediate release, adolescents and adults: 2%), limb pain (extended release, adults: 2%), joint swelling (extended release, adults: >1%)

Ophthalmic: Nystagmus (immediate release, adolescents and adults: 8%), diplopia (immediate release, adolescents and adults: 1% to 6%), amblyopia (immediate release: 3% to 4%), conjunctivitis (immediate release, adults: 1%)

Otic: Otitis media (immediate release, adults: 1%)

Respiratory: Bronchitis (immediate release, children: 3%), nasopharyngitis (extended release, adults: 3%), respiratory tract infection (immediate release, children: 3%), pharyngitis (immediate release, adolescents and adults: 1% to 3%), cough (immediate release, adolescents and adults: 2%), dry throat (immediate release, adolescents and adults: ≤2%), pneumonia (extended release, adults: >1%), upper respiratory tract infection (extended release, adults: >1%)

Miscellaneous: Fever (immediate release, children: 10%; extended release, adults: >1%), accidental injury (immediate release, adults: 3%)

<1%, postmarketing, and/or case reports: Agitation, altered serum glucose, anaphylaxis, angioedema, anorgasmia, breast hypertrophy, change in libido, DRESS syndrome, ejaculatory disorder, erythema multiforme, hyponatremia, increased creatine phosphokinase, increased liver enzymes, jaundice, movement disorder, rhabdomyolysis, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies

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 renal impairment; dose adjustment required.

• Seizure disorder: The safety and efficacy of the extended release formulation has not been studied in patients with epilepsy.

• Substance abuse: Use with caution in patients with a history of substance abuse, including alcohol, benzodiazepines, cannabis, cocaine, and opioids; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur (Evoy 2017; Mersfelder 2016).

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: Immediate release and extended release products are not interchangeable with each other or with gabapentin enacarbil 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 in patients with epilepsy or other withdrawal symptoms (eg, confusion, irritability, tachycardia, diaphoresis). Therapy should be withdrawn gradually over ≥1 week to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal (Norton 2001; Tran 2005).

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). Pregnancy registry outcome data following maternal use of gabapentin during pregnancy is limited (Holmes 2012). Folic acid supplementation is recommended prior to and during pregnancy in women using gabapentin (Borgelt 2016; Picchietti 2015).

Gabapentin is used off-label for the treatment of restless leg syndrome; however, current guidelines note there is insufficient evidence to recommend its use in pregnant women for this indication (Picchietti 2015). Pharmacological agents should not be used for the treatment of alcohol use disorder in pregnant women unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder.

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), swollen glands, 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, abnormal movements, difficulty swallowing, 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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