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Gabapentin

Medically reviewed by Drugs.com. Last updated on Jul 6, 2020.

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

Miscellaneous, Oral:

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

Solution, Oral:

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

Generic: 250 mg/5 mL (473 mL); 300 mg/6 mL (6 mL); 250 mg/5 mL (5 mL, 6 mL, 470 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 degradation 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. These effects on restless leg syndrome are unknown.

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, focal (partial) onset (immediate release only): As adjunctive therapy in the treatment of focal (partial) seizures with and without secondary generalization in adults and pediatric patients 3 years of age and older with epilepsy.

Off Label Uses

Alcohol use disorder, moderate to severe (alternative agent)

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 (APA) 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 (alternative agent)

Data from a randomized, double-blind, active-controlled study support the use of gabapentin in the outpatient treatment of mild alcohol withdrawal [Myrick 2009]. Similarly, a high heterogeneity meta-analysis that included only a limited number of randomized, controlled trials support the use of gabapentin in the treatment of alcohol withdrawal [Ahmed 2019].

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

Cough, chronic refractory (alternative agent)

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 (ACCP) 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]].

Fibromyalgia (alternative agent)

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 [eg, baclofen, cisapride, omeprazole, haloperidol, metoclopramide]) may be of benefit in the treatment 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]]. Data from meta-analyses support the use of IR 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 ER gabapentin in reducing pain by more than 50% and improving sleep in diabetic neuropathy [Sandercock 2009], [Sandercock 2012]. A meta-analysis of trials evaluating the treatment of trigeminal neuralgia supports the use of gabapentin in the treatment of trigeminal neuralgia [Yuan 2016].

Based on guidelines from the International Association for the Study of Pain (IASP), European Federation of Neurological Societies (EFNS), and Society of Critical Care Medicine (SCCM), gabapentin is effective and recommended for the management of peripheral neuropathy [EFNS [Attal 2010]], [IASP [Finnerup 2015]], [SCCM [Devlin 2018])]. Based on guidelines from the EFNS, IASP, and National Institute for Health and Care Excellence (NICE), 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 (AAN), 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 (ADA) recommends gabapentin as a second-line option [ADA [Pop-Busui 2017]]. Based on the European Academy of Neurology guideline on trigeminal neuralgia, gabapentin is recommended based on limited evidence as monotherapy or as an adjunct for trigeminal neuralgia when first-line agents are not effective or tolerated [EAN [Bendtsen 2019]].

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.

Pruritus, chronic (neuropathic or malignancy related) (alternative agent)

Data from a limited number of patients studied suggest that gabapentin may be beneficial for the treatment of chronic pruritus, including brachioradial pruritus [Bueller 1999], [Carvalho 2015], [Kanitakis 2006], [Winhoven 2004], [Yilmaz 2010].

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

Pruritus, uremic

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

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, alpha-2-delta 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 alpha-2-delta ligands (eg, gabapentin). However, the guidelines note that long-term studies are needed.

Social anxiety disorder, adjunct to antidepressants or monotherapy (alternative agent)

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].

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 [Li 2016], [Loprinzi 2009], [Toulis 2009]. 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) position 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

Note: For patients with respiratory disease, initiate therapy at the lowest dose (FDA 2019).

Alcohol use disorder, moderate to severe (alternative agent) (off-label use): Immediate release: Oral: Initial: 300 mg once daily; increase dose based on response and tolerability in increments of 300 mg every 1 to 2 days up to a target dose of 600 mg 3 times daily (Brower 2008; Mason 2014; VA/DoD 2015). Note: Gabapentin is suggested by some experts as an alternative when first-line agents cannot be used (Johnson 2019; 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):

Note: Withdrawal will progress at different rates in some patients; flexibility in dosing and duration is warranted (Holt 2018; VA/DoD 2015). The following is one suggested regimen based on a single randomized, double-blind trial:

Immediate release: Oral: Initial: 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).

Cough, chronic refractory (alternative agent) (off-label use): Immediate release: Oral: Initial: 300 mg once daily; increase dose gradually based on response and tolerability in increments of 300 mg to a maximum dose of 900 mg twice daily (ACCP [Gibson 2016]; Ryan 2012). Re-evaluate therapeutic need after 6 months (ACCP [Gibson 2016]).

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

Note: For patients who do not respond to or tolerate preferred agents (Goldenberg 2020):

Immediate release: Oral: Initial: 100 to 300 mg once daily at bedtime; increase dose gradually based on response and tolerability every 1 to 2 weeks to a target dose of 1.2 to 2.4 g/day in divided doses (Arnold 2007; Goldenberg 2020).

Hiccups (singultus) (off-label use): Immediate release: Oral: Usual dose range: 300 mg to 1.2 g/day in 3 to 4 divided doses (Hernández 2004; Jatzko 2007; Moretti 2004; Porzio 2010; Schuchmann 2007). Can be discontinued the day after hiccups subside; long-term therapy may be warranted for persistent or relapsing hiccups (eg, palliative care) (Lembo 2020). Note: In patients with refractory hiccups, may use in combination with a proton pump inhibitor, baclofen, or metoclopramide (Kohse 2017).

Neuropathic pain:

General dosing recommendations (for other than postherpetic neuralgia) (off-label use):

Note: For chronic use, an adequate trial with gabapentin may require 2 months or more (Bone 2002; Tauben 2020). For critically ill patients with neuropathic pain, gabapentin may be a useful component of multimodal pain control (SCCM [Devlin 2018]).

Immediate release: Oral: Initial: 100 to 300 mg 1 to 3 times daily (ADA [Pop-Busui 2017]; Dolgun 2014; Mishra 2012); increase dose based on response and tolerability to a target dose range of 300 mg to 1.2 g 3 times daily (AAN [Bril 2011]; ADA [Pop-Busui 2017]; EFNS [Attal 2010]; IASP [Finnerup 2015]).

Extended release: Oral: Initial: 300 mg at bedtime; increase dose based on response and tolerability to a target dose of 900 mg to 3.6 g once daily (IASP [Finnerup 2015]; Sandercock 2012).

Postherpetic neuralgia:

Immediate release: Oral: 300 mg once on day 1, 300 mg twice daily on day 2, and 300 mg 3 times daily on day 3, then increase as needed up to 1.8 to 3.6 g/day in divided doses. Additional benefit of doses >1.8 g/day has not been established.

Extended release: Oral: Initial: 300 mg once daily; increase by 300 mg each day up to 900 mg once daily. Further increase as needed up to 1.8 g once daily. Additional benefit of doses >1.8 g/day has not been established.

Postoperative pain (off-label use): Immediate release: Oral: 300 mg to 1.2 g as a single dose, given 1 to 2 hours prior to surgery or immediately following surgery as part of a multimodal analgesia regimen (Chou 2016; Doleman 2015; Peng 2007; Yu 2013). Note: Some experts avoid use in patients with sleep-disordered breathing (eg, obstructive sleep apnea) (Joshi 2020; Mariano 2018).

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

Note: For patients with pruritus resistant to preferred therapies (Matsuda 2016; Weisshaar 2012):

Neuropathic (eg, brachioradial pruritus, notalgia paresthetica) or malignancy-related pruritus: Immediate release: Oral: Initial: 300 mg/day in 1 to 3 divided doses; increase dose based on response and tolerability up to 1.8 g/day in divided doses (Kanitakis 2006; Winhoven 2004; Yilmaz 2010). Higher doses up to 3.6 g/day have been used in oncology populations (Demierre 2006; Lee 2010).

Uremic pruritus: Immediate release: Oral: Initial: 100 mg after dialysis on hemodialysis days; may increase dose based on response and tolerability up to 300 mg after dialysis on hemodialysis days (Gunal 2004; Kobrin 2018; Nofal 2016; Razeghi 2009).

Restless legs syndrome (off-label use): Immediate release: Oral: Initial: 100 to 300 mg once daily 2 hours before bedtime; may increase dose every 1 to 2 weeks until symptom relief is achieved (range: 300 mg to 2.4 g/day). Suggested maintenance dosing schedule for doses ≥600 mg/day: One-third of total daily dose given midday, remaining two-thirds of the total daily dose given in the evening (Garcia-Borreguero 2002; Happe 2003; IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]; Saletu 2010; Silber 2018; Vignatelli 2006).

Seizures, focal (partial) onset: Immediate release: Oral: Initial: 300 mg 3 times daily; increase dose based on response and tolerability. Usual dosage: 300 to 600 mg 3 times daily; doses up to 2.4 g/day and 3.6 g/day have been tolerated in long-term and short-term clinical studies, respectively. Some experts recommend a lower starting dose (eg, 100 mg 3 times daily) with titration as tolerated (Schachter 2018).

Social anxiety disorder (alternative agent) (off-label use):

Note: Monotherapy or adjunctive therapy for patients who do not tolerate or respond to preferred agents (Stein 2020):

Immediate release: Oral: 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 3.6 g/day in 3 divided doses (Pande 1999). Some experts recommend initiating with 100 mg 3 times daily in patients with respiratory disease (Stein 2020).

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

Immediate release: Oral: Initial: 300 to 400 mg once daily at bedtime; some experts use an initial dose of 100 mg once daily to avoid adverse effects (Santen 2018); increase gradually (eg, over 3 to 12 days) based on response and tolerability up to 600 mg to 2.4 g/day in 2 to 3 divided doses (ACOG 2014; NAMS 2015; Reddy 2006; Toulis 2009). Some experts suggest gabapentin for women whose symptoms occur primarily at night and favor a maximum dose of 900 mg to 1.2 g, given as one dose at bedtime (ES [Stuenkel 2015]; Santen 2018).

Extended release: Oral: Initial: 600 mg once daily at bedtime; increase gradually (eg, 600 mg every 3 days) to target dose of 600 mg in the morning and 1.2 g at bedtime (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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

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

Other indications: Initiate therapy at the lowest dose (FDA 2019). Refer to adult dosing. For postoperative pain (off-label use), some experts avoid use in patients >65 years of age (Joshi 2020).

Discontinuation of therapy: Refer to adult dosing.

Dosing: Pediatric

Note: Do not exceed 12 hours between doses with 3 times daily dosing. Pediatric doses presented as mg/kg/day and mg/kg/dose; use precaution.

Seizures, partial onset; adjunctive therapy: Oral: Immediate release: Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week.

Children 3 to <12 years:

Initial: 10 to 15 mg/kg/day divided into 3 doses daily; titrate dose upward over ~3 days

Maintenance usual dose:

Children 3 to 4 years: 40 mg/kg/day divided into 3 doses daily; maximum daily dose: In one long-term study, doses up to 50 mg/kg/day were well-tolerated

Children 5 to <12 years: 25 to 35 mg/kg/day divided into 3 doses daily; maximum daily dose: In one long-term study, doses up to 50 mg/kg/day were well-tolerated

Children ≥12 years and Adolescents: Initial: 300 mg 3 times daily; titrate dose upward if needed; usual maintenance dose: 900 to 1,800 mg/day divided into 3 doses daily; doses up to 2,400 mg/day divided into 3 doses daily are well tolerated long-term; maximum daily dose: Doses up to 3,600 mg/day have been tolerated in short-term studies.

Neuropathic pain: Limited data available: Oral: Immediate release: Children and Adolescents: Initial: 5 mg/kg/dose up to 300 mg at bedtime; day 2: Increase to 5 mg/kg/dose twice daily (up to 300 mg twice daily); day 3: Increase to 5 mg/kg/dose 3 times daily (up to 300 mg 3 times daily); further titrate with dosage increases (not frequency) to effect; American Pain Society (APS) recommends a lower initial dose of 2 mg/kg/day which may be considered if concurrent analgesics are also sedating; usual dosage range: 8 to 35 mg/kg/day divided into 3 doses daily (APS, 2008; Galloway, 2000); maximum daily dose: 3,600 mg/day

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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

Oral:

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. Capsules may be opened and sprinkled on food (eg, applesauce, orange juice, pudding) for patients unable to swallow capsules (Gidal 1998).

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. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

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

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 at lower doses in patients already receiving 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

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. 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

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lisuride: May enhance the CNS depressant 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. If anticonvulsants are being used for another indication, monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

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

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

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

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. 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 Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interupt oxybate salt treatment during short-term opioid use. Consider therapy modification

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

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

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%:

Infection: Viral infection (IR, children: 11%)

Nervous system: Ataxia (IR, adolescents and adults: 1% to 13%), dizziness (IR, adolescents and adults: 17% to 28% [placebo: 7% to 8%]; ER, adults: 11% [placebo: 2%]; IR, children: 3% [placebo: 2%]), drowsiness (IR, adolescents and adults: 19% to 21% [placebo: 5% to 9%]; IR, children: 8% [placebo: 5%]; ER, adults: 5% [placebo: 3%]), fatigue (IR, adolescents and adults: 11%; IR, children: 3%)

1% to 10%:

Cardiovascular: Hypertension (ER, adults: >1%), increased blood pressure (ER, adults: >1%), peripheral edema (adolescents and adults: 2% to 8%), vasodilation (IR, adolescents and adults: 1%)

Dermatologic: Excoriation of skin (IR, adolescents and adults: 1%), skin rash (ER, adults: >1%)

Endocrine & metabolic: Hyperglycemia (IR, adults: 1%), weight gain (2% to 3%)

Gastrointestinal: Constipation (adolescents and adults: 1% to 4%), dental disease (IR, adolescents and adults: 2%), diarrhea (IR, adults: 6%), dyspepsia (adolescents and adults: 1% to 2%), nausea (IR: ≤8%; ER, adults: >1%), viral gastroenteritis (ER, adults: >1%), vomiting (IR: ≤8%), xerostomia (adolescents and adults: ≤5%)

Genitourinary: Impotence (IR, adolescents and adults: 2%), urinary tract infection (ER, adults: 2%)

Infection: Herpes zoster infection (ER, adults: >1%), infection (IR, adults: 5%)

Nervous system: Abnormal gait (IR, adults: 2%), abnormality in thinking (IR: 2% to 3% [placebo: ≤1%]), amnesia (IR, adolescents and adults: 2%), confusion (ER, adults: >1%), depression (IR, adolescents and adults: 2%), dysarthria (IR, adolescents and adults: 2%), emotional lability (IR: 4% to 6% [placebo: 1% to 2%]), hostility (IR: 5% to 8% [placebo: 1% to 2%]), lethargy (ER, adults: 1%), memory impairment (ER, adults: >1%), pain (ER, adults: 1%), status epilepticus (IR, adolescents and adults: 2%), vertigo (ER, adults: 1%)

Neuromuscular & skeletal: Asthenia (IR, adults: 6%), back pain (adolescents and adults: 2%), hyperkinetic muscle activity (IR: 3% to 5% [placebo: 1% to 3%]), joint swelling (ER, adults: >1%), limb pain (ER, adults: 2%), tremor (IR, adolescents and adults: 7%)

Ophthalmic: Amblyopia (IR: 3% to 4%), conjunctivitis (IR, adults: 1%), diplopia (IR, adolescents and adults: 1% to 6%), nystagmus disorder (IR, adolescents and adults: 8%)

Otic: Otitis media (IR, adults: 1%)

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

Miscellaneous: Accidental injury (IR, adults: 3% [placebo: 1%]), fever (IR, children: 10%; ER, adults: >1%)

<1%:

Hypersensitivity: Anaphylaxis, angioedema

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Ragucci 2001; Scaparotta 2011)

Nervous system: Suicidal ideation (Molero 2019), suicidal tendencies (Molero 2019)

Postmarketing:

Cardiovascular: Cardiomyopathy (Tellor 2019), hypersensitivity angiitis (Sahin 2008)

Dermatologic: Bullous pemphigoid (Flamm 2017), dermatitis (interstitial granulomatous [Georgesen 2014]), erythema multiforme, Stevens-Johnson syndrome (Gonzales-Sicilia 1998)

Endocrine & metabolic: Altered serum glucose, amenorrhea (Berger 2004), change in libido, hypoglycemia (Penumalee 2003; Scholl 2015), hyponatremia (Falhammar 2018; Lu 2017; Wilton 2002), thyroiditis (Fyre 1999)

Genitourinary: Breast hypertrophy (Zylicz 2000), ejaculation failure (Labbate 1999), ejaculatory disorder, urinary incontinence (Rissardo 2019)

Hematologic & oncologic: Thrombocytopenia (Ataki 2015)

Hepatic: Hepatotoxicity (Jackson 2018), increased liver enzymes (Jackson 2018; Lasso-de-la-Vega 2001)

Infection: Parasitic infection (Lopez 2010)

Nervous system: Agitation (Childers 1997), anorgasmia (Labbate 1999), coma (Abdennour 2017; Butler 2003; Dogukan 2006), encephalopathy (Beauvais 2015), movement disorder (Allford 2007; Attupurath 2009; Palomeras 2000; Pina 2005; Raju 2007; Rohman 2014; Souzdalnitski 2014; Twardowschy 2008; Zesiewicz 2008), myoclonus (facial) (Hampton 2019; Hui 2019; Yeddi 2019), polyneuropathy (Gould 1998), stuttering (Nissani 1997), visual hallucination (Parsons 2016)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen, rhabdomyolysis (Bilgir 2009; Choi 2017; Coupal 2017; Lipson 2005; Tuccori 2007)

Respiratory: Respiratory depression (FDA Safety Alert, December 19, 2019)

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, that 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) 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).

• Respiratory effects: Serious, life-threatening, and fatal respiratory depression may occur in patients using gabapentin; risk may be increased with conditions such as chronic obstructive pulmonary disease, in the elderly, and with the concomitant use of opioids and other CNS depressants. Initiate gabapentin at the lowest dose and monitor patients for symptoms of respiratory depression and sedation in patients with underlying respiratory disease (FDA 2019).

• 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:

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).

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

• Respiratory disease: Gabapentin may cause respiratory depression; use caution and initiate with the lowest recommended dose in patients with respiratory compromise (FDA 2019).

• Seizure disorder: The safety and efficacy of the ER 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).

Dosage form specific issues:

• Product interchangeability: IR and ER products are not interchangeable with each other or with gabapentin enacarbil due to differences in formulations, indications, and pharmacokinetics.

Special populations:

Elderly: Gabapentin may cause respiratory depression; use caution and initiate with the lowest recommended dose in elderly patients (FDA 2019).

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)

Reproductive Considerations

Folic acid supplementation is recommended prior to pregnancy in women using gabapentin (Borgelt 2016; Picchietti 2015).

Pregnancy Risk Factor

C

Pregnancy Considerations

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 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

What is this drug used for?

• It is used to treat painful nerve diseases.

• It is used to help control certain kinds of seizures.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

• Diarrhea

• Dry mouth

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Swollen glands

• Behavioral changes

• Trouble with memory

• Vision changes

• Confusion

• Tremors

• Trouble breathing

• Slow breathing

• Shallow breathing

• Blue/gray skin discoloration

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Severe loss of strength and energy

• Involuntary eye movements

• Twitching

• Chills

• Sore throat

• Muscle pain

• Muscle weakness

• Abnormal movements

• Trouble swallowing

• Change in balance

• Trouble speaking

• Trouble focusing

• Severe fatigue

• Passing out

• Severe dizziness

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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

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