Gabapentin

N03A - Antiepileptics ATC N03AX12 Small molecule approved 1993 Oral Natural product

JFDA label: Nurona

Mechanism of Action

Modulator of Voltage-gated calcium channel — Voltage-gated calcium channel modulator

Target	Action	Gene / class
Voltage-gated calcium channel efficacy	MODULATOR

Indications

Approved

Postherpetic neuralgia
Seizures, partial onset (immediate release only)

Off-label

Alcohol dependence
Alcohol withdrawal
Brachioradial pruritus
Cough, chronic (refractory)
Diabetic neuropathy
Fibromyalgia syndrome
Hiccups (singultus)
Hot flashes
Neuropathic pain
Post-operative pain (adjunct)
Restless legs syndrome
Social anxiety disorder
Uremic pruritus

Contraindications

Source: Lexicomp

Hypersensitivity to gabapentin or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Common Peripheral edema · vasodilatation

Nervous system disorders (23)

Very Common ataxia · Dizziness · Dizziness · drowsiness · fatigue · Somnolence

Common abnormal gait · abnormality in thinking · amnesia · Ataxia · Cognitive impairment · depression · emotional lability · headache · Hostility · hyperesthesia · hyperkinesia · lethargy · nervousness · pain · tremor · twitching · vertigo

Renal and urinary disorders (2)

Common Impotence · urinary tract infection

Blood and lymphatic system disorders (2)

Common Decreased white blood cell count · leukopenia

Metabolism and nutrition disorders (3)

Common hyperglycemia · Weight gain · Weight gain

Gastrointestinal disorders (10)

Common abdominal pain · constipation · dental disease · Diarrhea · dry throat · dyspepsia · flatulence · increased appetite · nausea and vomiting · xerostomia

Skin and subcutaneous tissue disorders (2)

Common Pruritus · skin rash

Musculoskeletal and connective tissue disorders (6)

Common back pain · bone fracture · dysarthria · limb pain · myalgia · Weakness

Eye disorders (6)

Common amblyopia · blurred vision · conjunctivitis · diplopia · Nystagmus · Nystagmus

Ear and labyrinth disorders (1)

Common Otitis media

Infections and infestations (2)

Very Common Viral infection

Common Infection

General disorders and administration site conditions (3)

Common Fatigue · Fever · Peripheral oedema

Respiratory, thoracic and mediastinal disorders (7)

Common bronchitis · cough · nasopharyngitis · pharyngitis · respiratory tract infection · Rhinitis

Rare Respiratory depression (overdose, opioid combination)

Other (106)

Not Known Abnormal hepatic function · acute renal failure · agitation · altered serum glucose · anaphylaxis · anemia · angina pectoris · angioedema · aphasia · aspiration pneumonia · blindness · blood coagulation disorder · bradycardia · brain disease · breast hypertrophy · bronchospasm · cardiac arrhythmia (various) · cerebrovascular accident · change in libido · cholestatic hepatitis · CNS neoplasm · colitis · confusion · Cushingoid appearance · DRESS syndrome · drug abuse · drug dependence · dyspnea · ejaculatory disorder · erythema multiforme · facial paralysis · falling · fecal incontinence · fulminant hepatitis · gastroenteritis · glaucoma · glycosuria · gynecomastia · hearing loss · heart block · hematemesis · hematuria · hemiplegia · hemorrhage · hepatitis · hepatomegaly · herpes zoster · hyperlipidemia · hypersensitivity reaction · hypertension · hyperthyroidism · hyperventilation · hypoglycemia · hyponatremia · hypotension · hypothyroidism · hypoventilation · increased creatine phosphokinase · increased liver enzymes · increased serum creatinine · jaundice · joint swelling · leukocytosis · loss of consciousness · lymphadenopathy · lymphocytosis · memory impairment · meningism · migraine · movement disorder · myocardial infarction · myoclonus (local) · nephrolithiasis · nephrosis · nerve palsy · non-Hodgkin lymphoma · ovarian failure · palpitations · pancreatitis · paresthesia · peptic ulcer · pericardial effusion · pericardial rub · pericarditis · peripheral vascular disease · pneumonia · psychosis · pulmonary edema · pulmonary thromboembolism · purpura · retinopathy · rhabdomyolysis · seasonal allergy · sexual disorder · skin necrosis · status epilepticus · Stevens-Johnson syndrome · subdural hematoma · suicidal ideation · suicidal tendencies · syncope · tachycardia · thrombocytopenia · thrombophlebitis · tumor growth · withdrawal syndrome

Dosing

Source: Lexicomp

Postherpetic neuralgia: Oral: Immediate release: 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: Day 1: 300 mg, Day 2: 600 mg, Days 3 to 6: 900 mg once daily, Days 7 to 10: 1,200 mg once daily, Days 11 to 14: 1,500 mg once daily, Days ≥15: 1,800 mg once daily Seizures, partial onset: Oral: 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 Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week. Alcohol dependence (off-label use): Oral: Immediate release: 300 mg once daily on day 1, followed by dosage escalation, based on response and tolerability, in increments of 300 mg/day up to a target dose of 1,800 mg/day in 3 divided doses (Brower 2008; Mason 2014; VA/DoD 2015). Alcohol withdrawal (off-label use): Oral: Immediate release: 300 to 400 mg 3 times daily on days 1 through 3, then 300 to 400 mg twice daily on day 4, then discontinue. For breakthrough symptoms during days 1 through 4, consider providing single doses of 100 mg administered up to 3 times daily and a 300 mg dose reserved for the evening (Myrick 2009). Brachioradial pruritus (off-label use): Oral: Immediate release: Initial: 100 mg 3 times daily; increase dose based on response and tolerability up to 1,800 mg/day (Bueller 1999; Kanitakis 2006; Winhoven 2004; Yilmaz 2010). Additional data may be necessary to further define the role of gabapentin in this condition. Cough, chronic (refractory) (off-label use): Oral: Immediate release: 300 mg once daily on day 1, followed by dosage escalation in increments of 300 mg/day until cough symptoms cease, side effects are intolerable, or a maximum tolerated dose of 1,800 mg/day given in 2 divided doses is reached (ACCP [Gibson 2016]; Ryan 2012). Additional data may be necessary to further define the role of gabapentin in this condition. Diabetic neuropathy (off-label use): Immediate release: 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]) Extended release: 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) Fibromyalgia syndrome (off-label use): Oral: Immediate release: Initial: 300 mg once daily at bedtime, increase in increments of 300 to 600 mg/day every 1 to 2 weeks based on response and tolerability up to 2,400 mg/day in divided doses. Median dosage in clinical trial was 1,800 mg/day with a r

(For additional information see "Gabapentin: Pediatric drug information") 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. Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week

Refer to adult dosing. In the off-label management of restless legs syndrome, a starting dose of 100 mg once daily in patients >65 years has been recommended (Garcia-Borreguero 2016).

Warnings & Precautions

Source: Lexicomp

Anaphylaxis/angioedema

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

CNS depression

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

Multiorgan hypersensitivity

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

Neuropsychiatric effects

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

Suicidal ideation

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

Renal impairment

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

Seizure disorder

The safety and efficacy of the extended release formulation has not been studied in patients with epilepsy. Concurrent drug therapy issues:

Drug-drug interactions

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

Product interchangeability

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; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. The extended release formulation should be withdrawn over ≥1 week.

Pregnancy & Lactation

Pregnancy

FDA category C

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 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). 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

Lactation

RID 8.7%

Gabapentin is present in breast milk. The relative infant dose (RID) of gabapentin is 8.7% to 13% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 10 to 15 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is 25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000). The RID of gabapentin was calculated using a milk concentration of 8.7 mcg/mL, providing an estimated daily infant dose via

LactMed: monitor the infant.

Monitoring

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

Chemistry & Properties

Formula	C9H17NO2
Molecular weight	171.24 g/mol
IUPAC name	2-[1-(aminomethyl)cyclohexyl]acetic acid
CAS	60142-96-3
PubChem CID	3446
InChIKey	`UGJMXCAKCUNAIE-UHFFFAOYSA-N`
logP	1.37 (XLogP -1.1)
Polar surface area	63.32 Å²
H-bond acceptors / donors	2 / 2
Drug-likeness (QED)	0.67
Lipinski violations	0

SMILES

NCC1(CC(=O)O)CCCCC1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.19)

Receptor binding (top 2)

Target	Action	Affinity
Kv7.5 (KCNQ5)	Activator	pEC50 8.7
Kv7.3 (KCNQ3)	Activator	pEC50 8.3

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)B0+ amino acid transporter (Substrate)LAT (Substrate)MDR1 (Substrate)OATP1A2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (46, DDInter)

Interacting drug	Severity	Management
Codeine	major
Hydrocodone	major
Morphine	major
Morphine (liposomal)	major
Alimemazine	moderate
Azatadine	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Brompheniramine	moderate
Carbinoxamine	moderate
Cetirizine	moderate
Chloroquine	moderate
Chlorphenesin	moderate
Chlorpheniramine	moderate
Clemastine	moderate
Clofedanol	moderate
Cyproheptadine	moderate
Dexbrompheniramine	moderate
Dextromethorphan	moderate
Diphenhydramine	moderate
Doxepin	moderate
Doxepin (topical)	moderate
Doxylamine	moderate
Dronabinol	moderate
Ethanol	moderate
Hydroxychloroquine	moderate
Levocetirizine	moderate
Mefloquine	moderate
Mepyramine	moderate
Metoclopramide	moderate
Nabilone	moderate
Olopatadine (nasal)	moderate
Opium	moderate
Pentoxyverine	moderate
Promethazine	moderate
Sibutramine	moderate
Thalidomide	moderate
Trimethobenzamide	moderate
Tripelennamine	moderate
Triprolidine	moderate

Showing 40 of 46.

Registered Products (32)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Gabatrex	Tablet 100 mg	20 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	1.890
Gabatrex Capsules	Capsule 300 mg	10 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	2.090
Gabatrex Capsules	Capsule 400 mg	10 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	2.580
Nurona	Capsule 100 mg	20 cap pack varies	Pharma International Company/ Jordan	3.170
NERVATIN 300	Capsule 300.00 mg	(3x10âs CAP) pack varies	Omicron Pharma	4.190
NERVATIN 400	Capsule 400.00 CAP/1 mg	3x10âs Caps CAP/1 BOX pack varies	Omicron Pharma	4.780
Gabatrex Capsules	Capsule 300 mg	30 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	5.810
Nurona	Tablet 300 mg	30 tab pack varies	Pharma International Company/ Jordan	5.810
Volar	Capsule 300 mg	30 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	5.810
NERVATIN 300	Capsule 300.00 mg	(5 x 10âs CAP) pack varies	Omicron Pharma	6.990
Gabatrex Capsules	Capsule 400 mg	30 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	7.160
Neuroplex	Capsule 300 mg	50 cap	Sukhtian Group	7.530
NERVATIN 400	Capsule 400.00 CAP/1 mg	5 x 10âs CAP/1 BOX pack varies	Omicron Pharma	7.960
Nurona	Capsule 400 mg	30 cap pack varies	Pharma International Company/ Jordan	7.960
Volar	Capsule 400 mg	30 cap	Dar Al Dawa Development and Investment Co Ltd/Jordan	7.960
Gabanet	Capsule 100 mg	48 cap	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	8.170
Gabanet 300 Cap	Capsule 300 mg	48 cap	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	9.290
Gabatrex Capsules	Capsule 300 mg	50 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	9.680
Nurona	Tablet 300 mg	50 tab pack varies	Pharma International Company/ Jordan	9.680
Remebentin	Capsule 400 mg	50 cap	JAWEDA INT. DRUD STORE	10.450
Neuroplex	Tablet 400 mg	50 tab	Sukhtian Group	10.610
Neurontin (GABAPENTIN)	Tablet 300 mg	50 tab	Khoury Drug Store	10.750
Nurona	Tablet 100 mg	50 tab pack varies	Pharma International Company/ Jordan	11.090
Nurona	Tablet 300 mg	300 tab pack varies	Pharma International Company/ Jordan	11.390
Gabatrex 400 Capsules	Capsule 400 mg	50 cap pack varies	Hikma Pharmaceuticals Co.Ltd/Jordan	11.930
Gabanet 400 Cap	Capsule 400 mg	48 cap	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	12.730
Neurontin (GABAPENTIN)	Tablet 400 mg	50 tab	Khoury Drug Store	13.260
Nurona	Tablet 400 mg	50 tab pack varies	Pharma International Company/ Jordan	13.260
Gabatrex	Tablet 600 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	20.030
Gabatrex	Tablet 800 mg	30 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	23.070
Volar	Capsule 300 mg	500 cap pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	84.250
Nurona	Tablet 300 mg	500 tab pack varies	Pharma International Company/ Jordan	87.080