Gabapentin

Gabapentin is a an Antiseizure Agent belonging to pharmacology class of GABA Analog Class

Gabapentin can be used in the treatment of Postherpetic neuralgia, Seizures. It is also used to treat Alcohol use disorder, moderate to severe (alternative agent); Alcohol withdrawal; Cough, chronic refractory (alternative agent); Generalized anxiety disorder; Fibromyalgia (alternative agent); Hiccups (singultus); Neuropathic pain (other than postherpetic neuralgia); Pruritus, chronic (neuropathic or malignancy related) (alternative agent); Pruritus, uremic; Restless legs syndrome; Social anxiety disorder, adjunct to antidepressants or monotherapy (alternative agent); Vasomotor symptoms associated with menopause

It is Absorbed from the gastrointestinal tract. Increased rate and extent of absorption with food (gastroretentive tab). Bioavailability: Dose-dependent (inversely proportional to the dose). Time to peak plasma concentrations: 2-4 hours (conventional formulation); 8 hours (gastroretentive tab)and is Widely distributed in the body. Crosses the placenta and enters breast milk. Volume of distribution: 57.7 L. Plasma protein binding: <3%.

And get excretedVia urine (as unchanged drug). Elimination half-life: Approx 5-7 hours.

The common side effects associated with Gabapentin include erythema, bruising, swelling and pain, headache, nausea.

Gabapentin is available in the form of Capsule, solution, tablets.

The molecule is available in India, USA, Japan, Germany.

Gabapentin belonging to the GABA Analog Class acts a Antiseizure Agent. Gabapentin is structurally related to GABA. However, it does not bind to GABA_A or GABA_B 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.

Gabapentin is available in Capsule, solution, tablet

Oral:

Immediate release: May administer without regard to meals. Administer the first dose on the 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 (e.g., applesauce, orange juice, pudding) for patients unable to swallow capsules.

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

Gabapentin can be used in the treatment of Postherpetic neuralgia, Seizures. It is also used to treat Alcohol use disorder, moderate to severe (alternative agent); Alcohol withdrawal; Cough, chronic refractory (alternative agent); Generalized anxiety disorder; Fibromyalgia (alternative agent); Hiccups (singultus); Neuropathic pain (other than postherpetic neuralgia); Pruritus, chronic (neuropathic or malignancy related) (alternative agent); Pruritus, uremic; Restless legs syndrome; Social anxiety disorder, adjunct to antidepressants or monotherapy (alternative agent); Vasomotor symptoms associated with menopause.

Gabapentin is structurally related to the neurotransmitter GABA. However, it does not bind to GABA_A or GABA_B receptors nor influence the synthesis or uptake of GABA. The exact mechanisms are unknown but it has been shown that gabapentin binds with high affinity to the α-2-δ-1 subunit of voltage-gated Ca channels, which may be found presynaptically, and may facilitate the release of excitatory neurotransmitters that participate in epileptogenesis and nociception.

Gabapentin is approved for use in the following clinical 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.

Although not approved there have been certain off labelled uses documented for tocilizumab which include:

Alcohol use disorder, moderate to severe (alternative agent); Alcohol withdrawal; Cough, chronic refractory (alternative agent); Generalized anxiety disorder; Fibromyalgia (alternative agent); Hiccups (singultus); Neuropathic pain (other than postherpetic neuralgia); Pruritus, chronic (neuropathic or malignancy related) (alternative agent); Pruritus, uremic; Restless legs syndrome; Social anxiety disorder, adjunct to antidepressants or monotherapy (alternative agent); Vasomotor symptoms associated with menopause.

Alcohol use disorder, moderate to severe (alternative agent) (off-label use):

Note: Gabapentin is suggested by some experts as an alternative when first-line agents cannot be used. Gabapentin may be misused by some patients with substance use disorders; evaluate for risk and signs of addiction and dependence.

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 . Some experts consider alternative therapy if goals are not met within 6 months of treatment.

Alcohol withdrawal (off-label use):

Note: Withdrawal will progress at different rates in some patients; flexibility in dosing and duration is warranted. Regimens vary and depend on withdrawal history, degree of current withdrawal symptoms, quantity of alcohol consumption, concomitant medications for breakthrough symptoms, and whether the patient is treated inpatient or in the ambulatory setting. For example, in an inpatient study that enrolled patients with Clinical Institute Withdrawal Assessment (CIWA) scores >15 and offered no as-needed medications for breakthrough withdrawal symptoms, 3.2 g in divided doses was offered on day 1 of treatment . Many facilities only treat alcohol withdrawal in the ambulatory setting if CIWA score is ≤15 and there is no history of withdrawal seizures or delirium tremens. The following are two suggested regimens.

CIWA score <10: Immediate release: Oral: Initial: 300 mg every 6 hours on day 1, then 300 mg every 8 hours on day 2, then 300 mg every 12 hours on day 3, then 300 mg at night on day 4. In addition to scheduled doses, provide one additional as-needed 300 mg dose per day for breakthrough withdrawal symptoms.

CIWA score 10 to 18 (alternative agent): 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.

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. Re-evaluate therapeutic need after 6 months.

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

Note: For patients who do not respond to or tolerate preferred agents:

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.

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

Note: Adjunctive therapy for short-term symptom relief until concurrent therapy is effective (eg, 4 to 6 weeks, followed by tapering). Long-term augmentation may be considered when preferred treatments (eg, serotonin reuptake inhibitors) are partially effective.

Immediate release: Oral: Initial: 300 mg/day; may increase dose every ≥3 days based on response and tolerability up to 2.4 g/day, in 2 to 3 divided doses. Note: In patients sensitive to side effects, some experts suggest a lower starting dose of 100 mg/day and more gradual titration.

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

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 . For critically ill patients with neuropathic pain, gabapentin may be a useful component of multimodal pain control.

Immediate release: Oral: Initial: 100 to 300 mg 1 to 3 times daily; increase dose based on response and tolerability to a target dose range of 300 mg to 1.2 g 3 times daily .

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.

Postherpetic neuralgia:

Immediate release:Oral: 300 mg once on day one, 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.

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

Note: For patients with pruritus resistant to preferred therapies :

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 . Higher doses up to 3.6 g/day have been used in oncology populations.

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.

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.

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 .

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

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

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 . Some experts recommend initiating with 100 mg 3 times daily in patients with respiratory disease.

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 ; 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. 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.

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.

Capsule:

100 mg, 300 mg, 400 mg

Solution:

250 mg/5 mL (470 mL)

Tablet:

300 mg, 450 mg, 750 mg, 900 mg, 600 mg, 800 mg

It is available as Capsule, solution and tablet

• Dose Adjustment in Kidney impairment patient:

• Dose Adjustment in Hepatic Patient:

Initial or dose titration in patients with preexisting liver cirrhosis : Note: Use with caution in patients with hepatic encephalopathy, renal impairment, or concomitant use of other CNS depressants.

Child-Turcotte-Pugh class A: Oral: No dosage adjustment necessary.

Child-Turcotte-Pugh class B and C: Oral: Initial: ≤300 mg per day in 1 to 3 divided doses; may titrate as tolerated to the usual indication-specific maximum recommended dose

• Dose Adjustment in Pediatric Patients:

Seizures, partial onset; adjunctive therapy: Oral: Immediate release: Note: If gabapentin is discontinued or if another antiseizure medication 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 ; maximum daily dose: 3,600 mg/day.

The dietary restriction should be individualized as per patient requirements.

Gabapentin may be contraindicated in the following conditions:

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition.

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

• 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.

There is no sufficient scientific evidence traceable regarding use and safety of Gabapentin in concurrent use with alcohol.

Gabapentin is present in breast milk.

Data are available from 5 mother infant pairs, 14 to 97 days postpartum. In all cases, maternal use of gabapentin occurred during pregnancy and continued after delivery (dosage range 600 to 2100 mg/day). Breast milk samples were obtained prior to the morning dose and concentrations ranged from 7 to 51 µM (1.2 to 8.7 mcg/mL). After nursing, gabapentin was present in the serum of 3 infants and below the limit of quantification in a fourth infant (<4 µM; 0.7 mcg/mL); one infant was not breastfed. The authors of the study calculated the estimated daily infant dose of gabapentin via breast milk to be 0.2 to 1.3 mg/kg/day providing a relative infant dose (RID) of 1.3 to 3.8% compared to weight-adjusted maternal dose. Adverse events were not reported in the breastfed infants .

Data are also available from a patient 1.6 months postpartum taking gabapentin 600 mg 3 times daily for 6 weeks. Breast milk was sampled at intervals over ~23 hours after the maternal dose. Using the average breast milk concentration of 5.7 mcg/mL, the authors of the study calculated the estimated daily infant dose of gabapentin via breast milk to be 0.86 mg/kg/day, providing a RID of 2.34% compared to weight-adjusted maternal dose. The infant was breastfed 6 to 7 times daily and provided supplementary feedings at night; his plasma concentration of gabapentin was 0.4 mg/L.

There is no sufficient scientific evidence traceable regarding use and safety of Gabapentin in concurrent use with any particular food.

The adverse reactions related to Gabapentin can be categorized as

• Common Adverse effects: Anaphylaxis, angioedema, suicidal ideation and behaviour, acute pancreatitis, onset of new types of seizures, increase in seizure frequency; dizziness, somnolence, confusion, mental impairment; drug abuse and dependence, withdrawal symptoms

• Less Common Adverse effects: Gastrointestinal disorders: Nausea, vomiting, diarrhea, abdominal pain, dry mouth or throat, flatulence, dyspepsia, constipation, dental abnormalities, gingivitis.

• Rare Adverse effects: Pneumonia, respiratory tract infection, dyspnea, bronchitis, pharyngitis, cough, rhinitis. Skin and subcutaneous tissue disorders: Rash, pruritus, acne, purpura, abrasion.

The clinically relevant drug interactions of Gabapentin is briefly summarized here

Reduced bioavailability with antacids containing Al and Mg.

Potentially Fatal: Concomitant use with CNS depressants (e.g. opioids, benzodiazepines, antidepressants, antihistamines) may cause respiratory and CNS depression.

The common side of Gabapentin include the following

Anaphylaxis, angioedema, suicidal ideation and behavior, acute pancreatitis, the onset of new types of seizures, increase in seizure frequency; dizziness, somnolence, confusion, mental impairment; drug abuse and dependence, withdrawal symptoms.

Pregnancy

There are no adequate data on the developmental risks associated with the use of Gabapentin in pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin was developmentally toxic (increased fetal skeletal and visceral abnormalities, and increased embryofetal mortality) when administered to pregnant animals at doses similar to or lower than those used clinically .

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal data When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryofetal toxicity (increased incidences of skeletal variations) was observed at the two highest doses. The no-effect dose for embryofetal developmental toxicity in mice (500 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 3600 mg/kg on a body surface area (mg/m2 ) basis. In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day) during pregnancy, adverse effect on offspring development (increased incidences of hydroureter and/or hydronephrosis) were observed at all doses. The lowest dose tested is similar to the MRHD on a mg/m2 basis.

When pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryofetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). The lowest dose tested is less than the MRHD on a mg/m2 basis. In a published study, gabapentin (400 mg/kg/day) was administered by intraperitoneal injection to neonatal mice during the first postnatal week, a period of synaptogenesis in rodents (corresponding to the last trimester of pregnancy in humans). Gabapentin caused a marked decrease in neuronal synapse formation in brains of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown in vitro to interfere with activity of the α2δ subunit of voltage-activated calcium channels, a receptor involved in neuronal synaptogenesis. The clinical significance of these findings is unknown.

Lactation

Risk Summary

Gabapentin is secreted in human milk following oral administration. The effects on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Gabapentin and any potential adverse effects on the breastfed infant from Gabapentin or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness of Gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. Safety and effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established

• Geriatric Use

The total number of patients treated with Gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared to younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ³75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse reactions were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.

Clinical studies of Gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients.

Renal Impairment Dosage adjustment in adult patients with compromised renal function is necessary. Pediatric patients with renal insufficiency have not been studied.

Symptoms: Dizziness, drowsiness, lethargy, double vision, slurred speech, mild diarrhea, loss of consciousness; coma (particularly when used with other CNS depressants).

Management: Supportive treatment. Consider hemodialysis in patients with severe renal impairment.

• Pharmacodynamics:

Gabapentin is an anti-convulsant medication that inhibits the release of excitatory neurotransmitters, allowing for its use against pathologic neurotransmission such as that seen in neuropathic pain and seizure disorders. It has a wide therapeutic index, with doses in excess of 8000 mg/kg failing to cause a fatal reaction in rats.

Gabapentin is ineffective in absence seizures and should be used in caution in patients with mixed seizure disorders involving absence seizures. Gabapentin has been associated with drug reaction with eosinophilia and systemic symptoms (DRESS), otherwise known as multi-organ hypersensitivity.

• Pharmacokinetics:

1. https://www.uptodate.com/contents/Gabapentin -drug-information?search=Gabapentin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Gabapentin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Gabapentin ?type=full&mtype=generic#mechanism-of-action