DRUG INFORMATION

GABAPENTINE
Brand Names
Gralise, Neurontin
Generic Name
Gabapentin
CLASS: anticonvulsant
PHARMACOLOGY
Indication
In the United States, gabapentin is officially indicated for the treatment of
postherpetic neuralgia in adults and for the adjunctive treatment of partial-onset
seizures, with or without secondary generalization, in patients 3 years of age and
older. In Europe, gabapentin is indicated for adjunctive therapy in the treatment of
partial-onset seizures, with or without secondary generalization, in patients 6 years of
age and older and as monotherapy in patients 12 years of age and older. It is also used
in adults for the treatment of various types of peripheral neuropathic pain, such as
painful diabetic neuropathy.

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. This reaction can prove fatal and
early symptoms such as fever, lymphadenopathy, and rash should be promptly
investigated.

Mechanism of action
The precise mechanism through which gabapentin exerts its therapeutic effects is
unclear. The primary mode of action appears to be at the auxillary α2δ-1 subunit of
voltage-gated calcium channels (though a low affinity for the α2δ-2 subunit has also
been reported). The major function of these subunits is to facilitate the movement of
pore-forming α1 subunits of calcium channels from the endoplasmic reticulum to the
cell membrane of pre-synaptic neurons. There is evidence that chronic pain states can
cause an increase in the expression of α2δ subunits and that these changes correlate
with hyperalgesia. Gabapentin appears to inhibit the action of α2δ-1 subunits, thus
decreasing the density of pre-synaptic voltage-gated calcium channels and subsequent
release of excitatory neurotransmitters. It is likely that this inhibition is also
responsible for the anti-epileptic action of gabapentin.
 There is some evidence that gabapentin also acts on adenosine receptors and voltage-
gated potassium channels, though the clinical relevance of its action at these sites is
unclear.

Absorption
Absorption of gabapentin is thought to occur solely via facilitated transport by the
LAT1 transporter within the intestines.5As this process is saturable, the oral
bioavailability of gabapentin is inversely proportional to the administered dose - the
oral bioavailability of a 900mg/day regimen is approximately 60%, whereas a
4800mg/day regimen results in only 27% bioavailability. The Tmax of gabapentin has
been estimated to be 2-3 hours. Food has no appreciable effect on gabapentin
absorption.

Volume of distribution
The apparent volume of distribution of gabapentin after IV administration is 58±6 L.
The drug is found in the CSF in concentrations approximately 9-20% of the
corresponding plasma concentrations and is secreted into breast milk in
concentrations similar to that seen in plasma.

Protein binding
Less than 3% of an orally administered dose of gabapentin is bound to plasma
proteins.

Metabolism
Gabapentin is not appreciably metabolized in human - in humans, metabolites account
for less than 1% of an administered dose, with the remainder being excreted as
unchanged parent drug in the urine.

Route of elimination
Gabapentin is eliminated solely in the urine as unchanged drug. Cimetidine, an
inhibitor of renal tubular secretion, reduces clearance by approximately 12%,
suggesting that some degree of tubular secretion is involved in the renal elimination
of gabapentin.

Half-life
The elimination t1/2 of gabapentin in patients with normal renal function is 5-7 hours.
In patients with reduced renal function, the elimination t 1/2 may be prolonged - in
patients with a creatinine clearance of <30 mL/min, the reported half-life of
gabapentin was approximately 52 hours.

Clearance
Both the plasma clearance and renal clearance of gabapentin are directly proportional
to the patient's creatinine clearance due to its primarily renal elimination.

Adverse Effects

 blue-colored skin, lips, fingers, and toes;

 confusion, extreme drowsiness or weakness;
  problems with balance or muscle movement;
 unusual or involuntary eye movements; or
 increased seizures.
Gabapentin can cause life-threatening breathing problems. A person caring for you should
seek emergency medical attention if you have slow breathing with long pauses, blue colored
lips, or if you are hard to wake up. Breathing problems may be more likely in older adults or
in people with COPD.

Some side effects are more likely in children taking gabapentin. Contact your doctor if the
child taking this medicine has any of the following side effects:

 changes in behavior;
 memory problems;
 trouble concentrating; or
 acting restless, hostile, or aggressive.
Common side effects of gabapentin may include:

 fever, chills, sore throat, body aches, unusual tiredness;

 jerky movements;
 headache;
 double vision;
 swelling of your legs and feet;
 tremors;
 trouble speaking;
 dizziness, drowsiness, tiredness;
 problems with balance or eye movements; or
 nausea, vomiting.

Toxicity
The oral TDLo of gabapentin in humans is 2.86 mg/kg and the LD 50 in rats has been
found to be >8000 mg/kg.21 Symptoms of overdose are consistent with the drug's
adverse effect profile and involve CNS depression (e.g. dizziness, drowsiness, slurred
speech, lethargy, loss of consciousness) and gastrointestinal symptoms such as
diarrhea.18,17 Management of overdose should involve symptomatic and supportive
treatment. Gabapentin can be removed by hemodialysis - this may be of benefit in
some patients, such as those with impaired renal function.20

Multi-drug overdoses involving gabapentin, particularly in combination with other

CNS depressants such as opioids, can result in coma and death - this possibility
should be considered when managing overdosage.17
Pathways
Not Available
Pharmacogenomic Effects/ADRs

Not Available
 INTERACTIONS
Drug Interactions

DRUG INTERACTION
1,2- The risk or severity of CNS depression can be increased when Gabapentin is combined
Benzodiazepine with 1,2-Benzodiazepine.
Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is
combined with Gabapentin.
Acetophenazine The risk or severity of CNS depression can be increased when Gabapentin is combined
with Acetophenazine.
Agomelatine The risk or severity of CNS depression can be increased when Gabapentin is combined
with Agomelatine.
Alfentanil The risk or severity of CNS depression can be increased when Alfentanil is combined
with Gabapentin.
Alimemazine The risk or severity of CNS depression can be increased when Gabapentin is combined
with Alimemazine.
Almasilate The bioavailability of Gabapentin can be decreased when combined with Almasilate.
Almotriptan The risk or severity of CNS depression can be increased when Almotriptan is combined
with Gabapentin.
Alosetron The risk or severity of CNS depression can be increased when Alosetron is combined
with Gabapentin.
Alprazolam The risk or severity of CNS depression can be increased when Alprazolam is combined
with Gabapentin.

Dosing information
Usual Adult Dose for Epilepsy:

Initial dose: 300 mg orally on day one, 300 mg orally 2 times day on day two, then 300 mg
orally 3 times a day on day three
Maintenance dose: 300 to 600 mg orally 3 times a day
Maximum dose: 3600 mg orally daily (in 3 divided doses)
-Maximum time between doses in the 3 times a day schedule should not exceed 12 hours

-The safety and effectiveness of gabapentin available under the trade name Gralise or
Horizant in patients with epilepsy has not been studied.

Use: Adjunctive therapy in the treatment of partial onset seizures, with and without secondary
generalization

Usual Adult Dose for Postherpetic Neuralgia:

-Initial dose: 300 mg orally on day one, 300 mg orally 2 times day on day two, then 300 mg
orally 3 times a day on day three
-Titrate up as needed for pain relief
-Maximum dose: 1800 mg per day (600 mg orally 3 times a day)
Gabapentin available under the trade name Gralise:
-Maintenance dose: Gralise should be titrated to 1800 mg orally once daily with the evening
meal.
-Recommended titration schedule:
Day 1: 300 mg orally with the evening meal
Day 2: 600 mg orally with the evening meal
Days 3 through 6: 900 mg orally with the evening meal
Days 7 through 10: 1200 mg orally with the evening meal
Days 11 through 14: 1500 mg orally with the evening meal
Day 15: 1800 mg orally with the evening meal
COMMENT:
-Gralise is not interchangeable with other gabapentin products because of differing
pharmacokinetic profiles that affect the frequency of administration.

Gabapentin enacarbil extended release tablets are available under the trade name Horizant:
-The recommended dosage is 600 mg orally 2 times a day. Therapy should be initiated at a
dose of 600 mg orally in the morning for 3 days of therapy, then increased to 600 mg 2 times
a day (1200 mg/day) on day four.
COMMENT:
Gabapentin enacarbil extended release tablets available under the trade name Horizant and
gabapentin are not interchangeable.

Use: Postherpetic neuralgia