An increase in formation of adenocarcinomas was observed in rats during preclinical trials; however, the clinical significance of these results remains undetermined. Gabapentin is also known to induce pancreatic acinar cell carcinomas in rats through an unknown mechanism, perhaps by stimulation of DNA synthesis; these tumors did not affect the lifespan of the rats and did not metastasize.
In 2009 the U.S. Food and Drug Administration issued a warning of an increased risk of depression and suicidal thoughts and behaviors in patients taking gabapentin, along with other anticonvulsant drugs modifying the packaging insert to reflect this. A 2010 meta analysis confirmed the increased risk of suicide associated with gabapentin use.
Persons who accidentally or intentionally ingested overdoses may have drowsiness, sedation, blurred vision, slurred speech, somnolence and possibly death, if a very high amount was taken, particularly if combined with alcohol. Serum gabapentin concentrations may be measured to confirm diagnosis.
Some of its activity may involve interaction with voltage-gated calcium channels. Gabapentin binds to the α2δ subunit (1 and 2) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking of voltage-dependent calcium channels in the central nervous system. Another possible mechanism of action is that gabapentin halts the formation of new synapses.
Mechanism of action
The mechanism of the anticonvulsant action of gabapentin has not been fully described. Though similar in structure to the endogenous neurotransmitter GABA, gabapentin has not been shown to bind to GABA receptors at concentrations at or below 1000 µM. Gabapentin modulates the action of glutamate decarboxylase (GAD) and branched chain aminotransferase (BCAT), two enzymes involved in GABA biosynthesis. In human and rat studies, gabapentin was found to increase GABA biosynthesis, and to increase non-synaptic GABA neurotransmission in vitro.
Gabapentin (0.01-100 µM) has not been shown to interact with the sodium or L-type calcium ion channels targeted by the conventional anticonvulsant drugs phenytoin, carbamazepine and sodium valproate. Other neurophysiological findings indicate that gabapentin does not interact with glutamate, glycine, or NMDA receptors, further distinguishing its anticonvulsant mechanism from that of common antiepileptic medications.
Society and culture
Gabapentin is best known under the brand name Neurontin manufactured by Pfizer subsidiary Parke-Davis. A Pfizer subsidiary named Greenstone markets generic gabapentin.
In December 2004 the FDA granted final approval to a generic equivalent to Neurontin made by the Israeli firm Teva.
Neurontin began as one of Pfizer's best selling drugs; however, Pfizer has been criticized and under litigation for its marketing of the drug. They face allegations that Parke-Davis marketed the drug for at least a dozen supposed uses that the FDA had not approved. Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.
Although some small, non-controlled studies in the 1990s—mostly sponsored by gabapentin's manufacturer—suggested that treatment for bipolar disorder with gabapentin may be promising, the preponderance of evidence suggests that it is not effective. Subsequent to the corporate acquisition of the original patent holder, the pharmaceutical company Pfizer admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Pfizer case.
Reuters reported on March 25, 2010, that "Pfizer Inc violated federal racketeering law by improperly promoting the epilepsy drug Neurontin ... Under federal RICO law the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses."
Bloomberg News (3/26/10, Van Voris, Lawrence) added that "during the trial, Pfizer argued that Kaiser doctors continued to prescribe the drug even after the health insurer sued Pfizer in 2005. The insurer's website also still lists Neurontin as a drug for neuropathic pain, Pfizer lawyers said in closing argument."
The Wall Street Journal (3/26/10, Kamp) noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." He would later add that "the verdict and the judge's rulings are not consistent with the facts and the law."
By some estimates, off-label prescriptions account for roughly 90 percent of Neurontin sales.
While off-label prescriptions are common for a number of drugs and are legal, marketing of off-label uses of a drug is illegal. In 2004, Warner-Lambert (which subsequently was acquired by Pfizer) agreed to plead guilty for activities of its Parke-Davis subsidiary, and to pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes. The 2004 settlement was one of the largest in U.S. history, and the first off-label promotion case brought successfully under the False Claims Act.
The University of California, San Francisco (UCSF) has archived and studied the documents made public by this case, which opens a window into the illegal promotion and marketing of pharmaceuticals. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Warner-Lambert) in 2000. Several lawsuits are underway after people who had been prescribed gabapentin for off-label treatment of bipolar disorder later attempted or committed suicide.
Various suppliers of gabapentin market it under a number of brand names, including Neurostil, Neurontin, Fanatrex, Gabarone, Gralise, Nupentin, Gabrion, Penral, Gabapin.
A capsule of gabapentin
Gabapentin comes as:
100 mg, 300 mg, and 400 mg capsules
300 mg, 600 mg, and 800 mg tablets
a 250 mg/5 mL oral (by mouth) solution.
Inactive ingredients in the capsules include lactose, cornstarch, and talc.
The 100-mg capsule shell also contains: gelatin and titanium dioxide.
The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.
The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.
Inactive ingredients in the tablets include poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
Inactive ingredients in the oral solution include glycerin, xylitol, purified water, and artificial flavor.
Parke-Davis developed a drug called pregabalin as a successor to gabapentin. Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin. Another new drug atagabalin has been trialed by Pfizer as a treatment for insomnia.
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