Included as part of the PRECAUTIONS section.
Drug Reaction With Eosinophilia And Systemic Symptoms
Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS), also known as multiorgan hypersensitivity, has occurred with
NEURONTIN. Some of these reactions have been fatal or lifethreatening. DRESS
typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy,
in association with other organ system involvement, such as hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis sometimes
resembling an acute viral infection. Eosinophilia is often present. This
disorder is variable in its expression, and other organ systems not noted here
may be involved.
It is important to note that early manifestations of
hypersensitivity, such as fever or lymphadenopathy, may be present even though
rash is not evident. If such signs or symptoms are present, the patient should be
evaluated immediately. NEURONTIN should be discontinued if an alternative
etiology for the signs or symptoms cannot be established.
Anaphylaxis And Angioedema
NEURONTIN can cause anaphylaxis and angioedema after the
first dose or at any time during treatment. Signs and symptoms in reported
cases have included difficulty breathing, swelling of the lips, throat, and
tongue, and hypotension requiring emergency treatment. Patients should be
instructed to discontinue NEURONTIN and seek immediate medical care should they
experience signs or symptoms of anaphylaxis or angioedema.
Effects On Driving and Operating Heavy Machinery
Patients taking NEURONTIN should not drive until they
have gained sufficient experience to assess whether NEURONTIN impairs their
ability to drive. Driving performance studies conducted with a prodrug of
gabapentin (gabapentin enacarbil tablet, extended release) indicate that
gabapentin may cause significant driving impairment. Prescribers and patients
should be aware that patients' ability to assess their own driving competence,
as well as their ability to assess the degree of somnolence caused by NEURONTIN,
can be imperfect. The duration of driving impairment after starting therapy
with NEURONTIN is unknown. Whether the impairment is related to somnolence [see
Somnolence/Sedation And Dizziness] or other effects of NEURONTIN is
Moreover, because NEURONTIN causes somnolence and
dizziness [see Somnolence/Sedation And Dizziness], patients should be
advised not to operate complex machinery until they have gained sufficient experience
on NEURONTIN to assess whether NEURONTIN impairs their ability to perform such tasks.
Somnolence/Sedation And Dizziness
During the controlled epilepsy trials in patients older
than 12 years of age receiving doses of NEURONTIN up to 1800 mg daily,
somnolence, dizziness, and ataxia were reported at a greater rate in patients
receiving NEURONTIN compared to placebo: i.e., 19% in drug versus 9% in placebo
for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug
versus 6% in placebo for ataxia. In these trials somnolence, ataxia and fatigue
were common adverse reactions leading to discontinuation of NEURONTIN in
patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for
these events, respectively.
During the controlled trials in patients with
post-herpetic neuralgia, somnolence and dizziness were reported at a greater
rate compared to placebo in patients receiving NEURONTIN, in dosages up to 3600
mg per day: i.e., 21% in NEURONTIN-treated patients versus 5% in
placebo-treated patients for somnolence and 28% in NEURONTIN-treated patients
versus 8% in placebo-treated patients for dizziness. Dizziness and somnolence
were among the most common adverse reactions leading to discontinuation of
Patients should be carefully observed for signs of
central nervous system (CNS) depression, such as somnolence and sedation, when
NEURONTIN is used with other drugs with sedative properties because of
potential synergy. In addition, patients who require concomitant treatment with
morphine may experience increases in gabapentin concentrations and may require
dose adjustment [see DRUG INTERACTIONS].
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued
because of the possibility of increasing seizure frequency.
In the placebo-controlled epilepsy studies in patients
>12 years of age, the incidence of status epilepticus in patients receiving
NEURONTIN was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of
378). Among the 2074 patients >12 years of age treated with NEURONTIN across
all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status
epilepticus. Of these, 14 patients had no prior history of status epilepticus
either before treatment or while on other medications. Because adequate
historical data are not available, it is impossible to say whether or not
treatment with NEURONTIN is associated with a higher or lower rate of status
epilepticus than would be expected to occur in a similar population not treated
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including NEURONTIN, increase
the risk of suicidal thoughts or behavior in patients taking these drugs for
any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or
behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials
(mono- and adjunctive therapy) of 11 different AEDs showed that patients
randomized to one of the AEDs had approximately twice the risk (adjusted Relative
Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to
patients randomized to placebo. In these trials, which had a median treatment
duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among
16,029 placebo-treated patients, representing an increase of approximately one
case of suicidal thinking or behavior for every 530 patients treated. There
were four suicides in drug-treated patients in the trials and none in
placebo-treated patients, but the number is too small to allow any conclusion
about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with
AEDs was observed as early as one week after starting drug treatment with AEDs
and persisted for the duration of treatment assessed. Because most trials
included in the analysis did not extend beyond 24 weeks, the risk of suicidal
thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally
consistent among drugs in the data analyzed. The finding of increased risk with
AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not
vary substantially by age (5–100 years) in the clinical trials analyzed. Table
2 shows absolute and relative risk by indication for all evaluated AEDs.
TABLE 2 : Risk by Indication for Antiepileptic Drugs
in the Pooled Analysis
||Placebo Patients with Events Per 1000 Patients
||Drug Patients with Events Per 10 00 Patients
||Relative Risk: Incidence of Events in Drug Patients /Incidence in Placebo Patients
||Risk Difference: Additional Drug Patients with Events Per 1000 Patients
The relative risk for suicidal thoughts or behavior was
higher in clinical trials for epilepsy than in clinical trials for psychiatric
or other conditions, but the absolute risk differences were similar for the epilepsy
and psychiatric indications.
Anyone considering prescribing NEURONTIN or any other AED
must balance the risk of suicidal thoughts or behavior with the risk of untreated
illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal
thoughts and behavior. Should suicidal thoughts and behavior emerge during
treatment, the prescriber needs to consider whether the emergence of these
symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be
informed that AEDs increase the risk of suicidal thoughts and behavior and
should be advised of the need to be alert for the emergence or worsening of the
signs and symptoms of depression, any unusual changes in mood or behavior, or
the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Neuropsychiatric Adverse Reactions (Pediatric Patients
3–12 Years Of Age)
Gabapentin use in pediatric patients with epilepsy 3–12
years of age is associated with the occurrence of central nervous system
related adverse reactions. The most significant of these can be classified into
the following categories: 1) emotional lability (primarily behavioral
problems), 2) hostility, including aggressive behaviors, 3) thought disorder,
including concentration problems and change in school performance, and 4)
hyperkinesia (primarily restlessness and hyperactivity). Among the
gabapentintreated patients, most of the reactions were mild to moderate in
In controlled clinical epilepsy trials in pediatric
patients 3–12 years of age, the incidence of these adverse reactions was:
emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients);
hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7%
vs. 0%. One of these reactions, a report of hostility, was considered serious.
Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting
emotional lability and hyperkinesia and 0.9% of gabapentintreated patients
reporting hostility and thought disorder. One placebo-treated patient (0.4%)
withdrew due to emotional lability.
In an oral carcinogenicity study, gabapentin increased
the incidence of pancreatic acinar cell tumors in rats [see Nonclinical
Toxicology]. The clinical significance of this finding is unknown. Clinical
experience during gabapentin's premarketing development provides no direct
means to assess its potential for inducing tumors in humans.
In clinical studies in adjunctive therapy in epilepsy
comprising 2085 patient-years of exposure in patients >12 years of age, new
tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin's
lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in
11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following
discontinuation of NEURONTIN. Without knowledge of the background incidence and
recurrence in a similar population not treated with NEURONTIN, it is impossible
to know whether the incidence seen in this cohort is or is not affected by
Sudden And Unexplained Death In Patients With Epilepsy
During the course of premarketing development of
NEURONTIN, 8 sudden and unexplained deaths were recorded among a cohort of 2203
epilepsy patients treated (2103 patient-years of exposure) with NEURONTIN.
Some of these could represent seizure-related deaths in
which the seizure was not observed, e.g., at night. This represents an
incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected
in a healthy population matched for age and sex, it is within the range of
estimates for the incidence of sudden unexplained deaths in patients with
epilepsy not receiving NEURONTIN (ranging from 0.0005 for the general
population of epileptics to 0.003 for a clinical trial population similar to that
in the NEURONTIN program, to 0.005 for patients with refractory epilepsy).
Consequently, whether these figures are reassuring or raise further concern
depends on comparability of the populations reported upon to the NEURONTIN
cohort and the accuracy of the estimates provided.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Inform patients that NEURONTIN is taken orally with or
without food. Inform patients that, should they divide the scored 600 mg or 800
mg tablet in order to administer a half-tablet, they should take the unused
half-tablet as the next dose. Advise patients to discard half-tablets not used
within 28 days of dividing the scored tablet.
Drug Reaction With Eosinophilia And Systemic Symptoms
Prior to initiation of treatment with NEURONTIN, instruct
patients that a rash or other signs or symptoms of hypersensitivity (such as
fever or lymphadenopathy) may herald a serious medical event and that the
patient should report any such occurrence to a physician immediately [see WARNINGS
Anaphylaxis And Angioedema
Advise patients to discontinue NEURONTIN and seek medical
care if they develop signs or symptoms of anaphylaxis or angioedema [see WARNINGS
Dizziness And Somnolence And Effects On Driving and
Operating Heavy Machinery
Advise patients that NEURONTIN may cause dizziness,
somnolence, and other symptoms and signs of CNS depression. Other drugs with
sedative properties may increase these symptoms. Accordingly, although
patients' ability to determine their level of impairment can be unreliable,
advise them neither to drive a car nor to operate other complex machinery until
they have gained sufficient experience on NEURONTIN to gauge whether or not it
affects their mental and/or motor performance adversely. Inform patients that
it is not known how long this effect lasts [see WARNINGS AND PRECAUTIONS].
Suicidal Thinking And Behavior
Counsel the patient, their caregivers, and families that
AEDs, including NEURONTIN, may increase the risk of suicidal thoughts and
behavior. Advise patients of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct
patients to report behaviors of concern immediately to healthcare providers [see
WARNINGS AND PRECAUTIONS].
Use In Pregnancy
Instruct patients to notify their physician if they
become pregnant or intend to become pregnant during therapy, and to notify
their physician if they are breast feeding or intend to breast feed during
therapy [see Use In Specific Populations].
Encourage patients to enroll in the NAAED Pregnancy
Registry if they become pregnant. This registry is collecting information about
the safety of antiepileptic drugs during pregnancy. To enroll, patients can
call the toll free number 1-888-233-2334 [see Use In Specific Populations].
This product's label may have been updated. For full
prescribing information, please visit www.pfizer.com.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Gabapentin was administered orally to mice and rats in
2-year carcinogenicity studies. No evidence of drug-related carcinogenicity was
observed in mice treated at doses up to 2000 mg/kg/day. At 2000 mg/kg, the
plasma gabapentin exposure (AUC) in mice is approximately 2 times that in
humans at the MRHD of 3600 mg/day. In rats, increases in the incidence of
pancreatic acinar cell adenoma and carcinoma were found in male rats receiving
the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. At
1000 mg/kg, the plasma gabapentin exposure (AUC) in rats is approximately 5
times that in humans at the MRHD.
Studies designed to investigate the mechanism of
gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin
stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may
be acting as a tumor promoter by enhancing mitogenic activity. It is not known
whether gabapentin has the ability to increase cell proliferation in other cell
types or in other species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic
potential in three in vitro and four in vivo assays. It was negative in the
Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung
cells; it did not produce significant increases in chromosomal aberrations in
the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal
aberration assay and in the in vivo micronucleus test in Chinese hamster bone
marrow; it was negative in the in vivo mouse micronucleus assay; and it did not
induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin.
No adverse effects on fertility or reproduction were
observed in rats at doses up to 2000 mg/kg. At 2000 mg/kg, the plasma
gabapentin exposure (AUC) in rats is approximately 8 times that in humans at
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. In nonclinical studies in mice, rats, and rabbits, gabapentin
was developmentally toxic when administered to pregnant animals at doses
similar to or lower than those used clinically. NEURONTIN should be used during
pregnancy only if the potential benefit justifies the potential risk to the
When pregnant mice received oral doses of gabapentin
(500, 1000, or 3000 mg/kg/day) during the period of organogenesis, embryo-fetal
toxicity (increased incidences of skeletal variations) was observed at the two
highest doses. The no-effect dose for embryo-fetal developmental toxicity in
mice was 500 mg/kg/day or approximately ½ of 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 effect dose for
developmental toxicity in rats is approximately equal to the MRHD on a mg/m²
When pregnant rabbits were treated with gabapentin during
the period of organogenesis, an increase in embryo-fetal mortality was observed
at all doses tested (60, 300, or 1500 mg/kg). The lowest effect dose for
embryo-fetal developmental toxicity in rabbits is less than the MRHD on a mg/m²
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
voltageactivated calcium channels, a receptor involved in neuronal
synaptogenesis. The clinical significance of these findings is unknown.
To provide information regarding the effects of in utero exposure
to NEURONTIN, physicians are advised to recommend that pregnant patients taking
NEURONTIN enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry. This can be done by calling the toll free number 1- 888-233-2334, and
must be done by patients themselves. Information on the registry can also be
found at the website http://www.aedpregnancyregistry.org/.
Gabapentin is secreted into human milk following oral
administration. A nursed infant could be exposed to a maximum dose of approximately
1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown,
NEURONTIN should be used in women who are nursing only if the benefits clearly outweigh
Safety and effectiveness of NEURONTIN in the management of
postherpetic neuralgia in pediatric patients have not been established.
Effectiveness as adjunctive therapy in the treatment of
partial seizures in pediatric patients below the age of 3 years has not been
established [see Clinical Studies].
The total number of patients treated with NEURONTIN 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 with younger patients who received the same dosage. Since
gabapentin is almost exclusively eliminated by renal excretion, the larger
treatment effect observed in patients ≥ 75 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
Clinical studies of NEURONTIN 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 [see DOSAGE
AND ADMINISTRATION, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY].
Dosage adjustment in adult patients with compromised
renal function is necessary [see DOSAGE AND ADMINISTRATION and CLINICAL
PHARMACOLOGY]. Pediatric patients with renal insufficiency have not been
Dosage adjustment in patients undergoing hemodialysis is
necessary [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].