Date of approval.
Date of revision.
Gabapentin Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Gabapentin Capsules
English name: Gabapentin Capsules
Hanyu Pinyin: Jiabapending Jiaonang
Ingredients】The main ingredient of this product is gabapentin.
Chemical name: 1-(Aminomethyl)cyclohexylacetic acid
Chemical structure formula
Molecular formula: C9H17NO2
Molecular weight: 171.24
Product properties]: This product is a capsule, the contents of white or off-white powder and granules.
【Indications】.
1. Post-herpetic neuralgia: For the treatment of post-herpetic neuralgia in adults.
2. Epilepsy: For the adjunctive treatment of partial seizures with or without secondary generalized seizures in adults and children over 12 years of age. It can also be used for the adjunctive treatment of partial seizures in children aged 3 to 12 years.
Specification
(1) 0.1g (2) 0.3g (3) 0.4g
Dosage and Administration
1. Adult post-herpetic infection neuralgia: 0.3g of gabapentin on the first day at once, 0.6g on the second day in two doses; 0.9g on the third day in three doses. Subsequently, the dose can be gradually increased to 1.8g per day in three doses according to the need for pain relief. In foreign clinical studies, its efficacy was comparable in the dose range of 1.8g to 3.6g per day, and doses exceeding 1.8g per day did not show additional benefit.
2. Epilepsy: Gabapentin can be combined with other antiepileptic drugs for combination therapy.
Gabapentin is administered orally in divided doses (3 times daily). In patients over 12 years of age, gabapentin may be administered at 0.3 g once daily on the first day, 0.3 g twice daily on the second day, and 0.3 g three times daily on the third day, after which the dose is maintained. According to foreign research literature, the dose of gabapentin can be increased to 1.8g per day, and some patients can tolerate doses up to 2.4g per day. The safety of doses beyond 2.4 g per day is uncertain.
Pediatric patients 3 to 12 years of age: The starting dose should be 10 to 15 mg/kg/d three times daily, reaching an effective dose in approximately 3 days. The effective dose of gabapentin in patients over 5 years of age is 25 to 35 mg/kg/d three times daily. in pediatric patients 3 to 4 years of age, the effective dose is 40 mg/kg/d three times daily. If necessary, the dose may be increased to 50 mg/kg/d. Long-term clinical studies have shown that dose increases to 50 mg/kg/d are well tolerated.
The maximum interval between doses should not exceed 12 hours. To reduce the occurrence of adverse reactions such as dizziness and drowsiness, the first day of dosing can be taken at bedtime. There is no need to monitor gabapentin blood levels during gabapentin administration. Furthermore, because there are no significant pharmacokinetic interactions between gabapentin and other conventional antiepileptic drugs, combination therapy with this drug does not alter the plasma concentrations of these conventional antiepileptic drugs.
Discontinuation of gabapentin or addition of a new treatment regimen should be done gradually over the course of treatment, for a minimum of one week.
Creatinine clearance is difficult to measure in outpatients. Creatinine clearance (CCr) in patients with stable renal function can be reasonably estimated according to Cockcroft and Gault’s equation.
CCr for women = (0.85)(140-age)(weight)/[(72)(SCr)]
Male CCr = (140-age)(weight)/[(72)(SCr)
Where age in years, weight in kg, and SCr is serum creatinine in mg/dL.
The following dose adjustments are recommended for patients over 12 years of age with renal impairment or who are on hemodialysis.
Table 1. Dose adjustments for gabapentin administration based on patient renal function
Renal function status
Creatinine clearance
(mL/min) Total daily dose
(g/day)Dosing regimen
(g)>601.2 0.4T.I.D 30 to 600.6 0.3B.I.D 15 to 300.3 0.3Q.D <150.15 0.3Q.O.Da Hemodialysis
— 0.2 to 0.3ba . Administered every other day.
b. The initial dose for patients not previously treated with gabapentin is 0.3 to 0.4 g, followed by 0.2 to 0.3 g of gabapentin every 4 hours of dialysis.
No studies have been conducted with gabapentin in patients under 12 years of age with renal impairment.
Dosing in elderly patients.
Because elderly patients are likely to have decreased renal function, caution should be exercised in dose selection, and the dose administered to these patients should be adjusted according to creatinine clearance.
Adverse reactions]
See [Precautions] for the following serious adverse reactions
Drug reaction with eosinophilia and systemic symptoms (DRESS)/multi-organ hypersensitivity
Rapid-onset hypersensitivity and angioedema
Drowsiness/sedation and dizziness
Withdrawal rebound, seizure continuity
Suicidal behavior and ideation
Neuropsychiatric adverse reactions (pediatric patients 3 to 12 years of age)
Sudden unexplained death in patients with epilepsy
Clinical trial experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared with the incidence of adverse reactions observed in clinical trials of another drug and may not reflect the incidence of adverse reactions in actual use.
Postherpetic neuralgia
In adults, the most common adverse events associated with gabapentin use and occurring at higher rates than in the placebo group were dizziness, somnolence, and peripheral edema.
In 2 controlled trials of postherpetic neuralgia, 16% of the 336 patients treated with gabapentin discontinued treatment because of adverse effects compared with 9% of the 227 patients treated with placebo. The most common adverse reactions leading to withdrawal among patients in the gabapentin-treated group were dizziness, drowsiness, and nausea.
Table 2 lists the placebo-controlled trials conducted in patients with postherpetic neuralgia in which the incidence of adverse reactions was ≥1% in the gabapentin group and numerically higher than in the placebo group.
Table 2. Adverse reactions in placebo-controlled trials in postherpetic neuralgia (≥1% in the gabapentin-treated group and higher than in the placebo group) Body system/
Preferred term gabapentin
N=336
% placebo
N=227
% systemic
weakness
Infection
Accidental injury
6
5
3
5
4
1 Digestive system
Diarrhea
Dry mouth
Constipation
Nausea
Vomiting
Metabolic and nutritional abnormalities
Peripheral edema
Weight gain
Hyperglycemia
6
5
4
4
3
8
2
1
3
1
2
3
2
2
0
0 Nervous system
Dizziness
Drowsiness
Ataxia
abnormal thinking
Abnormal gait
Uncoordinated
28
21
3
3
2
2
8
5
0
0
0
0 Respiratory
pharyngitis
Special sensations
Amblyopiaa
conjunctivitis
diplopia
Otitis media
1
3
1
1
1
0
1
0
0
0a Reported as blurred vision
Other reactions with an incidence of more than 1% but with the same or higher incidence in the placebo group included: pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and influenza syndrome.
There were no clinically important differences in the type and incidence of adverse reactions between men and women. There are insufficient data to support reports on the ethnic distribution of adverse reactions because only a small number of patient races were filled in as non-white.
Partial-onset epilepsy (adjunctive therapy)
In patients older than 12 years, the most common adverse reactions to the combination of gabapentin and other antiepileptic drugs were drowsiness, dizziness, ataxia, fatigue, and nystagmus, whereas the same frequency was not seen in placebo-treated patients. In pediatric patients 3 to 12 years of age, the most common adverse reactions to the combination of gabapentin and other antiepileptic drugs were viral infection, fever, nausea and/or vomiting, drowsiness, and hostility (see [Precautions]). The same frequency did not occur in placebo-treated patients.
In premarketing clinical trials, approximately 7% of the 2074 patients >12 years of age and 449 pediatric patients 3 to 12 years of age who received gabapentin discontinued treatment because of adverse reactions. Among patients >12 years of age, the most common adverse reactions associated with treatment withdrawal were drowsiness (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). Among pediatric patients, the most common adverse reactions associated with withdrawal from treatment were emotional instability (1.6%), hostility (1.3%), and hypermobility (1.1%).
Table 3 lists adverse reactions that occurred in ≥1% and were numerically higher in the gabapentin group than in the placebo group in placebo-controlled clinical trials in which patients with epilepsy aged 12 years or older participated. In these studies, either gabapentin or placebo was added to the patients’ existing antiepileptic drug therapy.
Table 3: Incidence of adverse reactions in placebo-controlled trials (add-on treatment) in patients aged 12 years and older (≥1% in the gabapentin-treated group and higher than in the placebo group) Body system/
Preferred term gabapentina
N=543
% placeboa
N=378
% systemic
Fatigue
Weight gain
Back pain
Peripheral edema
11
3
2
2
5
2
1
1 Cardiovascular system
Vasodilation
1
0 Digestive system
Indigestion
Dry mouth or throat
Constipation
Malocclusion
2
2
2
2
1
1
1
0 Neurological
Drowsiness
Dizziness
Ataxia
Nystagmus
tremor
Dysarthria
memory loss
Depression
abnormal thinking
Coordination abnormalities
19
17
13
8
7
2
2
2
2
1
9
7
6
4
3
1
0
1
1
0 Respiratory
Pharyngitis
Cough
3
2
2
1 Skin and accessory tissues
Abrasions
1
0 Genitourinary system
Impotence
2
1 Special sensation
Diplopia
Amblyopiab
6
4
2
1a Plus for antiepileptic drug therapyb Amblyopia is commonly described as blurred vision.
Among adverse reactions with an incidence of at least 10% in patients treated with gabapentin, drowsiness and ataxia showed a positive dose-effect correlation.
The overall incidence and type of adverse reactions observed were similar in men and women treated with gabapentin. The incidence of adverse reactions increased slightly with age for either gabapentin or placebo treatment. Because only 3% of patients (28/921) in the placebo-controlled trial were not Caucasian (black or other races), there were insufficient data to support reports on the ethnic distribution of adverse reactions.
Table 4 lists the adverse reactions that occurred in ≥2% of the gabapentin-treated group and were numerically higher than the placebo group in placebo-controlled trials in patients aged 3 to 12 years with epilepsy.
Table 4: Incidence of adverse reactions in placebo-controlled trials (add-on treatment) in pediatric patients aged 3 to 12 years (≥2% in the gabapentin-treated group and higher than in the placebo group) Body system/
Preferred term gabapentina
N=119
% placeboa
N=128
% systemic
Viral infection
Fever
Weight gain
Fatigue
11
10
3
33
3
1
2 Digestive system
Nausea and/or vomiting
8
7 Nervous system
Drowsiness
Hostility
Emotional instability
Dizziness
Excessive exercise
8
8
4
3
3
5
2
2
2
1 Respiratory system
Bronchitis
Respiratory tract infection
3
3
1
1a Addition to antiepileptic drug therapy
Other reactions that occurred in more than 2% of pediatric patients aged 3 to 12 years, but occurred at the same or higher rate in the placebo group, included pharyngitis, upper respiratory tract infection, headache, rhinitis, convulsions, diarrhea, anorexia, cough, and otitis media.
Postmarketing Experience
The following adverse reactions have been reported in postmarketing use, and because they were reported by an uncertain population, it is not possible to reliably estimate the incidence and establish a relationship to drug exposure
Hepatobiliary system: jaundice
Laboratory tests: elevated creatine kinase, abnormal liver function tests
Metabolic and nutritional: hyponatremia
Musculoskeletal tissues: rhabdomyolysis
Neurological system: dyskinesia
Psychiatric system: agitation
Reproductive system: breast enlargement, altered libido, ejaculatory disorders, lack of orgasm
Skin and subcutaneous tissue: angioedema (see [precautions]), erythema multiforme, Stevens-Johnson syndrome
Adverse reactions have been reported following abrupt discontinuation of gabapentin, the most common reactions being anxiety, insomnia, nausea, pain, and sweating.
[Contraindications
Gabapentin is contraindicated in people with known hypersensitivity to any of the components of the drug.
Gabapentin is contraindicated in patients with acute pancreatitis.
Gabapentin is not effective in patients with primary generalized seizures, such as anhedonia.
Precautions]
Drug reaction with eosinophilia and systemic symptoms (DRESS)/multi-organ hypersensitivity
Drug reactions with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, have been reported in patients treated with antiepileptic drugs, including gabapentin. The typical but nonspecific presentation of DRESS is fever, rash, and/or lymphadenopathy with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis (sometimes resembling an acute viral infection). Eosinophilia is often present. Due to the variable presentation of the disease, other organ systems not listed here may also be involved.
It is important to note that hypersensitivity may present with early manifestations, such as fever or lymphadenopathy, although the rash is not yet obvious. If such signs or symptoms are present, the patient should be evaluated immediately. If it cannot be determined that these signs or symptoms are due to other etiologies, gabapentin should be discontinued.
Rapid-onset allergy and edema
Gabapentin can cause allergic reactions and angioedema at the first treatment or at any time during treatment. Signs and symptoms reported include dyspnea, swelling of the lips, throat, and tongue, and hypotension requiring urgent treatment. Advise patients to discontinue gabapentin and seek immediate medical attention at the first sign or symptom of an allergic reaction or angioedema.
Effects on driving and operating heavy machinery
Patients taking gabapentin should not operate vehicles until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive. Driving performance studies conducted with gabapentin premedication have shown that gabapentin may cause severe driving impairment. Physicians and patients should be aware that patients do not have the ability to assess their own driving ability and the ability to assess the degree of drowsiness caused by gabapentin. The duration of driving impairment following treatment with gabapentin is not known. Whether this impairment is related to drowsiness or to other effects of gabapentin is not known.
In addition, because gabapentin causes drowsiness and dizziness, patients are advised not to operate complex mechanical devices until they have gained sufficient experience to assess whether gabapentin impairs their ability to perform such tasks.
Drowsiness/sedation and dizziness
In controlled studies conducted in >12-year-old patients with epilepsy, patients taking up to 1800 mg of gabapentin daily had significantly higher rates of drowsiness, dizziness, and ataxia than placebo controls, with rates of 19% and 9% for the drowsy gabapentin group versus the placebo group, 17% and 7% for dizziness, and 13% and 6% for ataxia, respectively, in these studies drowsiness, ataxia, and fatigue were the most common adverse effects leading to discontinuation in patients over 12 years of age, at 1.2%, 0.8%, and 0.6%, respectively.
In clinical trials conducted in patients with postherpetic neuralgia, the incidence of drowsiness and dizziness was higher in the gabapentin group than in the placebo group at a dose of 3600 mg, with the incidence of drowsiness being 21% and 5% in the gabapentin and placebo groups, respectively, and dizziness being 28% and 8%, respectively. Dizziness and drowsiness were the most common adverse reactions leading to discontinuation of the drug.
Potential synergistic effects may occur when gabapentin is used in combination with other drugs with sedative effects, and signs of central nervous system depression, such as drowsiness and sedation, should be closely monitored. In addition, blood levels of gabapentin may increase if morphine is used concomitantly, necessitating dose adjustment.
Withdrawal rebound, persistent status epilepticus
Antiepileptic drugs should not be stopped abruptly because the frequency of seizures may be increased.
In placebo-controlled studies conducted in patients aged >12 years, the incidence of persistent status epilepticus was 0.6% (3/543) in patients receiving gabapentin and 0.5% (2/378) in those receiving placebo. Of the 2074 patients aged >12 years treated with gabapentin in all studies (control and non-control), 31 (1.5%) developed status epilepticus. Of these, 14 patients had no prior history of persistent status epilepticus (before treatment or while taking other medications). Due to the lack of adequate history information, it was not possible to determine whether the population treated with gabapentin had a higher or lower incidence of status epilepticus (compared with a similar population not treated with gabapentin).
Suicidal behavior and ideation
Patients treated with an antiepileptic drug (AED) for any indication for which the antiepileptic drug (including gabapentin) increases the patient’s risk of suicidal thoughts or behaviors should be monitored for the following symptoms or worsening of symptoms during AED treatment: depression, suicidal thoughts or behaviors, and/or any abnormal changes in mood or behavior.
A combined analysis of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) including 11 different AEDs found that patients in the AED treatment group had approximately twice the risk of suicidal thoughts or behaviors as those in the placebo group (adjusted relative risk 1.8, 95% confidence interval: 1.2, 2.7). The median duration of treatment in these clinical trials was 12 weeks, and the estimated incidence of suicidal behaviors or thoughts was 0.43% for the 27,863 patients in the AED treatment group compared with 0.24% for the 16,029 patients in the placebo group, indicating an increase of approximately 1 suicidal thought or behavior per 530 treated patients. There were four suicidal patients in the drug treatment group and none in the placebo group in the trial; however, the number of cases was too small to draw any conclusions about the effect of drugs on suicide.
The increased risk of suicidal thoughts or behaviors with AED treatment was observed one week after the start of AED treatment and persisted throughout the treatment evaluation period. Because most of the clinical trials included in the analysis did not exceed 24 weeks, the risk of suicidal thoughts or behaviors after 24 weeks could not be evaluated.
The risk of suicidal thoughts or behaviors was generally consistent across the drugs included in the data analysis. These risks were found across different mechanisms of action of AEDs and multiple indications, suggesting that this risk is prevalent across all indications of AED therapy. No significant changes in risk with age (5 to 100 years) were found in the clinical trials analyzed. Table 5 shows the absolute and relative risk of the evaluated AEDs for the different indications.
Table 5 Combined analysis of the risk of antiepileptic drugs for different indications
Indication Number of events per 1000 patients in the placebo group Number of events per 1000 patients in the drug group Relative risk: incidence of events in patients in the drug group/incidence of events in patients in the placebo group Risk difference: additional events per 1000 patients in the drug group Epilepsy 1.03.43.52.4 Psychosis 5.78.51.52.9 Other 1.01.81.90.9 Total 2.44.31.81.9
The relative risk of suicidal thoughts or behaviors in clinical trials for epilepsy was higher than in clinical trials for psychosis or other disorders, but the absolute risk difference was essentially similar for the two indications of epilepsy and psychosis.
When considering prescribing gabapentin or any other AED, the risk of suicidal thoughts or behaviors must be weighed against the risk of not treating the disorder. Epilepsy and many other conditions for which AED treatment is indicated are at an inherently higher risk for suicidal thoughts and behaviors due to the morbidity and mortality of the disease itself. Therefore, if suicidal thoughts and behaviors occur during treatment, the prescriber needs to consider whether the patient presenting with these symptoms is related to the disease for which he or she is being treated.
Patients, caregivers, and their family members should be informed that gabapentin and other AEDs have an increased risk of suicidal thoughts and behaviors. They should also be advised to watch for the onset or worsening of depressive symptoms and signs, any unusual mood or behavioral changes, or the onset of suicidal thoughts and behaviors, or the emergence of self-harm thoughts. Any suspicious behavior should be reported immediately to medical personnel.
Neuropsychiatric adverse reactions (pediatric patients aged 3 to 12 years)
The use of gabapentin in pediatric patients with epilepsy between the ages of 3 and 12 years has been associated with the occurrence of CNS-related adverse reactions. The most notable of these events can be divided into the following categories: 1) emotional instability (primarily behavioral problems), 2) hostility, including aggressive behavior, 3) thought disturbances, including difficulty concentrating and altered school performance, and 4) hypermobility (primarily fidgeting and hyperactivity). In patients treated with gabapentin, the majority of adverse reactions were mild to moderate.
In controlled trials conducted in pediatric patients aged 3 to 12 years, the incidence of these adverse reactions in gabapentin- and placebo-treated patients was 6% and 1.3% for emotional lability; 5.2% and 1.3% for hostility; 4.7% and 2.9% for hyperkinesia; and 1.7% and 0% for thought disorder, respectively. Of these, one report of hostility was determined to be severe. Gabapentin treatment was discontinued in 1.3% of patients reporting mood swings and hyperkinesia and in 0.9% of patients reporting hostility and thought disorder. One of the placebo-treated patients (0.4%) discontinued because of emotional instability.
Potential carcinogenic effects
In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic alveolar cell tumors in rats. The clinical significance of this finding is unclear. Clinical experience with pre-market development of gabapentin did not provide a direct method to assess its potential human carcinogenic effects.
Clinical studies of adjunctive treatment for epilepsy in >12-year-old patients included 2085 patient-years of exposure. During gabapentin treatment or within 2 years after discontinuation, 10 patients reported new tumors (2 in the breast, 3 in the brain, 2 in the lung, 1 in the adrenal gland, 1 non-Hodgkin’s lymphoma, and 1 endometrioma in situ) and 11 patients reported worsening of previous tumors (9 in the brain, 1 in the breast, and 1 in the prostate). The lack of background information on the incidence and recurrence rates in a similar population not treated with gabapentin makes it impossible to determine whether the incidence observed in the study cohort was treatment-related.
Sudden unexplained deaths in patients with epilepsy
During the premarket development phase of gabapentin, eight sudden unexplained deaths were recorded in 2203 patients treated (2103 patient-year exposures).
Some of these seizure-related deaths were not observed with seizures, for example, occurring at night. The incidence of death was 0.0038 per patient-year. Although this rate exceeds that expected for a healthy population (age- and sex-matched), it is still within its range when compared with the sudden unexplained mortality rate in epilepsy patients not treated with gabapentin (range: 0.0005 in the general epilepsy population; 0.003 in clinical trial populations similar to those studied with gabapentin; 0.005 in patients with refractory epilepsy). Therefore, whether these numbers are reliable or require further attention depends on the comparability of the gabapentin group populations and the accuracy of the estimates reported above.
Abuse
Gabapentin did not show affinity for benzodiazepines, opioids (μ, δ, or κ), or the receptor site for cannabinoid 1. A small number of post-marketing cases have reported misuse and abuse of gabapentin. These individuals were taking higher than recommended doses of gabapentin for unapproved uses. Most of the individuals described in these reports had a history of multiple substance abuse or used gabapentin to alleviate withdrawal symptoms of other substances. When prescribing gabapentin, patients should be carefully evaluated for a history of substance abuse and observed for signs and symptoms of misuse or abuse of gabapentin (e.g., tolerance development, self-administered dosing, and foraging behavior). Drug dependence
There are rare postmarketing reports of individuals experiencing withdrawal symptoms for a short period of time after discontinuing higher-than-recommended doses of gabapentin for the treatment of an unapproved condition. Such symptoms include agitation, disorientation, and confusion that appear after abrupt discontinuation of gabapentin and resolve upon reintroduction. Most of these individuals had a history of polysubstance abuse or used gabapentin to alleviate discontinuation symptoms of other substances. The potential dependence and abuse potential of gabapentin has not been evaluated in human studies.
Special Considerations
In controlled clinical studies, 16% of patients experienced potentially clinically significant fluctuations in blood glucose (<3.3 mmol/L or ≥7.8 mmol/L, normal range 3.5 to 5.5 mmol/L). Therefore, diabetic patients need to monitor their blood glucose frequently and adjust the dose of hypoglycemic drugs at any time if necessary.
There have been reports of hemorrhagic pancreatitis with gabapentin. Therefore, if clinical symptoms of pancreatitis (persistent abdominal pain, nausea, recurrent vomiting) appear, gabapentin should be discontinued immediately and a thorough physical examination, clinical and laboratory tests should be performed with a view to diagnosing pancreatitis as soon as possible.
In patients with chronic pancreatitis, there is no adequate experience with the use of gabapentin, and the use of gabapentin should be decided by a physician.
Pregnant women and nursing mothers
There is no experience with the use of gabapentin in pregnant women, and gabapentin should be used only after an adequate assessment of the benefits/risks.
Gabapentin is secreted in breast milk and the possibility that gabapentin may cause serious adverse reactions in infants cannot be ruled out. Therefore, breastfeeding women should discontinue breastfeeding or discontinue the use of gabapentin when gabapentin is necessary (taking into account the need for antiepileptic treatment of the mother).
[For children].
For dosage in children, see under [Dosage].
The safety and efficacy of gabapentin for the treatment of postherpetic neuralgia in children has not been established; the safety and efficacy of gabapentin for the adjunctive treatment of partial-onset epilepsy in children under 3 years of age has not been established.
[Geriatric Use].
The total number of patients using gabapentin in controlled clinical trials for postherpetic neuralgia was 336, of whom 102 (30%) were 65-75 years of age and 168 (50%) were 75 years of age or older. Patients 75 years of age and older had a greater treatment effect compared to younger patients receiving the same dose. Since gabapentin is almost completely eliminated by renal excretion, the greater treatment effect in patients over 75 years of age may be the result of higher plasma exposure at the given dose, which is associated with age-related decompensation of renal function. However, other causes cannot be excluded. The type and incidence of adverse effects were similar between age groups, except for peripheral edema and ataxia, the incidence of which increased with age.
Clinical trials of gabapentin in patients with epilepsy were unable to determine whether older patients responded differently than younger patients because there were not sufficient numbers of patients aged 65 years and older. Other reported experiences with clinical studies have not found differences in response between older and younger adults. In general, dose selection in the elderly should be cautious due to decreased hepatic, renal, and cardiac function as well as more concomitant disease or medication use, usually with lower starting doses.
Because gabapentin is excreted through the kidneys, patients with impaired renal function are at increased risk of toxic reactions with gabapentin. Because of the greater likelihood of decreased renal function in elderly patients, caution should be exercised in dose selection and dose adjustments should be made based on creatinine clearance.
[Drug Interactions].
Other antiepileptic drugs
Gabapentin is rarely metabolized and does not interfere with the metabolism of other generally co-administered antiepileptic drugs.
Opioids
Hydrocodone: Exposure to hydrocodone is reduced with the combination of gabapentin. Potential changes in exposure and possible effects of hydrocodone should be considered when starting or stopping gabapentin in patients taking hydrocodone.
Morphine: When gabapentin is combined with morphine, patients should be closely monitored for signs of central nervous system depression, such as drowsiness, sedation, or respiratory depression.
Antacids (aluminum hydroxide, magnesium hydroxide)
The mean bioavailability of gabapentin is reduced by approximately 20% with antacids containing aluminum hydroxide and magnesium hydroxide. It is recommended that gabapentin be taken at least 2 hours after taking antacids.
Drug/Laboratory Test Interactions
False positive readings have been reported with the Ames N-Multistix SG® dipstick assay for urine protein when gabapentin is added to other antiepileptic drugs, so a more specific sulfosalicylic acid precipitation assay is recommended to detect urine protein.
[Drug overdose].
Diplopia, slurred speech, drowsiness, apathy, and diarrhea have been reported in patients who overdosed on gabapentin up to 49 g. All patients recovered with supportive therapy. Coma has been reported in patients with chronic renal failure treated with gabapentin, which was relieved by dialysis.
Gabapentin is cleared by hemodialysis. Although hemodialysis was not performed in the few reported cases of drug overdose, it may be used depending on the clinical status of the patient or in patients with severe renal impairment.
[Pharmacology and Toxicology].
Pharmacological effects
The exact mechanism by which gabapentin exerts its analgesic and antiepileptic effects is not known. Gabapentin is structurally related to the neurotransmitter γ-aminobutyric acid (GABA), but has no effect on GABA binding, uptake or degradation. In vitro tests have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-gated calcium channels, but the relationship of this binding to the therapeutic effects of gabapentin is unclear.
Toxicological effects
Genotoxicity
The results of the Ames test with gabapentin, the in vitro HGPRT forward mutation test in Chinese hamster lung cells, the in vivo bone marrow chromosome aberration test and micronucleus test in Chinese hamsters, the in vivo micronucleus test in mice, and the in vivo extraprogrammed DNA synthesis (UDS) test in rat hepatocytes were all negative.
Reproductive toxicity
No adverse effects on fertility were observed in rats given gabapentin orally up to 2000 mg/kg/day [the exposure (AUC) of gabapentin in rats at this dose is approximately 8 times the exposure in humans given 3600 mg/day].
In pregnant mice given gabapentin 500, 1000, and 3000 mg/kg/day orally during organogenesis, embryo/fetus toxicity (increased incidence of skeletal variation) was observed at high and moderate doses, and the no-effect dose of 500 mg/kg/day for embryo/fetus development was lower than the human dose of 3600 mg/day (in mg/m2).
In rats given gabapentin 500 to 2000 mg/kg/day orally during gestation, adverse offspring developmental effects (increased incidence of ureteral effusion and/or pelvic effusion) were observed at all doses, with the lowest dose tested being approximately equivalent to the human dose of 3600 mg/day (in mg/m2).
In pregnant rabbits given gabapentin 60, 300, and 1500 mg/kg orally during the organogenesis period, increased embryo/fetal mortality was observed at all doses, with the lowest dose in the trial being less than the human dose of 3600 mg/day (in mg/m2).
In a published trial in which gabapentin was administered intraperitoneally to newborn mice at 400 mg/kg/day during the first week of life (rodent synaptogenesis, equivalent to late human gestation), gabapentin resulted in a significant reduction in neuronal synapse formation in the brain of intact mice and abnormal neuronal synapse formation in a mouse model of synaptic repair. Gabapentin has been shown to interfere in vitro with the activity of the α2δ subunit of voltage-gated calcium channels, a receptor involved in neuronal synapse formation. The clinical significance of these findings is unclear.
Carcinogenicity
Gabapentin was tested for carcinogenicity in mice and rats administered orally for 2 years. In mice, no drug-related carcinogenicity was seen at doses up to 2000 mg/kg/day, and the exposure (AUC) of gabapentin in mice given at 2000 mg/kg was approximately twice that in humans given at 3600 mg/day. In rats, an increased incidence of pancreatic follicular cell adenomas and carcinomas was observed in male rats at high doses (2000 mg/kg/day) and was not seen at doses of 250 or 1000 mg/kg/day; the exposure (AUC) in rats given a dose of 1000 mg/kg/day was approximately 5 times the exposure in humans given a dose of 3600 mg/day.
Tests aimed at investigating the mechanism of gabapentin-induced pancreatic carcinogenesis in rats showed that gabapentin stimulated DNA synthesis in rat pancreatic alveolar cells in vitro, thus possibly acting as a tumor initiation factor by enhancing mitotic activity. It is not known whether gabapentin has the ability to enhance cell proliferation in other cell types or other species, including humans.
[Pharmacokinetics].
All pharmacological effects of gabapentin after administration are derived from the parent compound; metabolism of gabapentin in humans is insignificant.
Oral bioavailability
The bioavailability of gabapentin is not proportional to the dose, and decreases when the dose is increased. The corresponding bioavailability of gabapentin given at 900, 1200, 2400, 3600, and 4800 mg/day (in 3 divided doses) was approximately 60%, 47%, 34%, 33%, and 27%, respectively. Food had only a slight effect on the rate and extent of gabapentin absorption (14% increase in AUC and Cmax).
Distribution
Less than 3% of gabapentin was bound to plasma proteins. The apparent volume of distribution after intravenous administration of 150 mg of gabapentin was 58 ± 6 L (mean ± SD). The steady-state trough concentration (Cmin) of gabapentin in the cerebrospinal fluid of patients with epilepsy was approximately 20% of the corresponding plasma concentration.
Clearance
Gabapentin is cleared from the body circulation in its native form by renal excretion. The metabolism of gabapentin in humans is not significant.
The clearance half-life of gabapentin is 5 to 7 hours and does not vary with the dose or frequency of administration. The clearance rate constant, plasma clearance, and renal clearance of gabapentin are directly proportional to creatinine clearance. The plasma clearance of gabapentin is decreased in elderly patients and in patients with impaired renal function. Hemodialysis removes gabapentin from the plasma.
For patients with impaired renal function or on hemodialysis, dose adjustment is recommended (see [DOSAGE AND ADMINISTRATION]).
Special Populations
Age
Age effects were studied in subjects 20 to 80 years of age. The apparent oral clearance (CL/F) of gabapentin decreases with age, ranging from approximately 225 mL/min in subjects under 30 years of age to approximately 125 mL/min in subjects over 70 years of age. renal clearance (CLr) and body surface area corrected CLr also decrease with age; the decrease in renal clearance of gabapentin with age can be explained in large part by decreased renal function. The decrease in gabapentin renal clearance with age can be largely explained by diminished renal function. Patients with age-related renal impairment require lower doses of gabapentin. (See [Geriatric Use] and [Dosage].)
Gender
Although there are no formal studies comparing the pharmacokinetics of gabapentin in men and women, pharmacokinetic parameters were shown to be similar in men and women, with no significant gender differences.
Race
Differences in pharmacokinetics due to race have not been studied. Because gabapentin is primarily cleared by the kidneys and there are no significant racial differences in creatinine clearance, it is not expected that race would cause pharmacokinetic differences.
Children
The pharmacokinetics of gabapentin were determined in 48 pediatric subjects (1 month to 12 years of age) administered at a dose of approximately 10 mg/kg. peak plasma concentrations were similar throughout the age groups and peaked 2 to 3 hours after dosing. Overall, drug exposure (AUC) was approximately 30% lower in pediatric subjects 1 month to less than 5 years of age than in children 5 years and older. Therefore, the younger the child, the higher the oral clearance normalized by body weight. Apparent oral clearance of gabapentin was positively related to creatinine clearance. The mean clearance half-life of gabapentin was 4.7 hours, which was similar in all age groups studied.
The population pharmacokinetics of gabapentin were analyzed in 253 pediatric subjects (1 month to 13 years of age) according to literature reports. Patients received doses of 10 to 65 mg/kg/day in 3 daily doses. Apparent oral clearance (CL/F) was similarly related to creatinine clearance after a single dose and after reaching steady state. After normalization by body weight, higher oral clearance values were observed in children younger than 5 years of age compared to children 5 years and older. There was high variability in clearance in infants younger than 1 year of age. CL/F values observed in children 5 years of age and older after a single dose were consistent with those observed in adults after normalization. The volume of oral distribution normalized by body weight remained consistent across the age range.
These pharmacokinetic data suggest that the effective daily dose for pediatric patients with epilepsy at 3 and 4 years of age should be 40 mg/kg/day to achieve similar mean blood concentrations to those achieved at a dose of 30 mg/kg/day in pediatric patients 5 years of age and older.
Adult Patients with Renal Insufficiency
In subjects (N=60) with renal insufficiency (mean creatinine clearance 13 to 114 mL/min), the mean half-life of gabapentin after a single oral dose of 400 mg gabapentin ranged from 6.5 hours (in patients with creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min), and the renal clearance of gabapentin was 90 mL/ min (>60 mL/min group) to 10 mL/min (<30 mL/min). The mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min.
Dose adjustment is required in adult patients with renal impairment. Pediatric patients with renal insufficiency have not been studied.
Hemodialysis
In studies in adult subjects without urine (N=11), the apparent clearance half-life of gabapentin was approximately 132 hours on non-dialysis days; on dialysis, the apparent clearance half-life of gabapentin was reduced to 3.8 hours. Thus, hemodialysis had a significant effect on gabapentin clearance in anuric subjects. Dose adjustments are required in patients undergoing hemodialysis.
Liver disease
Gabapentin has not been studied in patients with hepatic impairment because it is not metabolized.
Storage】Seal and store.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil, plus polyester/aluminum/polyethylene pharmaceutical composite bag.
(1) 0.1g: 10 capsules/plate×1 plate/box; 10 capsules/plate×2 plate/box; 10 capsules/plate×3 plate/box; 10 capsules/plate×5 plate/box; 12 capsules/plate×4 plate/box.
(2) 0.3g: 10 capsules/plate x 1 plate/box; 10 capsules/plate x 2 plates/box; 10 capsules/plate x 3 plates/box; 10 capsules/plate x 5 plates/box; 12 capsules/plate x 2 plates/box; 12 capsules/plate x 4 plates/box.
(3) 0.4g: 10 capsules/plate×1 plate/box; 10 capsules/plate×2 plate/box; 10 capsules/plate×3 plate/box.
Expiration date】24 months.
【Execution standard
【Approval number】
[Drug marketing license holder
Name: Beijing Sihuan Pharmaceutical Co.
Registered Address: East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing
Tel: 010-61563510
Manufacturer
Company Name: Beijing Sihuan Pharmaceutical Co.
Production Address: No. 13, Guangyuan West Street, Zhangjiawan Town, Tongzhou District, Beijing
Postal Code: 101113
Telephone number: 010-61563510
Fax number: 010-61563510
Web address: www.sihuanpharm.com
State Drug Administration
Standard
Gabapentin Capsules
Jiabapending Jiaonang
Gabapentin Capsules
This product contains gabapentin (C9H17NO2) should be 95.0%~105.0% of the labeled amount.
Properties
This product is a capsule, the contents of white or off-white powder and granules.
Identification】（1）Take appropriate amount of the contents of this product (about 10mg of gabapentin), add 10ml of water to dissolve, filter, take 2ml of filtrate, add about 2mg of ninhydrin, heat, the solution shows blue purple.
(2) In the chromatogram recorded under the content determination, the retention time of the main peak of the test solution should be the same as that of the main peak of the control solution.
Check]
Related substances
Take an appropriate amount of the contents of the product under the loading difference, weigh it precisely, add solvent (take 1.2g of potassium dihydrogen phosphate, dissolve it with water and dilute it to 1000ml, shake well, adjust the pH to 6.9 with 5mol/L potassium hydroxide solution), dissolve it by ultrasonication for 30 seconds, dilute it quantitatively with solvent to make a solution containing about 20mg in each 1ml, shake well, filter it, and take the filtrate as the test sample. Take about 25mg of corn starch, put it into a 10ml measuring flask, add the solvent, sonicate for 30 seconds, dilute with solvent to the scale, shake well, filter through, and take the filtrate as the blank coagent solution. According to the test of high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition IV General Rule 0512), using octylsilane bonded silica gel as filler (250mm×4.6mm, 5μm); using phosphate buffer solution (take 1.2g of potassium dihydrogen phosphate, add 940ml of water to dissolve, adjust the pH to 6.9 with 5mol/L potassium hydroxide solution)-acetonitrile (94:6) as mobile phase A, phosphate buffer solution (take 1.2g of potassium dihydrogen phosphate, add 700ml of water to dissolve, adjust the pH to 6.9 with 5mol/L potassium hydroxide solution)-acetonitrile (70:30) as mobile phase B, gradient elution according to the table below; the flow rate is 1.5ml per minute; the detection wavelength is 210nm; the column temperature is 30℃. The separation of gabapentin peak and adjacent impurity peak in the test solution should meet the requirements, and the trailing factor of gabapentin peak should not be more than 2.0. 50µl of the control solution was measured and injected into the liquid chromatograph, and the order of peaks was gabapentin and impurity A. 50µl of the test solution, blank cofactor solution and control solution were measured and injected into the liquid chromatograph respectively, and the chromatogram was recorded. The chromatogram of the test solution, minus the blank auxiliary
State Drug Administration Published Beijing Drug Testing Institute Review
State Drug Administration Drug Review Center Review Beijing Sihuan Pharmaceutical Co.
Material peaks, if there is a peak with impurity A retention time, according to the external standard method to peak area calculation, shall not be more than 0.4% of the labeled amount; if there are other impurities, according to the external standard method to gabapentin peak area calculation, shall not be more than 0.10% of the labeled amount of gabapentin; total impurities shall not be more than 1.0%.
Time (min) Mobile phase A (%) Mobile phase B (%) 010004100045010045.11000601000 Dissolution
Take this product, according to the method of determination of solubility and release (Chinese Pharmacopoeia 2015 edition of four general rules 0931 second method), with 0.06 mol/L hydrochloric acid solution (51→10000) 900ml as the dissolution medium, the speed is 50 revolutions per minute, according to the operation of the law, after 20 minutes, take the appropriate amount of solution, filtered, and take the filtrate as the test solution; Also take the appropriate amount of gabapentin control. The solution was weighed precisely, dissolved with dissolution medium and diluted quantitatively to make a solution containing 0.11mg (0.1g specification) or 0.33mg (0.3g specification) or 0.44mg (0.4g specification) per 1ml, as the control solution. The amount of dissolution of each capsule was calculated by the method under content determination. The limit is 85% of the labeled amount, which should be in accordance with the regulations.
Other
Should comply with the relevant provisions under the capsule (Chinese Pharmacopoeia 2015 Edition, Part IV General Provisions 0103).
Content determination】 Determination by high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition IV General Rules 0512).
Chromatographic conditions and system applicability test
The mobile phase was acetonitrile (94:6) and phosphate buffer solution (1.2g of potassium dihydrogen phosphate, 940ml of water, pH adjusted to 6.9 with 5mol/L potassium hydroxide solution); the detection wavelength was 210nm; the flow rate was 1.2ml per minute. The theoretical plate number was calculated by the peak of gabapentin not less than 7000, and the trailing factor of gabapentin peak should not be more than 2.0.
Determination method
Take the contents of the product under the difference of loading and research well, weigh the appropriate amount (about 100mg of gabapentin), put it into a 25ml measuring flask, add solvent (take 1.2g of potassium dihydrogen phosphate, dissolve with water and dilute to 1000ml, shake well, adjust pH to 6.9 with 5mol/L potassium hydroxide solution) in appropriate amount, sonicate for 60 seconds to dissolve, dilute with solvent to the scale, shake well, filter through Then, take the test solution as the test solution; precisely measure 50µl of the test solution, inject into liquid chromatograph and record the chromatogram; take an appropriate amount of gabapentin control, weigh precisely, dissolve with solvent and dilute quantitatively to make a solution containing about 4.0mg of gabapentin in each 1ml; determine by the same method. According to the external standard method to calculate the peak area, that is obtained.
【Class】 Anti-epileptic drugs.
Specification】（1）0.1g （2）0.3g （3）0.4g
Storage]
Keep sealed.
Expiration date
24 months
Impurity A
C9H15NO 153.22
2-azaspiro[4,5]decan-3-one