Active ingredients: Gabapentin
Neurontin 100 mg hard capsules
Neurontin 300 mg hard capsules
Neurontin 400 mg hard capsules
Why is Neurontin used? What is it for?
Neurontin belongs to a group of medicines used to treat epilepsy and peripheral neuropathic pain (long lasting pain caused by damage to the nerves).
The active ingredient of Neurontin is gabapentin.
Neurontin is used to treat:
- Various forms of epilepsy (seizures initially limited to certain areas of the brain, whether the seizures spread to other parts of the brain or not). Your doctor will prescribe Neurontin to help you treat epilepsy when your current treatment does not fully control your condition. You should take Neurontin in addition to your current treatment unless you receive other instructions. Neurontin can also be used by only for the treatment of adults and children over 12 years of age.
- Peripheral neuropathic pain (long lasting pain caused by damage to the nerves). A variety of different diseases can cause peripheral neuropathic pain (occurs mainly in the legs and / or arms), such as diabetes or shingles. Pain sensations can be described as heat, burning, throbbing, lightning pain, aches stabbing, sharp pains, cramping pains, aching, tingling, numbness, stinging pains, etc.
Contraindications When Neurontin should not be used
Do not take Neurontin
- if you are allergic (hypersensitive) to gabapentin or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Neurontin
Talk to your doctor or pharmacist before taking Neurontin:
- if you have kidney problems your doctor may prescribe a different dosage
- if you are on hemodialysis (to remove waste from kidney failure) tell your doctor if you develop muscle pain and / or weakness
- if you develop signs such as persistent stomach pain, nausea and vomiting, contact your doctor immediately as these may be symptoms of acute pancreatitis (an 'inflammation of the pancreas).
Cases of abuse and dependence have been reported for gabapentin from post-marketing experience. Tell your doctor if you have a history of abuse or dependence.
A small number of patients being treated with antiepileptic medicines such as gabapentin have developed thoughts of suicide or self harm. If at any time you have such thoughts, contact your doctor immediately.
Important information on potentially serious reactions
A small number of patients being treated with Neurontin have had an allergic reaction or potentially serious skin reactions which, if left untreated, can develop into more serious problems. You need to know these symptoms to be able to recognize them while you are taking Neurontin.
Read the description of these symptoms in section 4 of this leaflet under "Contact your doctor immediately if you experience any of the following symptoms after taking this medicine as they can be serious"
Muscle weakness, aches or pains and particularly if you feel unwell and have a fever at the same time, it can be caused by a muscle breakdown which can be life-threatening and can lead to kidney problems. Discoloration of the urine and abnormal blood tests (in particular increased creatine phosphokinase) may also occur. If you experience any of these signs or symptoms, please contact your doctor immediately.
Interactions Which drugs or foods can modify the effect of Neurontin
Other medicines and Neurontin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Medicines containing opioids such as morphine
If you are taking medicines that contain opioids (such as morphine), tell your doctor or pharmacist because opioids can increase the effect of Neurontin. Also, the combination of Neurontin with opioids can cause symptoms such as sleepiness and / or decreased breathing. .
Antacids for poor digestion
If Neurontin and antacids containing aluminum and magnesium are taken together, the absorption of Neurontin from the stomach may be reduced. It is therefore recommended to take Neurontin no earlier than two hours after taking the antacid.
Neurontin:
- It is not expected to interact with other antiepileptic medicines or the birth control pill.
- It can interfere with some laboratory tests; if you need a urine test, tell your doctor or hospital what you are taking.
Neurontin with food
Neurontin can be taken with or without food.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Neurontin should not be taken during pregnancy unless your doctor has told you otherwise. Women of childbearing age must use an effective method of contraception.
No specific studies have been conducted to evaluate the use of gabapentin in pregnant women, but an increased risk for the development of the child has been reported for other medicines used to treat seizures, particularly when more than one drug is taken at the same time. a medicine for seizures. Therefore, whenever possible, you should try to take only a medicine for epilepsy during pregnancy and only on medical advice.
Contact your doctor immediately if you are pregnant, think you may be pregnant or plan to become pregnant while taking Neurontin. Do not suddenly stop taking this medicine as this can cause a sudden onset of seizures which can have serious consequences for you and your baby.
Feeding time
Gabapentin, the active ingredient in Neurontin, passes into breast milk. As the effect on the baby is not known, it is recommended that you do not breastfeed during treatment with Neurontin.
Fertility
Animal studies have shown no effect on fertility.
Driving and using machines
Neurontin can cause dizziness, sleepiness and fatigue. You should not drive vehicles, operate complex machinery or engage in other potentially dangerous activities until you understand whether this medicine may affect your ability to perform these activities.
Neurontin contains lactose
Neurontin hard capsules contain lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Neurontin: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Your doctor will work out the right dose for you.
Epilepsy, the recommended dose is:
Adults and adolescents:
Take the number of capsules your doctor has prescribed for you. Your doctor will usually increase the dose gradually. The starting dose will generally be between 300 mg and 900 mg per day. Subsequently, the dose may be increased, on the doctor's recommendation, up to a maximum of 3600 mg per day and your doctor will tell you to take this dose in 3 separate doses, i.e. once in the morning, once in the afternoon and once in the evening.
Children aged 6 and over:
The dose to be given to the child will be determined by the doctor because it is calculated based on the weight of the child. Treatment is started with a low starting dose which is gradually increased over approximately 3 days. The usual dose for controlling epilepsy is 25-35 mg / kg per day. It is usually given in 3 divided doses, taking the capsule each day usually once in the morning, once in the afternoon and once in the evening.
Neurontin is not recommended for children under 6 years of age.
Peripheral neuropathic pain, the recommended dose is:
Adults:
Take the number of capsules according to your doctor's instructions. Your doctor will usually increase the dose gradually. The starting dose will generally be between 300 mg and 900 mg per day. Subsequently, the dose may be increased on the doctor's recommendation up to a maximum of 3600 mg per day and your doctor will tell you to take the medicine in 3 divided doses, i.e. once in the morning, once in the afternoon and once in the evening.
If you have kidney problems or are on hemodialysis
If you have kidney problems or are on hemodialysis, your doctor may prescribe a different schedule for taking this medicine and / or a different dose.
If you are an elderly patient (over 65 years of age) you should take the normal dose of Neurontin, unless you have kidney problems. If you have kidney problems, your doctor may prescribe a different schedule of taking the medicine and / or a different dose.
If you have the impression that the effect of Neurontin is too strong or too weak, tell your doctor or pharmacist as soon as possible.
Method of administration
Neurontin is taken orally. Always swallow the capsules whole with a large amount of water.
Continue treatment with Neurontin until your doctor tells you to stop.
Overdose What to do if you have taken an overdose of Neurontin
If you take more Neurontin than you should
A higher dose than recommended may lead to increased side effects including loss of consciousness, dizziness, double vision, difficulty in speaking, sleepiness and diarrhea.
Contact your doctor immediately or go to the nearest emergency department if you take more Neurontin than prescribed by your doctor. Take the capsules you did not take with you together with the pack and the package leaflet so that the hospital can easily understand how much medicine you have taken.
If you forget to take Neurontin
If you forget to take a dose, take it as soon as you remember, unless it is time for your next dose. Do not take a double dose to make up for a forgotten dose.
If you stop taking Neurontin
Do not stop taking Neurontin unless your doctor tells you to. Withdrawal of treatment should be done gradually over at least 1 week. If you suddenly stop taking Neurontin or before your doctor prescribes it, the risk of seizures increases.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Neurontin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
You should contact your doctor right away if you notice any of the following symptoms after taking this medicine as they can be serious:
- severe skin reactions that require immediate attention, swelling of the lips and face, rash and redness of the skin, and / or hair loss (these may be symptoms of a severe allergic reaction)
- persistent stomach pain, nausea and vomiting as these may be symptoms of acute pancreatitis (an 'inflammation of the pancreas).
- Neurontin can cause a severe or life-threatening allergic reaction, which can affect the skin or any other part of the body such as the liver or blood. When you have this type of reaction, you may or may not have a rash. This can cause you to be hospitalized or to stop taking Neurontin.
Call your doctor immediately if you have any of the following symptoms:
- skin rashes
- urticaria
- fever
- swelling of the lymphatic glands which tends not to disappear
- swelling of the lips and tongue
- yellowing of the skin or the whites of the eyes
- unusual bleeding or bruising
- severe fatigue or weakness
- sudden muscle pain
- frequent infections
These symptoms can be the first signs of a serious reaction. Your doctor should examine you to decide whether to continue taking Neurontin.
- If you are on hemodialysis, tell your doctor if you experience muscle pain and / or weakness.
Other side effects include:
Very common (may affect more than 1 in 10 people):
- Viral infections
- Feeling sleepy, dizzy, lack of coordination
- Feeling tired, fever
Common (may affect up to 1 in 10 people):
- Pneumonia, respiratory infections, urinary tract infection, ear inflammation or other infections
- Low white blood cell count
- Anorexia, increased appetite
- Anger towards other people, confusion, mood changes, depression, anxiety, nervousness, difficulty thinking
- Convulsions, jerking movements, difficulty speaking, memory loss, tremors, sleep disturbances, headache, skin sensitivity, decreased sensation (numbness), difficulty in coordination, abnormal eye movement, increase, decrease or absence of reflections
- Blurred vision, double vision
- Dizziness
- High blood pressure, flushing of the face or dilation of blood vessels
- Difficulty in breathing, bronchitis, sore throat, cough, dry nose
- Vomiting, nausea, dental problems, sore gums, diarrhea, stomach pain, indigestion, constipation, dry mouth or throat, flatulence
- Facial swelling, bruising, rash, itching, acne
- Joint pain, muscle pain, back pain, muscle twitching
- Erection problems (impotence)
- Swelling of the legs and arms, difficulty walking, weakness, pain, feeling unwell, flu-like symptoms
- Reduction in white blood cells, weight gain
- Accidental wounds, fractures, abrasions
In addition, aggressive behavior and jerking movements were commonly reported in clinical trials in children.
Uncommon (may affect up to 1 in 100 people):
- Allergic reaction such as urticaria
- Movement reduction
- Increased heart rate
- Swelling which may affect the face, trunk and limbs
- Abnormal blood test values that suggest liver problems.
- Mental impairment
- Falls
- Increase in blood glucose levels (seen more often in patients with diabetes)
Rare (may affect up to 1 in 1,000 people):
- Loss of consciousness
- Decrease in blood glucose levels (observed more often in patients with diabetes)
The following side effects have been reported post-marketing:
- Reduction in platelets (cells that clot the blood)
- Hallucinations
- Problems with abnormal movements such as convulsive shaking, jerking movements and stiffness
- I tinkled in my ear
- A group of side effects, including swollen lymph nodes (small isolated lumps under the skin), fever, rash and inflammation of the liver, which may occur together
- Yellowing of the skin and eyes (jaundice), inflammation of the liver
- Acute renal failure, incontinence
- Breast tissue enlargement, breast enlargement
- Adverse events occurring after abrupt withdrawal of gabapentin (anxiety, sleep disturbances, feeling sick, pain, sweating), chest pain
- Muscle fiber injury (rhabdomyolysis)
- Abnormalities in blood tests (increased creatine phosphokinase)
- Problems with sexual function including inability to reach orgasm, delayed ejaculation
- Low levels of sodium in the blood
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.
Do not store Neurontin hard capsules above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Neurontin contains
The active ingredient is gabapentin. Each hard gelatin capsule contains 100 mg, 300 mg or 400 mg of gabapentin.
The other ingredients of Neurontin capsules are:
Capsule contents: lactose monohydrate, corn starch and talc.
Capsule shell: gelatin, purified water and sodium lauryl sulfate.
The 100 mg capsules contain the color E171 (titanium dioxide), the 300 mg capsules contain the colorants E171 (titanium dioxide) and E172 (yellow iron oxide) and the 400 mg capsules contain the colorants E171 (titanium dioxide) and E172 (red and yellow iron oxide). The ink used in all capsules contains shellac, E171 (titanium dioxide) and E132 (indigo carmine).
What Neurontin looks like and contents of the pack
Hard capsules
The 100 mg capsules are hard and white, imprinted with "Neurontin 100 mg" and "PD".
The 300 mg capsules are yellow hard and imprinted with "Neurontin 300 mg" and "PD".
The 400 mg capsules are orange hard and imprinted with "Neurontin 400 mg" and "PD".
PVC / PVDC / aluminum blister packs of 20, 30, 50, 60, 84, 90, 98, 100, 200, 500, 1000 capsules.
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NEURONTIN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 100 mg hard capsule contains 100 mg of gabapentin.
Each 300 mg hard capsule contains 300 mg of gabapentin.
Each 400 mg hard capsule contains 400 mg of gabapentin.
Excipients:
Each 100 mg hard capsule contains 13 mg of lactose (as monohydrate).
Each 300 mg hard capsule contains 41 mg of lactose (as monohydrate).
Each 400 mg hard capsule contains 54 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules
Neurontin 100 mg hard capsules: White opaque hard capsule, imprinted with "Neurontin 100 mg" and "PD", and containing a white to off-white powder.
Neurontin 300 mg hard capsules: opaque yellow hard capsule, imprinted with "Neurontin 300 mg" and "PD", and containing a white to off-white powder.
Neurontin 400 mg hard capsules: opaque orange hard capsule imprinted with "Neurontin 400 mg" and "PD", and containing a white to off-white powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Epilepsy
Gabapentin is indicated as adjunct therapy in the treatment of partial seizures in the presence or absence of secondary generalization in adults and children aged 6 years and older (see section 5.1).
Gabapentin is indicated as monotherapy for the treatment of partial seizures in the presence or absence of secondary generalization in adults and adolescents 12 years of age and older.
Treatment of peripheral neuropathic pain
Gabapentin is indicated in adults for the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and post-herpetic neuralgia.
04.2 Posology and method of administration
Oral use.
Gabapentin can be taken with or without food and must be swallowed whole with a sufficient amount of fluid (eg a glass of water).
Table 1 describes the titration scheme for initiating treatment for all indications; This dosing regimen is recommended for both adults and adolescents 12 years of age and older. Instructions on the posology to be used in children under 12 years of age are given in a subsequent sub-chapter of this section.
Discontinuation of gabapentin
In accordance with current clinical practice, if gabapentin treatment is to be discontinued it is recommended that this be done gradually at least over a week regardless of the indication being treated.
Epilepsy
Epilepsy generally requires long-term treatments. The dosage is established by the treating physician on the basis of tolerability and efficacy for the individual patient.
Adults and adolescents:
In clinical studies, the effective dose range was 900 to 3600 mg / day.Treatment can be initiated through dose titration as described in Table 1 or by administering 300 mg three times daily (TID) on the first day of treatment. Thereafter, based on individual patient response and tolerability, the dose may be further increased by 300 mg / day at a time every 2-3 days up to a maximum of 3600 mg / day. Slower titration of gabapentin dosage may be appropriate in some patients. The minimum time to reach the 1800 mg / day dose is one week, for the 2400 mg / day dose it is a total of 2 weeks and for 3600 mg / day it is a total of 3 weeks. Doses up to 4800 mg / day have been well tolerated in long-term open-label clinical studies. The maximum daily dose should be divided into three single administrations and the maximum interval between doses to prevent sudden onset of seizures. it must not exceed 12 hours.
Children aged 6 years or older:
The starting dose should vary between 10 and 15 mg / kg / day and the effective dose is achieved by increasing the titration over a period of approximately three days. The effective dose of gabapentin in children 6 years of age and older is 25-35 mg / kg / day. Doses up to 50 mg / kg / day have been well tolerated in a long-term clinical study. The total daily dose should be divided into three single administrations and the maximum dose interval should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Furthermore, gabapentin can be used in combination with other antiepileptic substances without the risk of altering the plasma concentrations of gabapentin or the serum concentrations of other antiepileptic medicinal products.
Peripheral neuropathic pain
Adults
Therapy can be initiated through dose titration as described in Table 1. Alternatively, the starting dose is 900 mg / day divided into three equal administrations. Thereafter, based on individual patient response and tolerability, the dose may be further increased by 300 mg / day at a time every 2-3 days up to a maximum of 3600 mg / day. Slower titration of gabapentin dosage may be appropriate in some patients. The minimum time to reach the 1800 mg / day dose is one week, for the 2400 mg / day dose it is a total of 2 weeks and for 3600 mg / day it is a total of 3 weeks.
In the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been investigated in clinical trials for treatment periods longer than 5 months. If a patient requires treatment for more than 5 months for peripheral neuropathic pain, the treating physician should evaluate the patient's clinical condition and determine the need for prolongation of treatment.
Instructions for all indications
In patients with poor general health conditions, eg low body weight, organ transplant patients, etc., dose titration should be done more slowly, using lower dosages or longer time intervals between dosage increases.
Use in elderly patients (over 65 years of age)
Dosage adjustment may be required in elderly patients due to age-related decrease in renal function (see Table 2). Somnolence, peripheral edema and asthenia may be more common in elderly patients.
Use in patients with impaired renal function
In patients with impaired renal function and / or in those undergoing hemodialysis, dose adjustment is recommended as described in Table 2. 100 mg gabapentin capsules can be used to follow the dosing recommendations in patients with renal insufficiency.
a The total daily dosage should be administered in three divided doses. Reduced dosages are indicated for patients with impaired renal function (creatinine clearance
b To be administered at a dosage of 300 mg every other day.
c For patients with creatinine clearance
Use in patients undergoing hemodialysis
In hemodialysis patients with anuria who have never been treated with gabapentin, a loading dose of 300-400 mg is recommended, followed by 200-300 mg of gabapentin after each 4-hour hemodialysis session. On hemodialysis free days, gabapentin treatment should not be given.
In patients with renal impairment undergoing hemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations given in Table 2. In addition to the maintenance dose, an additional "200-300 mg dose is recommended after each hemodialysis session. 4 hours.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use
Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs in their various indications. A meta-analysis of randomized trials of anti-epileptic drugs versus placebo also found a small increase in the risk of suicidal ideation and behavior.
The mechanism of this risk has not been established and the available data do not exclude the possibility of an increased risk with gabapentin.
Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered if so. Patients (and caregivers) should be instructed to notify their treating physician if signs of suicidal ideation or behavior emerge.
If a patient develops acute pancreatitis during gabapentin treatment, discontinuation of gabapentin treatment should be considered (see section 4.8).
Although there is no evidence of recurrence of seizures epileptics with gabapentin, abrupt discontinuation of anticonvulsants in epileptic patients may stimulate status epilepticus (see section 4.2).
With gabapentin, as with other antiepileptic medicines, some patients may experience an increased frequency of seizures or the onset of new types of seizures.
As with other antiepileptics, attempts to discontinue antiepileptics given concurrently with gabapentin in patients refractory to treatment with multiple antiepileptic drugs in order to achieve gabapentin monotherapy have a low success rate.
Gabapentin is not considered effective in treating seizures in the presence of primary generalization, such as absences, and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures, including absences.
No systematic studies have been conducted with gabapentin in patients 65 years of age or older. In a double-blind study in patients with neuropathic pain, somnolence, peripheral edema and asthenia occurred in a slightly higher percentage in patients 65 years of age or older than in younger patients. Apart from these data, clinical evaluations in this patient group do not indicate a different safety profile from that observed in younger patients.
The effects of long-term therapy (greater than 36 weeks) on learning, intelligence and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.
Drug rash with eosinophilia and systemic symptoms (DRESS)
Serious, possibly life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptics, including gabapentin (see section 4.8).
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may occur, even if the rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. If an alternative etiology for these signs or symptoms cannot be established, gabapentin treatment should be discontinued.
Laboratory tests
In the semi-quantitative determination of total proteinuria with the dipstick test false positive results can be obtained. It is therefore recommended to verify a positive dipstick test result with methods based on a different analytical principle, such as the Biuret method, turbidimetric or colorimetric binding methods, or to use these alternative methods from the start.
Neurontin hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
In a study in healthy volunteers (N = 12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, the mean gabapentin AUC increased by 44%. compared to when gabapentin was administered without morphine Therefore, patients should be carefully observed for any signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.
No interactions were observed between gabapentin and phenobarbital, phenytoin, valproic acid or carbamazepine.
The pharmacokinetics of gabapentin allo steady-state it is similar in healthy subjects and in patients with epilepsy being treated with these antiepileptic agents.
Concomitant administration of gabapentin and oral contraceptives containing norethindrone and / or ethinylestradiol does not change the overall pharmacokinetics. steady-state of the two components.
Concomitant administration of gabapentin and antacids containing aluminum and magnesium reduces the bioavailability of gabapentin by up to 24%. It is recommended that gabapentin be taken at the earliest two hours after administration of the antacids.
Renal excretion of gabapentin is not affected by probenecid.
The slight reduction in renal excretion of gabapentin observed when co-administered with cimetidine is not expected to be of clinical importance.
04.6 Pregnancy and lactation
Risks generally related to epilepsy and antiepileptic medicinal products
The risk of birth defects increases 2-3 times in the offspring of women treated with an antiepileptic medicine. The most frequently reported defects are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a greater risk of congenital malformations than monotherapy and therefore it is important to use monotherapy whenever possible. Women who are likely to become pregnant or who are of childbearing age should be given specialist advice and the need for antiepileptic treatment should be reassessed when a woman is planning to become pregnant. A sudden interruption of antiepileptic therapy should not be carried out because this can cause the onset of seizures which can have serious consequences for both mother and baby. Developmental delay in children born to epileptic women has rarely been observed. it is possible to distinguish whether the developmental delay is caused by genetic or social factors, by the mother's epilepsy or by antiepileptic treatment.
Risks related to gabapentin
There are no adequate data from the use of gabapentin in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus.
No definitive conclusions can be drawn regarding the possible association between gabapentin and an increased risk of congenital malformations when the drug is taken during pregnancy; this is due to the epilepsy itself and the presence of antiepileptic drugs used concomitantly during the individual pregnancies examined.
Gabapentin is excreted in breast milk. As the effects on the infant during lactation are not known, caution should be exercised when gabapentin is administered to lactating women. Gabapentin should only be used during breastfeeding if the benefits clearly outweigh the risks.
04.7 Effects on ability to drive and use machines
Gabapentin may have "mild or moderate influence on the ability to drive or use machines. Gabapentin acts on the central nervous system and may cause sleepiness, dizziness or other related symptoms. Even if they have been mild or moderate in severity, these side effects may cause be potentially dangerous in patients who drive vehicles or use machines. This is especially true at the start of treatment and after an increase in dosage.
04.8 Undesirable effects
Adverse reactions observed in clinical trials in epilepsy (adjunctive and monotherapy) and neuropathic pain are presented in a unique list below divided by system organ class and frequency very common (≥ 1/10), common ( ≥ 1/100 to ≤ 1/10), uncommon (≥ 1 / 1,000 to
Other reactions reported from post-marketing experience are included with a frequency Not Known (cannot be estimated from the available data) in italics in the list below.
Within each frequency group, undesirable effects are reported in order of decreasing severity.
System organ class Adverse reactions
Infections and infestations
Very common viral infection
Common pneumonia, respiratory infection, urinary tract infection, infection, otitis media.
Disorders of the blood and lymphatic system
Common leukopenia
Not known thrombocytopenia
Disorders of the immune system
Uncommon allergic reactions (e.g. hives)
Not known hypersensitivity syndrome, a systemic reaction with a variable manifestation which may include fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms.
Metabolism and nutrition disorders
Common anorexia, increased appetite
Psychiatric disorders
Common hostility, confusion and emotional instability, depression, anxiety, nervousness, abnormal thinking
Not known hallucinations
Nervous system disorders
Very common somnolence, dizziness, ataxia
Common seizures, hyperkinesia, dysarthria, amnesia, tremors, insomnia, headache, sensations such as paraesthesia, hypoaesthesia, abnormal coordination, nystagmus, increased, decreased or absent reflexes
Uncommon hypokinesia
Not known other movement disorders (eg, choreoathetosis, dyskinesia, dystonia)
Eye disorders
Common vision disturbances such as amblyopia, diplopia
Ear and labyrinth disorders
Common dizziness
Not known tinnitus
Cardiac pathologies
Uncommon palpitations
Vascular pathologies
Common hypertension, vasodilation
Respiratory, thoracic and mediastinal disorders
Common dyspnoea, bronchitis, pharyngitis, cough, rhinitis
Gastrointestinal disorders
Common vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence
Not known pancreatitis
Hepatobiliary disorders
Not known hepatitis, jaundice
Skin and subcutaneous tissue disorders
Common face edema, purpura most often described as bruising following physical trauma, rash, pruritus, acne
Not known Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (see section 4.4)
Musculoskeletal and connective tissue disorders
Common arthralgia, myalgia, back pain, muscle twitching
Not known rhabdomyolysis, myoclonus
Renal and urinary disorders
Not known acute renal failure incontinence
Diseases of the reproductive system and breast
Common impotence
Not known breast hypertrophy, gynecomastia
General disorders and administration site conditions
Very common fatigue, fever
Common peripheral edema, walking disturbances, asthenia, pain, malaise, flu syndrome
Uncommon generalized edema
Not known withdrawal reactions (mostly anxiety, insomnia, nausea, pain, sweating), chest pain. There have been reports of unexplained sudden death for which a causal relationship with gabapentin treatment has not been established.
Diagnostic tests
Common decrease in white blood cells (white blood cell count), weight gain
Uncommon increased liver function indices SGOT (AST), SGPT (ALT) and bilirubin
Not known changes in blood glucose levels in diabetic patients, increased creatine phosphokinase
Injury and poisoning
Common accidental wounds, fractures, abrasions,
Cases of acute pancreatitis have been reported with gabapentin treatment. The causal relationship with gabapentin is unclear (see section 4.4).
In patients undergoing hemodialysis, myopathy and elevated creatine kinase levels due to end stage renal damage have been reported.
Respiratory tract infections, otitis media, seizures and bronchitis have only been reported in clinical trials in children. In addition, aggressive behavior and hyperkinesis were commonly reported in clinical trials in children.
04.9 Overdose
No life-threatening acute toxicity episodes have been observed with gabapentin overdoses up to doses of 49 g. Symptoms of overdose included: dizziness, double vision, slurred speech, somnolence, lethargy and mild diarrhea. All patients recovered fully with supportive care. Reduced absorption of gabapentin with higher doses may limit the "absorption of the drug at the time of overdose and therefore can minimize the toxicity resulting from overdoses.
Overdoses of gabapentin, particularly when associated with the use of other CNS depressant drugs, can lead to coma.
Although gabapentin can be eliminated by hemodialysis, it has been found that this is not necessary based on previous experience. However, in patients with severe renal impairment, hemodialysis may be indicated.
A lethal oral dose of gabapentin was not identified in mice and rats treated with doses up to 8000 mg / kg. Signs of acute toxicity in animals included: ataxia, labored breathing, ptosis, hypoactivity or excitement.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other antiepileptics.
ATC code: N03AX12.
The exact mechanism of action of gabapentin is not known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action differs from that of numerous other active substances that interact with GABAergic synapses such as valproate, barbiturates, benzodiazepines, inhibitors of GABA transaminases, inhibitors of GABA uptake, GABA agonists, and GABA prodrugs. Education in vitro performed with radiolabelled gabapentin identified a novel peptide binding site in rat brain tissues, including the neocortex and hippocampus, which may refer to the anticonvulsant and analgesic activity of gabapentin and its structural derivatives. The gabapentin binding site was identified as alpha2-delta subunits of voltage gated calcium channels.
Gabapentin at clinically relevant concentrations does not bind to other common drugs or brain neurotransmitter receptors including GABAA, GABAB and benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Gabapentin does not interact in vitro with sodium channels thus differentiating from phenytoin and carbamazepine. Gabapentin partially reduces responses to the glutamatergic agonist N-methyl-d-aspartate (NMDA) in some systems in vitro, but only at concentrations above 100 mcM that cannot be reached in vivo. Gabapentin slightly reduces the release in vitro of monoamine neurotransmitters. Administration of gabapentin to rats increases GABA turnover in numerous brain regions in a similar manner to sodium valproate, albeit in different brain regions. The relationship between these different gabapentin activities and anticonvulsant effects has yet to be defined. In animals, gabapentin readily penetrates the brain and prevents seizures caused by maximal electroshock, by seizure substances including inhibitors of GABA synthesis, and in genetic models of seizures.
A clinical study on adjunctive therapy in the treatment of partial seizures in pediatric patients aged 3 to 12 years showed a numerical but not statistically significant difference in the 50% response rate in favor of the gabapentin group compared to to the placebo group. Further post-hoc analyzes of response rates calculated by age did not reveal a statistically significant effect of age, either as a continuous variable or as a dichotomous variable (age groups 3-5 years and 6-12 years).
The data from this further post-hoc analysis are summarized in the table below:
*The population intent-to-treat modified was defined as all patients randomized to study drug who also had evaluable epileptic episode diaries for 28 days during both baseline and double-blind phases.
05.2 Pharmacokinetic properties
Absorption
After oral administration, maximum plasma gabapentin concentrations are observed between the second and third hours. The bioavailability of gabapentin (fraction of the absorbed dose) tends to decrease with increasing dose. The absolute bioavailability of a 300 mg capsule of gabapentin is approximately 60%. Food, including a high-fat diet, does not has a clinically significant effect on gabapentin pharmacokinetics.
The pharmacokinetics of gabapentin are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2 mcg / mL and 20 mcg / mL in clinical studies, these concentrations were not indicative of safety or efficacy. Pharmacokinetic parameters are shown in Table 3.
Table 3
Summary of pharmacokinetic parameters of mean (% CV) gabapentin allo concentrations steady-state after administration every 8 hours
Distribution
Gabapentin is not bound to plasma proteins and has a volume of distribution of 57.7 liters. In epileptic patients, the concentrations of gabapentin in the cerebrospinal fluid (CSF) are approximately 20% of the corresponding plasma concentrations at steady-state. Gabapentin is present in the breast milk of lactating women.
Metabolism
There is no evidence of gabapentin metabolism in humans. Gabapentin does not induce mixed function oxidizing liver enzymes responsible for metabolism of the substance.
Elimination
Gabapentin is eliminated unchanged by the kidney only. The elimination half-life of gabapentin is dose independent and averages 5-7 hours.
In elderly patients and in patients with renal impairment, the plasma clearance of gabapentin is reduced. The elimination constant, plasma clearance and renal clearance of gabapentin are directly proportional to creatinine clearance.
Gabapentin is removed from the plasma by hemodialysis. Dosage adjustments are recommended in patients with impaired renal function or in patients on hemodialysis (see section 4.2).
The pharmacokinetics of gabapentin in children were determined in 50 healthy subjects aged 1 month to 12 years. In general, plasma gabapentin concentrations in children aged> 5 years are comparable to those seen in adults when the drug was administered on a mg / kg basis.
An approximately 30% lower exposure (AUC), lower Cmax and higher clearance per body weight were observed in a pharmacokinetic study of 24 healthy pediatric subjects aged 1 month to 48 months compared to data. reported in children older than 5 years.
Linearity / Non-linearity
The bioavailability of gabapentin (fraction of the absorbed dose) decreases with increasing dose and this confers non-linearity to the pharmacokinetic parameters, including the bioavailability parameter (F), eg Ae%, CL / F, Vd / F. Elimination pharmacokinetics (pharmacokinetic parameters that do not include bioavailability parameters such as CLr and T½) are best described by linear pharmacokinetics. steady-state are predictable from the data relating to single administrations.
05.3 Preclinical safety data
Carcinogenesis
Gabapentin was administered via diet to mice (200, 600, 2000 mg / kg / day) and rats (250, 1000, 2000 mg / kg / day) for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumors was found only in male rats at the highest dose. The maximum plasma drug concentration in rats at 2000 mg / kg / day was 10 times higher than the plasma concentration in rats. "man with 3600 mg / day. Pancreatic acinar cell tumors in male rats have a low degree of malignancy, did not affect survival, did not result in metastasis or invasion of surrounding tissues and were similar to those observed in control animals. The relationship between these pancreatic acinar cell tumors in male rats and the cancer risk in humans is unclear.
Mutagenesis
Gabapentin has no genotoxic potential. It was not mutagenic in standard tests in vitro conducted with bacterial or mammalian cells. Gabapentin did not induce chromosomal structural aberrations in mammalian cells in vitro or in vivo and did not induce micronucleus formation in hamster bone marrow cells.
Impaired fertility
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg / kg (approximately five times the maximum daily human dose on a mg / m2 body surface area basis).
Teratogenesis
Gabapentin did not increase the incidence of malformations compared to controls in the offspring of mice, rats or rabbits with doses respectively up to 50, 30 and 25 times the daily human dose of 3600 mg (four, five or eight, respectively. times the daily dose used in humans on a mg / m2 basis).
Gabapentin caused a delay in the ossification process of the skull, vertebrae, forelimbs and lower limbs in rodents and this is indicative of a delay in fetal growth. These effects occurred in pregnant female mice treated with oral doses of 1000 or 3000 mg / kg / day during organogenesis and in rats treated with doses of 500, 1000 or 2000 mg / kg before and during mating and during gestation. These doses are approximately 1-5 times the human dose of 3600 mg on a mg / m2 basis.
No effects were observed in pregnant female mice treated with 500 mg / kg / day (approximately ½ of the human dose on a mg / m2 basis).
An increase in the incidence of hydroureter and / or hydronephrosis was observed in rats treated with 2000 mg / kg / day in a fertility and general reproduction study, with 1500 mg / kg / day in a teratology study and respectively. 500, 1000 and 2000 mg / kg / day in a perinatal and postnatal study. The significance of these data is unknown, but they have been associated with developmental delay. These doses are approximately 1-5 times the dose used in humans equal to 3600 mg on a mg / m2 basis.
In a teratology study conducted in rabbits, there was an increase in the incidence of post-implantation fetal losses with doses of 60, 300 and 1500 mg / kg / day during organogenesis. These doses correspond to approximately 1 / 4-8 times the daily human dose of 3600 mg on a mg / m2 basis.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Hard capsule
Each hard capsule contains the following inactive ingredients: lactose monohydrate, corn starch and talc.
Operculum: gelatin, purified water and sodium lauryl sulfate.
The 100 mg hard capsules contain the coloring agent E171 (titanium dioxide), the 300 mg hard capsules contain the coloring agents E171 (titanium dioxide) and E172 (yellow iron oxide) and the 400 mg hard capsules contain the coloring agents E171 (titanium dioxide) and E172 (yellow and red iron oxide).
The ink used for all the capsules contains shellac, and the dyes E171 (titanium dioxide) and E132 (indigo carmine).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
PVC / PVDC / aluminum blisters
Packs of 20, 30, 50, 60, 84, 90, 98, 100, 200, 500, 1000 capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l. via Isonzo, 71 - 04100 Latina.
08.0 MARKETING AUTHORIZATION NUMBER
50 capsules of 100 mg: A.I.C. n. 028740013
50 capsules of 300 mg: A.I.C. n. 028740025
30 capsules of 400 mg: A.I.C. n. 028740037
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
100 mg capsules: 18 July 1995/28 May 2007
300 mg capsules: July 18, 1995 / May 28, 2007
400 mg capsules: 18 July 1995/28 May 2007
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 10 June 2013
