Active ingredients: Zonisamide
Zonegran 25 mg, 50 mg and 100 mg hard capsules
Why is Zonegran used? What is it for?
Zonegran contains the active ingredient zonisamide and is used as an antiepileptic drug.
Zonegran is used to treat seizures affecting part of the brain (partial seizures), which may or may not be followed by a seizure affecting the whole brain (secondary generalization).
Zonegran can be used:
- on its own for the treatment of seizures in adults
- with other antiepileptic medicines for the treatment of seizures in adults, adolescents and children from 6 years of age.
Contraindications When Zonegran should not be used
Do not take Zonegran
- if you are allergic to zonisamide or any of the other ingredients of this medicine (listed in section 6),
- if you are allergic to other sulfonamide medicines, for example: sulfonamide antibiotics, thiazide diuretics and sulphonylurea-based diabetes medicines.
Precautions for use What you need to know before taking Zonegran
Zonegran belongs to a group of medicines (sulfonamides) which can cause severe allergic reactions, severe skin rashes and blood disorders, which very rarely can lead to death (see section 4. Possible side effects).
Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.
Talk to your doctor or pharmacist before taking Zonegran if:
- are under the age of 12 because you may be at increased risk for reduced sweating, heat stroke, pneumonia and liver problems. If you are under 6, Zonegran is not recommended for you.
- you are elderly, because your dose of Zonegran may need to be adjusted and because you may be more likely to develop an allergic reaction, severe rash, swelling of the feet and legs and itching when taking Zonegran (see section 4 Possible side effects).
- suffer from liver problems as your dose of Zonegran may need to be adjusted.
- have eye problems, such as glaucoma.
- suffer from kidney problems as your dose of Zonegran may need to be adjusted.
- have suffered from kidney stones in the past, as there may be an increased risk of them developing again. To reduce the risk of kidney stones, drink enough water.
- lives or is on vacation in a place where the weather is warm. Zonegran can cause a decrease in sweating, which could cause a rise in body temperature. To reduce the risk of an excessive rise in body temperature, drink enough water and try to stay cool.
- are underweight or have lost a lot of weight, as Zonegran may cause you to lose weight further. Tell your doctor, as this may need to be observed. If any of these apply to you, tell your doctor before taking Zonegran.
Children and adolescents
Talk to your doctor about the following risks:
Prevention of heat and dehydration in children
Zonegran can reduce your child's sweating levels and lead to heat and if your child is not properly treated, it can cause brain damage and death. Children are most at risk, especially in very hot weather.
While his son hires Zonegran:
- Keep your child cool, especially in very hot weather
- Your child must avoid any strenuous physical activity, especially when it is very hot
- Give your child plenty of cold water to drink
- Your child must not take these medicines:
- carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).
If your child's skin is very hot but sweating is low or absent, if your child feels confused, if he has muscle cramps, or his heartbeat or breathing becomes faster:
- Take your child to a cool, shady place
- You wipe your child's skin with a sponge soaked in cool (but not cold) water
- Give your child cold water to drink
- Contact your doctor urgently.
Body weight: Check your child's weight every month and see your doctor as soon as possible if your child's weight is not gaining enough. Zonegran is not recommended for children who are underweight or with a poor appetite, and should be used with caution in children weighing less than 20 kg.
Increased levels of acids in the blood and kidney stones: reduce these risks by ensuring that your child drinks enough water and is not taking other medicines that can lead to kidney stones (see Other medicines). Your doctor will monitor the bicarbonate levels in your child's blood and kidneys (see also section 4).
Do not give this medicine to children under 6 years of age, as in this age group it is not known whether the possible benefits outweigh the risks.
Interactions Which drugs or foods may change the effect of Zonegran
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
- Zonegran should be used with caution in adults, when they are also taking medicines that can cause kidney stones, such as topiramate or acetazolamide. In children, this combination is not recommended.
- Zonegran may increase the levels of some medicines, such as digoxin and quinidine, in the blood; therefore, their dose may need to be reduced.
- Other medicines, such as phenytoin, carbamazepine, phenobarbital and rifampicin, can reduce the levels of Zonegran in the blood. This may require an adjustment of the Zonegran dosage.
Zonegran with food and drink
Zonegran can be taken with or without food.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are a woman of childbearing potential, you must use adequate contraception while taking Zonegran and for one month after stopping it.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
You should only take Zonegran during pregnancy if instructed by your doctor. Research has shown an increased risk of birth defects in children of women treated with antiepileptic drugs.
Do not breastfeed when taking Zonegran or for one month after you stop taking Zonegran.
There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals have shown changes in fertility parameters.
Driving and using machines
Zonegran may affect your concentration and your ability to react / respond and may make you feel drowsy, particularly at the start of treatment or after increasing the dose. Take special care while driving or using machines if these effects occur after taking Zonegran.
Important information regarding some of the components of Zonegran
Zonegran contains sunset yellow FCF (E110) and allura red AC (E129) Zonegran hard capsules of 100 mg contain a yellow dye called sunset yellow FCF (E110) and a red dye called allura red AC (E129), which can cause reactions allergic.
Dose, Method and Time of Administration How to use Zonegran: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Recommended dose for adults
When taking Zonegran alone:
- The starting dose is 100 mg, taken once a day.
- This dose can be increased in increments of up to 100 mg at one to two week intervals.
- The recommended dose is 300 mg once a day.
When taking Zonegran with other antiepileptic medicines:
- The starting dose is 50 mg per day, taken in two equal doses of 25 mg.
- This dose may be increased up to 100 mg at one to two week intervals.
- The recommended daily dose is between 300 mg and 500 mg.
- Some people respond to lower dosages. The dose may be increased more slowly in case of side effects, elderly people or kidney or liver problems.
Use in children (6 to 11 years) and adolescents (12 to 17 years) with a body weight of at least 20 kg:
- The starting dose is 1 mg for every kg of body weight, taken once a day.
- This dose can be increased by 1 mg for every kg of body weight, at intervals of one to two weeks.
- The recommended daily dose is 6 to 8 mg for a child weighing up to 55 kg or 300 to 500 mg for a child weighing over 55 kg (whichever is the lowest), taken once daily. .
Example: A child weighing 25 kg must take 25 mg once a day for the first week, and then increase the daily dose by 25 mg at the beginning of each week, until a daily dose of between 150 and 200 mg is reached.
If you have the impression that the effect of Zonegran is too strong or too weak, talk to your doctor or pharmacist.
- Zonegran capsules should be swallowed whole with water.
- Do not chew the capsules.
- Zonegran can be taken once or twice a day, according to the doctor's instructions.
- If you take Zonegran twice a day, half of the daily dose should be taken in the morning and half in the evening.
If you forget to take Zonegran
- If you forget to take a dose, don't worry and take the next dose when it's time.
- Do not take a double dose to make up for a forgotten dose.
If you stop taking Zonegran
- Zonegran is intended to be taken as a long-term medicine. Do not reduce the dose or stop taking this medicine unless your doctor tells you to.
- If your doctor advises you to stop taking Zonegran, the dose will be reduced gradually to reduce the risk of further seizures.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Zonegran
If it is possible that you have taken more Zonegran than you should, immediately inform your carer (relative or friend), doctor or pharmacist, or contact the emergency department of the nearest hospital, taking the medicinal. Taking too much dose may cause drowsiness and loss of consciousness. You may also experience nausea, stomach pain, muscle twitching, eye movements, feeling faint, slow heart rate, and decreased breathing and kidney function. Don't try to drive.
Side Effects What are the side effects of Zonegran
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Zonegran belongs to a group of medicines (sulfonamides) which can cause severe allergic reactions, severe skin rashes and blood disorders, which very rarely can lead to death.
Contact your doctor immediately if:
- have difficulty breathing, swelling of the face, lips or tongue or a severe rash, as these symptoms could indicate a severe allergic reaction.
- have signs of heat - elevated body temperature but with little or no sweating, rapid heartbeats and rapid breathing, muscle cramps and confusion.
- have thoughts of harming or killing yourself. A small number of people treated with antiepileptics such as Zonegran have had thoughts of harming or killing themselves.
- have aching muscles or a feeling of weakness, as this could be a sign of abnormal muscle breakdown which could lead to kidney problems.
- you have sudden pain in your back or stomach, have pains in urinating or notice blood in your urine, as this could be a sign of kidney stones.
- visual problems, such as eye pain or blurred vision, occur during treatment with Zonegran.
Contact your doctor as soon as possible if:
- an 'unexplained rash appears, as it may develop into a more severe' rash or peeling.
- you feel unusually tired or feverish, have a sore throat, swollen glands or if you notice that you bruise easily, as this could mean a 'change in blood.
- signs of increased acid levels in the blood appear - headache, sleepiness, shortness of breath and loss of appetite. This may require monitoring or treatment by your doctor. Your doctor may decide to stop taking Zonegran. The most common side effects of Zonegran are mild. They occur during the first month of treatment and usually subside with continued treatment. In children 6 to 17 years of age, side effects were consistent with those described below, with the following exceptions: pneumonia, dehydration, decreased sweating (common) and liver enzyme abnormalities (uncommon).
Very common side effects (may affect more than 1 in 10 people):
- agitation, irritability, confusion, depression.
- poor muscle coordination, dizziness, poor memory, sleepiness, double vision.
- loss of appetite, reduction in the levels of bicarbonate in the blood (a substance that prevents the blood from becoming acidic).
Common side effects (may affect up to 1 in 10 people):
- trouble sleeping, strange or unusual thoughts, anxiety or emotionality.
- slowed thoughts, loss of concentration, speech abnormalities, abnormal sensation on the skin (tingling), tremor, involuntary eye movements.
- kidney stones.
- rash, itching, allergic reactions, fever, fatigue, flu symptoms, hair loss.
- bruising (small bruise on the skin caused by leaking blood from a ruptured blood vessel).
- weight loss, nausea, indigestion, stomach pains, diarrhea (loose stools), constipation.
- swelling of the feet and legs.
Uncommon side effects (may affect up to 1 in 100 people):
- anger, aggression, suicidal thoughts, suicide attempt.
- He retched.
- inflammation of the gallbladder, gallstones.
- urinary stones.
- lung infection / inflammation, urinary tract infections.
- low levels of potassium in the blood, convulsions / seizures.
Very rare side effects (may affect up to 1 in 10,000 people):
- hallucinations, memory loss, coma, neuroleptic malignant syndrome (inability to move, sweating, fever, incontinence), status epilepticus (prolonged or repeated seizures).
- breathing problems, wheezing, inflammation of the lungs.
- inflammation of the pancreas (severe pain in the stomach or back).
- liver problems, kidney failure, increased levels of creatinine (a waste product normally eliminated by the kidneys) in the blood.
- severe skin rash or peeling (you may feel unwell at the same time or you may have a fever).
- abnormal muscle degeneration (you may feel muscle pain or weakness), which could lead to kidney problems.
- swollen glands, blood changes (reduction in the number of blood cells, which can increase the likelihood of infections and make you look pale, feeling tired and feverish and bruising).
- decreased sweating, excessive increase in body temperature.
- glaucoma, which is a blockage of fluid inside the eye that causes an increase in eye pressure. Eye pain, blurred vision or decreased vision may occur, which may be signs of glaucoma.
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. You can also report side effects directly via the national reporting system listed in Annex V.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 blister and carton after EXP / EXP. The expiry date refers to the last day of that month.
Do not store above 30 ° C.
Do not use this medicine if you notice damage to the capsules, blister or carton or visible signs of deterioration in the medicine. Return the pack to your pharmacist.
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.
Other information
What Zonegran contains
The active substance in Zonegran is zonisamide.
Zonegran 25 mg hard capsules contain 25 mg of zonisamide. Zonegran 50 mg hard capsules contain 50 mg of zonisamide. Zonegran 100 mg hard capsules contain 100 mg of zonisamide.
- The other ingredients present in the capsule are microcrystalline cellulose, hydrogenated vegetable oil and sodium lauryl sulfate.
- The capsule shell contains gelatin, titanium dioxide (E171), shellac, propylene glycol, potassium hydroxide, black iron oxide (E172). In addition, the 100 mg capsule shell contains sunset yellow FCF (E110) and red allura (E129).
See section 2 for important information on the excipients: sunset yellow FCF (E110) and allura red AC (E129).
What Zonegran looks like and contents of the pack
- Zonegran 25 mg hard capsules have a white opaque body and white opaque cap, imprinted with a logo and "ZONEGRAN 25" in black.
- Zonegran 50 mg hard capsules have a white opaque body and gray opaque cap, imprinted with a logo and "ZONEGRAN 50" in black.
- Zonegran 100 mg hard capsules have a white opaque body and a red opaque cap, imprinted with a logo and "ZONEGRAN 100" in black.
Zonegran hard capsules are packed in blisters, supplied in packs containing:
- 25 mg: 14, 28, 56 and 84 capsules
- 50 mg: 14, 28, 56 and 84 capsules
- 100 mg: 28, 56, 84, 98 and 196 capsules.
Not all pack sizes may be available.
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
ZONEGRAN 25 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 25 mg of zonisamide.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule.
White opaque body and white opaque head, embossed with a logo and "ZONEGRAN 25" in black.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Zonegran is referred to as:
• monotherapy in the treatment of partial seizures, with or without secondary generalization, in adults with newly diagnosed epilepsy (see section 5.1);
• adjunctive therapy in the treatment of partial seizures, with or without secondary generalization, in adults, adolescents and children from 6 years of age.
04.2 Posology and method of administration
Posology - Adults
Increase in dose and maintenance dose
Zonegran can be taken on its own or added to existing therapy in adults. The dose should be titrated according to the clinical effect. Recommended dose increases and maintenance doses are shown in Table 1. Some patients, especially those not taking CYP3A4 inducing agents, may respond to lower doses.
Suspension
If it is necessary to discontinue treatment with Zonegran, it should be withdrawn gradually (see section 4.4). In clinical trials in adult patients, a dose reduction of 100 mg at weekly intervals was applied, with concomitant dose adjustments of the other antiepileptic drugs (if necessary).
Table 1. Adults - Recommended dose escalation and maintenance regimen
General dosing recommendations for Zonegran in special patient populations
Pediatric population (from 6 years of age) Dose increase and maintenance dose
Zonegran should be added to existing therapy in pediatric patients from 6 years of age. The dose should be titrated according to the clinical effect. Recommended dose increases and maintenance doses are shown in Table 2. Some patients, especially those not taking CYP3A4 inducing agents, may respond to lower doses.
Physicians should bring the Patient Warning Section (in the package leaflet) to the attention of pediatric patients and their parents / caregivers regarding the prevention of heatstroke (see section 4.4: Pediatric population) .
Table 2. Pediatric population (from 6 years of age) - Increase in dose and regimen of maintenance recommended
Note:
to. To ensure maintenance of an adequate therapeutic dose, it is necessary to monitor the child's body weight and adjust the dose at each change, up to a body weight of 55kg. The dosage is 6-8mg / kg / day up to a maximum dose of 500mg / day.
The safety and efficacy of Zonegran in children aged less than 6 years, or weighing less than 20 kg, have not yet been established.
There are limited data in clinical studies in patients weighing less than 20 kg. Therefore, children from 6 years of age and weighing less than 20 kg should be treated with caution.
Suspension
If treatment with Zonegran needs to be discontinued, it should be withdrawn gradually (see section 4.4). In clinical trials in pediatric patients, tapering of the dose was completed by reducing the dose at weekly intervals in approximately 2 mg / kg decreases (i.e. consistent with the schedule shown in Table 3).
Table 3. Pediatric population (from 6 years of age) - Gradual reduction program of the recommended dose
Note:
* All doses are intended once a day.
Senior citizens
Caution should be exercised when initiating treatment with Zonegran in elderly patients, as there is limited information on the use of Zonegran in these patients. Prescribing physicians should also take into account the safety profile of Zonegran (see section 4.8).
Patients with impaired renal function
Caution should be exercised when treating patients with impaired renal function with Zonegran as there is limited information for such patients and slower titration may be required. Since zonisamide and its metabolites are excreted renally, treatment should be discontinued in patients who develop acute renal failure or where a sustained, clinically significant increase in serum creatinine is observed.
In subjects with impaired renal function, renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance
Patients with impaired hepatic function
Use in patients with hepatic impairment has not been studied. Use in patients with severe hepatic impairment is therefore not recommended. Caution should be exercised when treating patients with mild to moderate hepatic impairment in whom slower titration of Zonegran may be required.
Method of administration
Zonegran hard capsules are for oral use.
Effect of food
Zonegran can be taken with or without food (see section 5.2).
04.3 Contraindications
Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to sulfonamides.
04.4 Special warnings and appropriate precautions for use
Rash of an unexplained nature
Serious rash, including cases of Stevens-Johnson syndrome, can occur in association with Zonegran therapy.
The possibility of discontinuing the administration of Zonegran in patients who develop rash of an unexplained nature should be considered. All patients who develop rash while taking Zonegran should be carefully observed, with particular attention to patients being given concomitant antiepileptic drugs that could independently induce skin rash.
Seizures at the time of withdrawal
In accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy should be done through a gradual dose decrease in order to reduce the possibility of seizures upon withdrawal. There are insufficient data on discontinuation. of other concomitant antiepileptic drugs, once seizure control has been achieved with Zonegran given as adjunct, in order to achieve monotherapy with Zonegran Concomitant antiepileptic medicinal products should therefore be withdrawn with caution.
Reactions to sulfonamides
Zonegran is a benzisoxazole derivative, which contains a sulfonamide group. Serious immune-based adverse reactions associated with medicinal products containing a sulfonamide group include rash, allergic reaction and major haematological abnormalities, including aplastic anemia, which are very rarely fatal.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and leukocytosis have been reported. There is insufficient information to assess the possible relationship between dose / duration of treatment and these events.
Suicidal ideation and behavior
Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of placebo-controlled randomized clinical trials of antiepileptic medicinal products also demonstrated a slightly increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonegran.
Patients should therefore be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered if necessary. Patients (and their carers) should be advised of the need to consult their physician if signs of suicidal ideation or behavior emerge.
Kidney stones
In some patients, particularly those with a predisposition to developing nephrolithiasis, there may be an increased risk of kidney stones and related signs and symptoms, such as renal colic, renal pain or flank pain. Nephrolithiasis can cause chronic kidney damage. Risk factors for nephrolithiasis include previous stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors can be a reliable predictor of the onset of stones during treatment with zonisamide. Patients taking other therapies at risk of developing nephrolithiasis may be at increased risk. Increased fluid intake and diuresis it can help reduce the risk of kidney stone formation, particularly in people with predisposing risk factors.
Metabolic acidosis
Treatment with Zonegran is associated with hyperchloraemic metabolic acidosis without anion gap (i.e. a decrease in serum bicarbonate below the normal range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal loss of bicarbonate due to the inhibitory effect of zonisamide on carbonic anhydrase. This electrolyte imbalance has been observed with the use of Zonegran in placebo-controlled clinical trials and in the post-marketing period. Zonisamide-induced metabolic acidosis generally occurs at initiation of treatment, although cases may occur at any time during the course of treatment. The reduction in bicarbonate levels is usually mild to moderate (mean reduction of approximately 3.5 mEq / l at daily doses of 300 mg in adults); more severe reductions may occur rarely in patients. acidosis (such as kidney disease, severe breathing disorders, status epilepticus, diarrhea, surgery, ketogenic diet or medications) may potentiate the bicarbonate-lowering effects of zonisamide.
The risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients. Serum bicarbonate levels should be appropriately assessed and monitored in patients treated with zonisamide who have clinical conditions predisposing to an increased risk of acidosis, in patients at increased risk of developing adverse reactions of metabolic acidosis and in patients with symptoms Indicative of metabolic acidosis In case of development and persistence of metabolic acidosis, consideration should be given to reducing the dose or discontinuing Zonegran (with tapering of the drug), as this may lead to the development of osteopenia.
If a decision is made to continue administration of Zonegran despite persistent acidosis, alkali treatment should be considered.
Zonegran should be used with caution in adult patients receiving concomitant treatment with carbonic anhydrase inhibitors, such as topiramate or acetazolamide, as there are insufficient data to rule out a pharmacodynamic interaction (see also section 4.4 Pediatric population and section 4.5).
Heat stroke
Cases of decreased sweating and elevated body temperature have been reported mainly in pediatric patients (see section 4.4 Pediatric population for full warning).
Caution should be exercised in adults when prescribing Zonegran concomitantly with other medicinal products that predispose patients to heat related ailments; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see also section 4.4 Pediatric population).
Pancreatitis
In patients taking Zonegran who develop clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels be monitored. If there is evidence of pancreatitis, in the absence of any other obvious cause, it is recommended that discontinuation of Zonegran be considered and appropriate treatment instituted.
Rhabdomyolysis
In patients taking Zonegran who develop severe muscle pain and / or weakness, with or without fever, assessment of markers of muscle damage, including serum creatine phosphokinase and aldolase levels, is recommended. In the event of an increase in these parameters, in the absence of another obvious cause, such as trauma or grand mal seizure, it is recommended that discontinuation of Zonegran be considered and appropriate treatment instituted.
Women of childbearing age
Women of childbearing potential must use adequate contraception during treatment with Zonegran and for one month after its discontinuation (see section 4.6). Physicians treating patients with Zonegran should seek to ensure that appropriate contraception is used and to assess, based on clinical judgment, whether oral contraceptives, or dosages of oral contraceptive components, are appropriate for the clinical condition. of the individual patient.
Body weight
Zonegran can cause weight loss. A dietary supplement or increased dietary intake may be considered if the patient exhibits weight loss or is underweight during therapy. If significant unwanted weight loss occurs, discontinuation of Zonegran should be considered. Weight loss is potentially more severe in children (see section 4.4 Pediatric population).
Pediatric population
The above warnings and precautions also apply to adolescent and pediatric patients. The following warnings and concerns are more relevant to pediatric and adolescent patients.
Heat stroke and dehydration
Prevention of hyperthermia and dehydration in children
Zonegran can reduce sweating levels in children and lead to hyperthermia, and if the child is not properly treated, it can cause brain damage and death. Children are most at risk, especially when the outside temperature is high.
While a child takes Zonegran:
The child must keep cool, especially in very high temperatures
The child should avoid any strenuous physical activity, especially in the case of high temperatures
The child should drink plenty of cold water
The child should not take these medicines:
carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).
IN THE PRESENCE OF ANY OF THE FOLLOWING SITUATIONS, THE CHILD NEEDS URGENT MEDICAL ATTENTION:
The skin is very hot but there is little or no sweating, or the child feels confused, or muscle cramps or his heartbeat or breathing is rapid.
Take the baby to a cool, shady place
Keep the baby's skin cool with some water
Give the baby cold water to drink
Cases of decreased sweating and elevated body temperature have been reported mainly in pediatric patients. In some cases, heat stroke was diagnosed which required hospital treatment. Heatstroke which required hospital treatment and resulted in death was reported. Most of the reports occurred during periods of heat. Physicians should discuss with patients or caregivers the potential severity of heatstroke, the situations in which they may occur, and what steps to take in the event of signs or symptoms. , or caregivers, should be warned of the need to maintain hydration and avoid exposure to excessive temperatures and strenuous physical exertion, depending on the patient's condition. Prescribers should bring pediatric patients' attention and care. of their parents / caregivers the advice given in the Package Leaflet regarding the prevention of heatstroke and hyperthermia in children. In the event of signs or symptoms of dehydration, oligohydrosis or high body temperatures, consider the "interruption of Zonegran.
Zonegran should not be used concomitantly in pediatric patients with other medicinal products that predispose patients to heat related complaints; these include carbonic anhydrase inhibitors and drugs with anticholinergic activity.
Body weight
Weight loss, resulting in deterioration of general condition and failure to take antiepileptic drugs, has been linked to a fatal outcome (see section 4.8). Zonegran is not recommended in pediatric patients who are underweight (definition in accordance with WHO categories for age-adjusted BMI) or inappetent.
The incidence of weight reduction is consistent across age groups (see section 4.8). However, given the potential severity of body weight loss in children, weight monitoring is required in this population. Consider administration of dietary supplements or " increased food intake if patient weight does not increase congruently with growth charts, otherwise Zonegran should be discontinued.
There are limited data from clinical studies in patients with body weight less than 20 kg. Therefore, children from 6 years of age with a body weight below 20 kg should be treated with caution. The long-term effect of weight loss on growth and development in the pediatric population is unknown.
Metabolic acidosis
The risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in pediatric and adolescent patients. Appropriate assessment and monitoring of serum bicarbonate levels in this population is required (see section 4.4 - Metabolic acidosis for full warning; see section 4.8 for incidence of low bicarbonate levels). Not known. "long-term effect of low bicarbonate levels on growth and development.
Zonegran should not be used concomitantly in pediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.5).
Kidney stones
Stones have occurred in pediatric patients (see section 4.4 Kidney stones for full warning). Some patients, particularly those with a predisposition to nephrolithiasis, may have an increased risk of kidney stones and related signs and symptoms such as renal colic, pain kidney or flank pain. Nephrolithiasis can cause chronic kidney damage. Risk factors for nephrolithiasis include previous stone formation, family history of nephrolithiasis, and hypercalciuria. None of these risk factors can be a reliable predictor of stone onset during treatment with zonisamide.
Increased fluid intake and urinary excretion may help reduce the risk of stones, particularly in patients with predisposing risk factors. Renal ultrasound should be performed at the physician's discretion. If kidney stones are found, discontinue treatment with Zonegran.
Hepatic dysfunction
Elevated levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate amino transferase (AST), gamma-glutamyltransferase (GGT) and bilirubin have been observed in pediatric and adolescent patients, with no consistent pattern in observations of values above the upper limit of normal. . However, if a hepatic event is suspected, evaluate liver function and consider discontinuing Zonegran.
Cognition
Cognitive impairment in epileptic patients has been associated with the underlying disease and / or administration of antiepileptic therapies. In a placebo-controlled study of the administration of zonisamide to pediatric and adolescent patients, the proportion of patients with cognitive impairment was numerically higher in the zonisamide group compared to the placebo group.
04.5 Interactions with other medicinal products and other forms of interaction
Effect of Zonegran on cytochrome P450 enzymes
In vitro studies using human liver microsomes have shown no or poor pharmacokinetics (pharmacokinetics of other medicinal products via cytochrome P450 mediated mechanisms, as demonstrated in vivo for carbamazepine, phenytoin, ethinyl estradiol and desipramine.
Potential for Zonegran to affect other medicinal products
Antiepileptic medicines
In epileptic patients, administration to the steady-state of Zonegran did not produce clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin or sodium valproate.
Oral contraceptives
In clinical studies in healthy subjects, steady-state administration of Zonegran did not affect the serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Carbonic anhydrase inhibitors
Zonegran should be used with caution in adult patients receiving concomitant treatment with carbonic anhydrase inhibitors, such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction (see section 4.4).
Zonegran should not be used concomitantly in pediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.4 Pediatric population).
Substrates of P-gp
An in vitro study demonstrates that zonisamide is a weak inhibitor of P-gp (MDR1) with an CI50 of 267 μmol / l and there is theoretical potential for zonisamide to affect the pharmacokinetics of substances that are substrates of P-gp. Caution is advised when starting or stopping treatment with zonisamide or when changing the dose of zonisamide in patients who are also taking medicinal products that are P-gp substrates (e.g. digoxin, quinidine).
Potential drug interactions affecting Zonegran
In clinical studies, concomitant administration of lamotrigine had no obvious effect on the pharmacokinetics of zonisamide. The combination of Zonegran with other medicinal products that already present a risk of urolithiasis may potentiate this risk, therefore concomitant administration of such medicinal products should be avoided.
Zonisamide is metabolised in part by CYP3A4 (reductive cleavage) and also by N-acetyl-transferase and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes can affect the pharmacokinetics of zonisamide:
Enzyme induction: Zonisamide exposure is lower in epileptic patients receiving CYP3A4 inducing agents, such as phenytoin, carbamazepine and phenobarbital. These effects are unlikely to be clinically significant if Zonegran is added to existing therapy; however, variations in concentrations of zonisamide if, concomitantly, antiepileptics or other CYP3A4 inducing medicinal products are withdrawn or introduced, or their dosage is adjusted; in this case, a dose adjustment of Zonegran may be required. Rifampicin is a potent inducer of CYP3A4. If co-administration is required, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed.
• CYP3A4 inhibition: Based on clinical data, it appears that known inhibitors of CYP3A4, specific and non-specific, have no clinically relevant effect on the pharmacokinetic exposure parameters of zonisamide. Steady-state administration of ketoconazole (400 mg / day) or cimetidine (1200 mg / day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide administered to healthy subjects. Therefore, no dosage modification of Zonegran should be required when co-administered with known CYP3A4 inhibitors.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use effective contraception during treatment with Zonegran and for one month after its discontinuation.
Pregnancy
There are no adequate data from the use of zonisamide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Zonegran should not be used during pregnancy unless it is absolutely necessary, in the opinion of the doctor, and only if the potential benefit is believed to justify the risk to the fetus. The need for antiepileptic treatment should be considered in patients planning pregnancy. If Zonegran is prescribed, careful monitoring is recommended.
Specialist advice should be given to women likely to become pregnant in order to consider the optimal treatment during pregnancy. Women of childbearing potential should be given specialist advice regarding the possible effects of Zonegran on the fetus and the risks versus benefits should be discussed with the patient before starting treatment. The risk of birth defects was increased by 2 to 3 times in the children of mothers treated with antiepileptic drugs. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple therapy with antiepileptic medicinal products may be associated with a higher risk of congenital malformations than monotherapy.
Antiepileptic therapy should not be stopped suddenly, as this could lead to recurrence of the seizures, which could have serious consequences for the mother and baby.
Feeding time
Zonisamide is excreted in breast milk; the concentration in breast milk is similar to that in maternal plasma. A decision must be made whether to discontinue breastfeeding or to discontinue / abstain from Zonegran therapy. Due to the long retention time of zonisamide in the body, breastfeeding should not be resumed until one month after completion of Zonegran therapy.
Fertility
There are no clinical data available on the effects of zonisamide on human fertility. Animal studies have shown changes in fertility parameters (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. However, as some patients may experience drowsiness or difficulty concentrating, particularly in the first phase of treatment or after a dose increase, patients should be informed of the need to exercise caution during activities that require a high degree of vigilance, eg driving vehicles or using machines.
04.8 Undesirable effects
Summary of the safety profile
Zonegran has been administered to over 1,200 patients in clinical trials, more than 400 of whom have taken Zonegran for at least 1 year. In addition, there is extensive post-marketing experience with zonisamide in Japan since 1989 and in the United States since 2000.
It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulfonamide group. Serious immune-based adverse reactions associated with medicinal products containing a sulfonamide group include rash, allergic reaction and major haematological abnormalities, including aplastic anemia, which very rarely can be fatal (see section 4.4).
The most common adverse reactions in controlled adjunct therapy studies were somnolence, dizziness and anorexia. The most common adverse reactions observed in a randomized, controlled monotherapy clinical trial comparing zonisamide with prolonged-release carbamazepine were decreased bicarbonate levels, decreased appetite and weight loss. The incidence of marked abnormal reduction in serum bicarbonate levels (a reduction to less than
17 mEq / l and more than 5 mEq / l) was 3.8%. The incidence of marked weight loss of 20% or more was 0.7%.
Tabular list of adverse reactions
Adverse reactions associated with Zonegran, obtained from clinical studies and post-marketing surveillance, are summarized in the tables below. The frequency is reported according to the following scheme:
very common ≥1 / 10
common ≥1 / 100,
uncommon ≥1 / 1,000,
rare ≥1 / 10,000,
very rare
not known frequency cannot be estimated from the available data
Table 4 Adverse reactions associated with Zonegran, obtained from clinical therapy studies additional and post-marketing surveillance
In addition, there have been isolated cases of sudden unexplained death in epileptic patients (SUDEP) taking Zonegran.
Table 5 Adverse Reactions in a Randomized Controlled Monotherapy Clinical Study, which compared zonisamide with prolonged-release carbamazepine
† MedDRA version 13.1
Additional information on special populations
Senior citizens
A "pooled analysis of safety data on 95 elderly subjects showed a relatively higher reporting rate of peripheral edema and pruritus than in the adult population."
Review of post-marketing data indicates that, compared to the general population, patients 65 years of age and older report the following events more frequently: Stevens-Johnson syndrome (SJS) and drug hypersensitivity syndrome (DIHS) .
Pediatric population
The adverse event profile of zonisamide in pediatric patients aged 6-17 years in placebo-controlled clinical trials was consistent with that in adults. Among 465 subjects in the pediatric safety database (including 67 additional subjects from the extension of the controlled clinical study), there were 7 deaths (1.5%; 14.6 / 1000 person-years): 2 cases of status epilepticus, one of which correlated with severe weight loss (10% within 3 months) in an underweight subject, and subsequent failure to take drug therapy; 1 case of head trauma / hematoma, and 4 deaths in subjects with previous functional neurological deficits, for various causes (2 cases of sepsis induced by pneumonia / organ failure, 1 SUDEP and 1 head injury). A total of 70.4 % of pediatric patients who received ZNS in the controlled study, or its open label extension, had at least one treatment-emergent bicarbonate measurement of less than 22 mmol / L. The persistence of low bicarbonate levels was also long (median 188 days).
A "pooled analysis of safety data on 420 pediatric subjects (183 subjects aged 6 to 11 years, and 237 subjects aged 12 to 16 years, with an average duration of exposure of approximately 12 months), showed a relatively higher reporting rate of pneumonia, dehydration, decreased sweating, abnormal liver function tests, otitis media, pharyngitis, sinusitis and upper respiratory tract infection, cough, epistaxis and rhinitis, abdominal pain, vomiting, rash, eczema and fever, compared to the adult population (particularly in subjects less than 12 years of age), and also low incidence of amnesia, increased creatinine, lymphadenopathy and thrombocytopenia. The incidence of weight loss of 10% or more was 10.7% (see section 4.4). In some cases of weight loss, there was a delay in transition to the next Tanner stage and in bone maturation.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
There have been cases of accidental and intentional overdose in adult and pediatric patients. In some cases, overdose was asymptomatic, particularly where emesis or gastric lavage was timely. In other cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, decreased renal function, hypotension and respiratory depression. A very high plasma concentration of 100.1 mcg / ml of zonisamide was recorded approximately 31 hours after a patient took Zonegran and clonazepam; the patient entered a coma and presented with respiratory depression, but regained consciousness. five days later and had no sequelae.
Treatment
There is no specific antidote available for Zonegran overdose. Following suspected recent overdose, stomach emptying by gastric lavage or induction of emesis may be indicated, with the usual precautions to protect the respiratory tract. General supportive care is indicated, including frequent monitoring of vital functions and careful observation. Zonisamide has a long elimination half-life, so its effects may persist over time. Although it has not been formally studied for the treatment of overdose, the "hemodialysis reduced plasma concentrations of zonisamide in a patient with impaired renal function and can be considered as an overdose treatment if clinically indicated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, other antiepileptics, ATC code: N03AX15
Zonisamide is a benzisoxazole derivative. It is an antiepileptic drug with weak carbonic anhydrase activity in vitro. It is chemically unrelated to other antiepileptic agents.
Mechanism of action
The mechanism of action of zonisamide is not fully understood, but it appears to act on voltage-gated sodium and calcium channels, thus hindering synchronized neuronal firing, reducing the spread of epileptic discharges and hindering subsequent epileptic activity. Zonisamide has also a modulatory effect on GABA-mediated neuronal inhibition.
Pharmacodynamic effects
The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species with induced or spontaneous seizures, and zonisamide appears to act as a broad spectrum antiepileptic in these models. Zonisamide prevents maximal electroshock seizures and limits the spread of seizures. seizures, including the propagation of seizures from the cortex to subcortical structures and suppresses the activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, however, zonisamide preferably acts on seizures originating from the cortex.
Clinical efficacy and safety
Monotherapy in partial seizures, with or without secondary generalization
The efficacy of zonisamide monotherapy was established in a non-inferiority, double-blind, parallel-group comparison with prolonged-release (RP) carbamazepine in 583 adult subjects with newly diagnosed partial seizures, with or without tonic seizures. secondary generalized clones. Subjects were randomized to treatment with carbamazepine and zonisamide, for a duration of up to 24 months, depending on response. Subjects were titrated to the initial target dose of 600 mg of carbamazepine or 300 mg of zonisamide. Subjects experiencing a seizure were titrated to the next target dose, ie 800 mg carbamazepine or 400 mg zonisamide. Subjects experiencing a "further seizure were titrated to the maximum target dose of 1200 mg carbamazepine or 500 mg of zonisamide. Seizure-free subjects for 26 weeks at the target dose level continued on this dose for an additional 26 weeks.
The main outcomes of this study are presented in the table below:
Table 6 Efficacy results for monotherapy study 310
PP = Population By Protocol; ITT = Intent To Treat Population
* Primary endpoint
Adjunctive therapy in the treatment of partial seizures, with or without secondary generalization, in adults
In adults, efficacy was demonstrated with Zonegran in 4 double-blind, placebo-controlled studies lasting up to 24 weeks, administered once or twice daily. These studies demonstrate that the median reduction in seizure frequency partial is related to the dose of Zonegran, with sustained efficacy at doses of 300-500 mg per day.
Pediatric population
Adjunctive therapy in the treatment of partial seizures, with or without secondary generalization, in adolescent and pediatric patients (from 6 years of age)
In pediatric patients (from 6 years of age), the efficacy of zonisamide was demonstrated in a 24-week, double-blind, placebo-controlled study which included 207 subjects. A reduction of 50% or Greater than baseline seizure frequency over the 12-week stable dose period was found in 50% of zonisamide-treated subjects and 31% of placebo-treated subjects.
The specific safety issues that emerged in the pediatric studies were: decreased appetite and weight loss, reduced bicarbonate levels, increased risk of kidney stones and dehydration. All these effects, and more specifically weight loss, can have pathological implications for growth. and in body development, and can cause a general deterioration of health conditions Overall, long-term data on growth and development are limited.
05.2 Pharmacokinetic properties
Absorption
Zonisamide is absorbed almost completely after oral administration, typically reaching peak serum or plasma concentrations within 2-5 hours of administration. First pass metabolism is believed to be negligible. Absolute bioavailability is estimated to be approximately 100%. Oral bioavailability is not affected by food, although peak plasma and serum concentrations may be delayed.
Zonisamide AUC and Cmax values increased almost linearly after a single dose, over the dose range of 100-800 mg, and after multiple doses over the dose range of 100-400 mg once daily. The increase at steady state was slightly greater than expected by dose, possibly due to saturable binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater than expected accumulation occurs relative to single administration. .
Distribution
Zonisamide is 40-50% bound to human plasma proteins while studies in vitro have shown that the presence of various antiepileptic drugs (such as phenytoin, phenobarbital, carbamazepine and sodium valproate) has no influence on this. The apparent volume of distribution is approximately 1.1 - 1.7 L / kg in adults, indicating that zonisamide is widely distributed into tissues. The ratio of erythrocytes to plasma is about 15 at low concentrations and about 3 at higher concentrations.
Biotransformation
Zonisamide is metabolised primarily by reductive cleavage of the benzisoxazole ring of the parent drug by CYP3A4 to form 2-sulfamoylacetylphenol (SMAP) and also by N-acetylation. Parent drug and SMAP may also be glucuronidated.
metabolites, which were not detected in plasma, lack anticonvulsant activity. There is no evidence that zonisamide induces its own metabolism.
Elimination
The apparent clearance of zonisamide at steady state after oral administration is approximately 0.70 l / h and the terminal elimination half-life is approximately 60 hours, in the absence of CYP3A4 inducers. The elimination half-life is independent of dose and not affected by repeated administration. The fluctuation in serum or plasma concentrations over a dose interval is low (
Linearity / Non-linearity
Exposure to zonisamide increases over time until steady state is reached within approximately 8 weeks. When comparing the same dose level, subjects of higher body weight appear to have lower steady state serum concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and gender, after adjustment for the effects of body weight, have no apparent effect on zonisamide exposure in epileptic patients during steady state dosing. No dose adjustment is required for any antiepileptics, including CYP3A4 inducers.
Pharmacokinetic / pharmacodynamic relationship
Zonisamide reduces the mean seizure frequency over 28 days, and this reduction is proportional (log-linear) to the mean concentration of zonisamide.
Special patient groups
In people with impaired renal function, renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance
Patients with impaired liver function: The pharmacokinetics of zonisamide in patients with impaired hepatic function have not been adequately studied.
Senior citizens: No clinically significant differences in pharmacokinetics were observed between young (aged 21 to 40 years) and elderly (65 to 75 years) subjects.
Children and adolescents (5-18 years): Limited data indicate that the pharmacokinetics in children and adolescents at steady state doses of 1, 7 or 12 mg / kg per day, in divided doses, are similar to that observed in adults after adjustment for body weight.
05.3 Preclinical safety data
Results not observed in clinical studies, but seen in dogs at exposure levels similar to clinical use, were hepatic changes (enlargement, dark brown coloration, slight hepatocyte volume increase with concentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with an increase in metabolism.
Zonisamide was not genotoxic and has no carcinogenic potential.
Zonisamide caused developmental abnormalities in mice, rats and dogs and was embryolethal in monkeys when administered during the period of organogenesis at zonisamide dosage and maternal plasma levels similar to or below therapeutic levels in humans.
In a repeat-dose toxicity study in juvenile rats, with exposure levels similar to those seen in pediatric patients at the maximum recommended dose, weight reductions and changes in histopathology and clinical pathology parameters were observed in the kidney, as well as behavioral disturbances. Alterations of histopathology and clinical pathology parameters affecting the kidneys have been considered correlated to the inhibition of carbonic anhydrase by zonisanide. Effects at this dose were reversible during the recovery period. At higher doses (2-3 times the systemic exposure, compared to the therapeutic exposure), the effects on renal histopathology were more severe and partially reversible. Most of the adverse effects observed in juvenile rats were similar to those found in studies. repeat dose toxicity for zonisamide in adult rats, however hyaline droplet genesis in renal tubules and transactional hyperplasia were observed only in the juvenile rat study. At this higher dose. Juvenile rats exhibited decreased relative parameters. growth, learning and development These effects were thought to be likely related to weight loss and the potent pharmacological effects of zonisamide at the maximum tolerated dose.
In rats, reductions in the number of corpora lutea and implantation sites were observed at exposure levels equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a reduction in the number of live fetuses were observed with exposure levels three times higher.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents
Microcrystalline cellulose
Hydrogenated vegetable oil
Sodium lauryl sulfate
Capsule shell
Jelly
Titanium dioxide (E171)
Shellac
Propylene glycol
Potassium hydroxide
Black iron oxide (E172)
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 14, 28, 56 and 84 hard capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Eisai Limited
European Knowledge Center
Mosquito Way
Hatfield
Hertfordshire AL10 9SN United Kingdom
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/307/001
EU / 1/04/307/005
EU / 1/04/307/002
EU / 1/04/307/013
036959017
036959029
036959056
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 10/03/2005
Date of the last renewal: 10/03/2010
10.0 DATE OF REVISION OF THE TEXT
D.CCE December 2014
