Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Amdipharm Limited, 3 Burlington Road, Dublin 4, D04 RD68, Ireland
Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to sulphonamides.
Zonegran contains Hydrogenated vegetable oil (from soyabean). Patients must not take this medicinal product if they are allergic to peanut or soya.
Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.
Consideration must be given to discontinuing Zonegran in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonegran must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes.
In accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy must be accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are insufficient data for the withdrawal of concomitant antiepileptic medicines once seizure control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with Zonegran. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution.
Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances, including aplastic anaemia, which very rarely can be fatal.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in adult and paediatric patients receiving zonisamide. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, and ocular hyperaemia (redness) and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms may occur within hours to weeks of initiating therapy. Treatment includes discontinuation of zonisamide, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss. Caution should be used when treating patients with history of eye disorders with zonisamide.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonegran.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment. In addition, patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors.
Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide- induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may be additive to the bicarbonate lowering effects of zonisamide.
The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonegran (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop. If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali treatment should be considered.
Zonegran should be used with caution in adult patients being treated concomitantly 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 Paediatric population and section 4.5).
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see also section 4.4 Paediatric population).
In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered and appropriate treatment initiated.
In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation be considered and appropriate treatment initiated.
Women of childbearing potential must use effective contraception during treatment with Zonegran and for one month after discontinuation (see section 4.6). Zonegran must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist medical advice should be given to women treated with zonisamide who are of childbearing potential. The woman should be fully informed of and understand the possible effects of Zonegran on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Before the initiation of treatment with Zonegran in a woman of childbearing potential, pregnancy testing should be considered. Women planning a pregnancy should meet with their specialists to reassess treatment with Zonegran and to consider other therapeutic options prior to conception and before contraception is discontinued. Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant and is taking Zonegran. Physicians treating patients with Zonegran should ensure that patients are fully informed about the need to use appropriate effective contraception, and should use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based on the individual patient’s clinical situation.
Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered. Weight loss is potentially more serious in children (see section 4.4. Paediatric population).
The warnings and precautions mentioned above are also applicable to adolescent and paediatric patients. The warnings and precautions mentioned below are more relevant to paediatric and adolescent patients.
Zonegran can cause children to sweat less and overheat and if the child is not treated this can lead to brain damage and death. Children are most at risk especially in hot weather.
When a child is taking Zonegran:
IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL ATTENTION:
The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, or the child’s heartbeat or breathing become rapid.
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Heat stroke requiring hospital treatment and leading to death has been reported. Most reports occurred during periods of warm weather. Physicians should discuss with patients and their carers the potential seriousness of heat stroke, situations in which it might arise, as well as action to take in the event of any signs or symptoms. Patients or their carers must be warned to take care to maintain hydration and avoid exposure to excessive temperatures and strenuous physical exercise depending on the condition of the patient. Prescribers should draw the attention of paediatric patients and their parent/ carers to the advice in the Packaging Leaflet on preventing heat stroke and overheating in children as provided. In the event of signs or symptoms of dehydration, oligohydrosis, or elevated body temperature, discontinuation of Zonegran should be considered.
Zonegran should not be used as co-medication in paediatric patients with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric patients who are underweight (definition in accordance with the WHO age adjusted BMI categories) or have a decreased appetite.
The incidence of decreased body weight is consistent across age groups (see section 4.8); however, given the potential seriousness of weight loss in children, weight should be monitored in this population. A dietary supplement or increased food intake should be considered if the patient is failing to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued.
There are limited data from clinical studies in patients with a body weight of less than 20 kg. Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated with caution. The long term effect of weight loss in the paediatric population on growth and development is unknown.
The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in paediatric and adolescent patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in this population (see section 4.4 – Metabolic acidosis for full warning; see section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on growth and development is unknown.
Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.5).
Kidney stones have occurred in paediatric patients (see section 4.4 Kidney stones for full warning). Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment.
Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the physician. In the event kidney stones are detected, Zonegran should be discontinued.
Increased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) and bilirubin have occurred in paediatric and adolescent patients, without any consistent pattern in the observations of values above the upper limit of normal. Nevertheless, if a hepatic event is suspected, liver function should be evaluated and discontinuation of Zonegran should be considered.
Cognitive impairment in patients affected by epilepsy has been associated with the underlying pathology and/or the administration of anti-epileptic treatment. In a zonisamide placebo-controlled study conducted in paediatric and adolescent patients, the proportion of patients with impaired cognition was numerically greater in the zonisamide group compared with the placebo group.
In vitro studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations. Therefore, Zonegran is not expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine in vivo.
In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Zonegran should be used with caution in adult patients treated concomitantly 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 as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.4 Paediatric population).
An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of 267 μmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics of substances which are P-gp substrates. Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving medicinal products which are P-gp substrates (e.g. digoxin, quinidine).
In clinical studies co-administration of lamotrigine had no apparent effect on zonisamide pharmacokinetics. The combination of Zonegran with other medicinal products that may lead to urolithiasis may enhance the risk of developing kidney stones; therefore the concomitant administration of such medicinal products should be avoided.
Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide:
Enzyme induction: Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing anti-epileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed.
CYP3A4 inhibition: Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors.
Interaction studies have only been performed in adults.
Women of childbearing potential must use effective contraception during treatment with Zonegran, and for one month after discontinuation.
Zonegran must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist medical advice should be given to women treated with zonisamide who are of childbearing potential. The woman should be fully informed of and understand the possible effects of Zonegran on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with zonisamide. Women planning a pregnancy should meet with their specialists to reassess treatment with zonisamide and to consider other therapeutic options prior to conception and before contraception is discontinued.
As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic medicinal product therapy may be associated with a higher risk of congenital malformations than monotherapy.
There are limited data from the use of Zonegran in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). In humans the potential risk of major congenital malformations and neurodevelopmental disorders is unknown.
Data from a registry study suggest an increase in the proportion of babies born at a low birth weight (LBW), pre-term or small for gestational age (SGA). These increases are from about 5% to 8% for LBW, from about 8% to 10% for pre-term birth and from about 7% to 12% for SGA, all compared with mothers treated with lamotrigine monotherapy.
Zonegran must not be used during pregnancy unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. If Zonegran is prescribed during pregnancy, patients should be fully informed of the potential harm to the foetus and use of the minimal effective dose is advised along with careful monitoring.
Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed until one month after Zonegran therapy is completed.
There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals have shown changes in fertility parameters (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. However, given that some patients may experience drowsiness or difficulty with concentration, particularly early in treatment or after a dose increase, patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g., driving or operating machines.
Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom received Zonegran for at least 1 year. In addition there has been extensive post-marketing experience with zonisamide in Japan since 1989 and in the USA since 2000.
It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal (see section 4.4).
The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. The most common adverse reactions in a randomised, controlled monotherapy trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, decreased appetite, and decreased weight. The incidence of markedly abnormally low serum bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of marked decreases in weight of 20% or more was 0.7%.
Adverse reactions associated with Zonegran obtained from clinical studies and post-marketing surveillance are tabulated below. The frequencies are arranged according to the following scheme:
very common ≥1/10
common ≥1/100 to <1/10
uncommon ≥1/1,000 to <1/100
rare ≥1/10,000 to <1/1,000
very rare <1/10,000
not known cannot be estimated from the available data
Table 4. Adverse reactions associated with Zonegran obtained from adjunctive use clinical studies and post-marketing surveillance:
| System Organ Class (MedDRA terminology) | Very Common | Common | Uncommon | Very Rare |
|---|---|---|---|---|
| Infections and infestation | Pneumonia Urinary tract infection | |||
| Blood and lymphatic system disorders | Ecchymosis | Agranulocytosis Aplastic anaemia Leucocytosis Leucopoenia Lymphadenopathy Pancytopenia, Thrombocytopenia | ||
| Immune system disorders | Hypersensitivity | Drug-induced hypersensitivity syndrome Drug rash with eosinophilia and systemic symptoms | ||
| Metabolism and nutrition disorders | Anorexia | Hypokalaemia | Metabolic acidosis Renal tubular acidosis | |
| Psychiatric Disorders | Agitation Irritability Confusional state Depression | Affect lability Anxiety Insomnia Psychotic disorder | Anger Aggression Suicidal ideation Suicide attempt | Hallucination |
| Nervous system disorders | Ataxia Dizziness Memory impairment Somnolence | Bradyphrenia Disturbance in attention Nystagmus Paraesthesia Speech disorder Tremor | Convulsion | Amnesia Coma Grand mal seizure Myasthenic syndrome Neuroleptic malignant syndrome Status epilepticus |
| Eye disorders | Diplopia | Angle closure glaucoma Eye pain Myopia Vision blurred Visual acuity reduced | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea Pneumonia aspiration Respiratory disorder Hypersensitivity-type Pneumonitis | |||
| Gastrointestinal disorders | Abdominal pain Constipation Diarrhoea Dyspepsia Nausea | Vomiting | Pancreatitis | |
| Hepatobiliary disorders | Cholecystitis Cholelithiasis | Hepatocellular damage | ||
| Skin and subcutaneous tissue disorders | Rash Pruritus Alopecia | Anhidrosis Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis | ||
| Musculoskeletal and connective tissue disorders | Rhabdomyolysis | |||
| Renal and urinary disorders | Nephrolithiasis | Calculus urinary | Hydronephrosis Renal failure Urine abnormality | |
| General disorders and administration site conditions | Fatigue Influenza-like illness Pyrexia Oedema peripheral | |||
| Investigations | Decreased bicarbonate | Weight decreased | Blood creatine phosphokinase increased Blood creatinine increased Blood urea increased Liver function tests abnormal | |
| Injury, poisoning and procedural complications | Heat stroke |
In addition there have been isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP) receiving Zonegran.
Table 5. Adverse reactions in a randomised, controlled monotherapy trial comparing zonisamide with carbamazepine prolonged release:
| System Organ Class (MedDRA terminology†) | Very Common | Common | Uncommon |
|---|---|---|---|
| Infections and infestation | Urinary tract infection Pneumonia | ||
| Blood and lymphatic disorders | Leukopenia Thrombocytopenia | ||
| Metabolism and nutrition disorders | Decreased appetite | Hypokalaemia | |
| Psychiatric Disorders | Agitation Depression Insomnia Mood swings Anxiety | Confusional state Acute psychosis Aggression Suicidal ideation Hallucination | |
| Nervous system disorders | Ataxia Dizziness Memory impairment Somnolence Bradyphrenia Disturbance in attention Paraesthesia | Nystagmus Speech disorder Tremor Convulsion | |
| Eye disorders | Diplopia | ||
| Respiratory, thoracic and mediastinal disorders | Respiratory disorder | ||
| Gastrointestinal disorders | Constipation Diarrhoea Dyspepsia Nausea Vomiting | Abdominal pain | |
| Hepatobiliary disorders | Cholecystitis acute | ||
| Skin and subcutaneous tissue disorders | Rash | Pruritus Ecchymosis | |
| General disorders and administration site conditions | Fatigue Pyrexia Irritability | ||
| Investigations | Decreased bicarbonate | Weight decreased Blood creatinine phosphokinase increased Alanine aminotransferase increased Aspartate aminotransferase increased | Urine analysis abnormal |
† MedDRA version 13.1
A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting frequency of oedema peripheral and pruritus compared to the adult population.
Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug Induced Hypersensitivity syndrome (DIHS).
The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety database (including a further 67 subjects from the extension phase of the controlled clinical trial) there were 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related to severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to take medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP and 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled study or its open label extension had at least one treatment-emergent bicarbonate measurement below 22 mmol/L. The duration of low bicarbonate measurements was also long (median 188 days).
A pooled analysis of safety data on 420 paediatric subjects (183 subjects aged 6 to 11 years, and 237 subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has shown a relatively higher reporting frequency 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 and eczema, and fever compared to the adult population (particularly in subjects aged below 12 years) and, at a low incidence, amnesia, creatinine increased, lymphadenopathy, and thrombocytopenia. The incidence of a decrease in body weight of 10% or more was 10.7% (see section 4.4). In some cases of weight decrease there was a delay in transition to the next Tanner stage and in bone maturation.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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 listed in Appendix V.
Not applicable.
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