In Section 4.4 Special warnings and precautions for use

The following text has been added under Women of childbearing potential:

 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 advice should be given to women who are of childbearing potential regarding 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. Women planning a pregnancy should meet with their specialists to reassess treatment with Zonegran and to consider other therapeutic options.

The following paragraph has been amended:

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.

In Section 4.6 Fertility, pregnancy and lactation

The following text has been added under Women of childbearing potential

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. Women planning a pregnancy should meet with their specialists to reassess treatment with zonisamide and to consider other therapeutic options.

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.

The following changes have been made under Pregnancy

The following paragraph has been deleted

Specialist advice should be given to women who are likely to become pregnant in order to consider the optimal treatment during pregnancy. Women of childbearing potential should be given specialist advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the patient in relation to the benefits before starting treatment. 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.

No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.

New text added

 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.

The text in the following paragraph has been amended

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.

ISection 10. Date of revision of the text has been updated to 01/2018

Addition of text:

Change in text:

From: Women of childbearing potential must use adequate contraception during treatment with Zonegran and for one month after discontinuation (see section 4.6).

Change in text:

From: Women of childbearing potential must use adequate contraception during treatment with Zonegran and for one month after discontinuation.

To: Women of childbearing potential have to use effective contraception during treatment with Zonegran and for one month after discontinuation.

Change in text:

From: There are no adequate data from the use of Zonegran in pregnant women.

Section 4.1: Addition of paediatric indication as adjunctive therapy.

Section 4.2: Addition of paediatric dosing information.

Section 4.4: Addition of warnings and precautions specifically related to the paediatric

Section 4.5: Addition of clarification of co-medication in the paediatric population.

Section 4.8: Addition of paediatric undesirable effects profile and information regarding reporting of suspected adverse reactions.

Section 5.1: Addition of paediatric pivotal study.

Section 10: Date of revision of text amended to 2nd October 2013.

Zonegran SPC

Change in section 4.8 ‘Undesirable effect’ of pruritis from very rare to common; oedema peripheral added as common undesirable effect.

Additional information on special populations in section 4.8:

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

Drug-induced hypersensitivity syndrome and drug rash with eosinophilia and systemic symptoms.

In addition to minor formatting changes, please see below a summary of changes:

Section 2: Qualitative and quantitative composition

The following sentence has been added:

“100mg: Excipients: 0.002 mg of sunset yellow FCF (E110) and 0.147 mg of allura red AC (E129).”

Section 4.2: Posology and method of administration

Children and adolescents

The wording has been amended to read:

“Zonegran is not recommended for use in children below 18 due to insufficient data on safety and efficacy.” 

Section 4.3: Contraindications

The word “zonisamide has been changed to “the active substance”

Section 4.4: Special warnings and precautions for use

In the second paragraph, the word “medications” has been changed to “medicines”

In the fifth and eighth paragraphs, the word “drugs” has been changed to “medicinal products”

Section 4.5: Interaction with other medicinal products and other forms of interaction

In the second paragraph, the word “drugs” has been changed to “medicinal products”

Carbonic anhydrase inhibitors

The wording has been amended to read:

“Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic interaction (see section 4.4).”

In the fifth paragraph, the first mention of the word “drugs” has been changed to “substances” and the second mention to “medicinal products”

Section 4.6: Pregnancy and lactation

In the third paragraph, the word “drug” has been changed to “medicinal product”

Section 4.7: Effects on ability to drive and use machines

The wording has been amended to read:

“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.”

The date of renewal of the authorisation and revision of text has been updated to 21 December 2009

Section 4.4 Special warnings and precautions for use

Addition of the following information:

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 drugs) 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). If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali treatment should be considered.

Section 4.8 Undesirable effects

Addition of 'Renal tubular acidosis' as a 'very rare' metabolism and nutrition disorders.

Section 6.5 - Nature of packaging

The composition of the immediate packaging materials of the finished product is being changed from a PVC/PCTFE/Aluminium to PVC/PVDC/Aluminium foil blister. This section of the SmPC now states:

25 mg:   PVC/PVDC/Aluminium foil blisters, packs of 14, 28, 56 and 84 hard capsules.
50 mg:   PVC/PVDC/Aluminium foil blisters, packs of 14, 28, 56 and 84 hard capsules.
100 mg: PVC/PVDC/aluminium foil blisters, packs of 28, 56, 84, 98 and 196 hard capsules.

Section 10 Date of revision of text

Updated to: July 2009

Section 7: Marketing authorisation

The MA address has been updated to:

Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Herts, AL10 9SN, UK

Section 10: Date of revision of text

The date of revision of text has been updated to March 2009

Addition of the following statement regarding suicide ideation and behaviour:

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 drugs 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.

Section 4.7 - Undesirable effects

Addition of Toxic epidermal necrolysis as a very rare side effect to the skin and subcutaneous tissue disorders section of the undesirable effects.

Section 10 Date of revision of text

Date of revision updated to 02/2009

Zonegran SmPC changes ¨C March 2008

4.4         Special warnings and precautions for use

There has been additional text added to the warning regarding immune based adverse reactions associated with medicinal products containing a sulphonamide:

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.

4.8         Undesirable effects

Addition of information regarding  Zonegran being a benzisoxazole derivative:

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).

Change from > to ¡Ý in the definition of frequencies of adverse event for very common, common, uncommon and rare

There have been the following changes to the adverse event table:

Addition of ecchymosis as a common blood and lymphatic system disorder.

Deletion of insomnia and psychotic disorder as uncommon psychiatric disorders.

Addition of affect lability, anxiety, insomnia, psychotic disorder as common sychiatric Disorders.

 Addition of bradyphrenia, nystagmus, paraesthesia and tremor as common nervous system disorders.

Addition of status epilepticus as a very rare nervous system disorder.

Addition of constipation and dyspepsia as common gastrointestinal disorders.

Addition of nephrolithiasis as a common renal and urinary disorder.

Deletion of nephrolithiasis as an uncommon renal and urinary disorder.

Renal failure insufficiency changed to renal failure as a very rare renal and urinary disorders.

Addition of fatigue and influenza-like illness as common general disorders and administration site conditions.

Addition of decreased bicarbonate as a very common investigations adverse reaction.

Addition of blood creatinine increased as a very rare investigations adverse reaction.

Addition of information on special populations:

Additional information on special populations:

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).

10.   DATE OF REVISION OF THE TEXT  

Date of revision of text changed to:

31 March 08

Section 4.4 - Special warnings and precautions for use

Minor textual changes

Section 4.5 - Interaction with other medicinal products and other forms interactions

Effect of Zonegran on cytochrome P450 enzymes

2B6, 2C8, added

New information on interaction studies of zonisamide with drugs that are P-gp substrates:

P-gp substrate  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 drugs 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 drugs which are P-gp substrates (e.g. digoxin, quinidine).

Section 2 - QUALITATIVE AND QUANTITATIVE COMPOSITION

Changed to: For a full list of excipients, see section 6.1.

Section 4.4 - Special warnings and precautions for use

The following statement: “Serious rashes have occurred in association with Zonegran therapy, including cases of Stevens‑Johnson syndrome” has been moved from the 4th paragraph to the start of this section in bold type in a box. Also the word ‘isolated’ has been removed.

Section 4.6- Pregnancy and lactation

This section now reads: (new information in bold)

Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician, and only if the potential benefit is considered to justify the risk to the foetus…

Specialist advice should be given to women who are likely to become pregnant in order to consider the optimal treatment during pregnancy. Women of childbearing potential should be given specialist advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the patient in relation to the benefits before starting treatment.  The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic medication. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy.

Women of childbearing potential must use adequate contraception during treatment with Zonegran, and for one month after discontinuation.

Section 4.8- Undesirable effects

“Suicidal ideation” has moved from “very rare” to “uncommon”

The following have been added to the “uncommon” section:

“Anger”, “Aggression” & “Suicidal attempt”

“Abnormal pain” is now “abdominal pain”

Section 6 - PHARMACEUTICAL PARTICULARS

Section 6.5 - Nature and contents of container:

An 84 pack size has been added to each strength

The title has changed to the following:

Section 6.6 - Special precautions for disposal

Section 10: Date of revision of the text

This has changed to the 29^th March 2007