Eisai Ltd

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

Additional wording in bold, deleted text crossed out:

Children and Adolescents (512-18 years): Limited data indicate that pharmacokinetics in children and adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those observed in adults, after adjustment for bodyweight.

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

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.

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

Changes to the Zonegran Summary of Product Characteristics (SmPC) February 2009

Section 4.4 - Special warnings and precautions for use’

Zonegran SmPC changes – 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 ≥ 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 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