Change to section 4 - possible side effects

Change to section 6 - date of revision

PRAC - Drug reaction with eosinophilia and systemic symptoms (DRESS)

Changes to MA Holder and Date of Revision following a MA Transfer

Changes to sections 4.4 special warnings and precautions for use, Section 4.8 undesirable effects  and Section 10 – Date of revision of the text following approval of PSUSA/00002886/201707

SPC Change Details: In section 4.4, updates on “Opportunistic infections and reactivation of infections” and “HBV” have been added. In section 4.8, uncommon side effects for “Infections and infestations” and “Endocrine disorders” have been added.

Section 4.8 Undesirable effects has been amended as follows:

Post-marketing experience:
Under System Organ Class 'Hepatobiliary disorders' all ADRs have had frequency realignment:
'liver enzymes elevations' has moved from unknown to common
'hyperbilirubinemia, cholestasis, hepatitis, hepatic injury, hepatic failure' have moved from unknown to uncommon.

Contact details for reporting suspected adverse reactions has been updated as follows:

HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 4.4 Special warnings and precautions for use

-        This section has been updated to include information on severe liver injuries including those with fatal outcome (hepatocellular injury; hepatocellular failure) and the recommendation of carrying out a liver function test prior and depending on the length of treatment during treatment with temozolomide.

Section 4.8 - Undesirable Effects

-        The following frequency groupings have been added for this section-  Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000).

We have received favorable CHMP opinion for a type II variation EMEA/H/C/0229/II/62 (to add information regarding pulmonary fibrosis to the SPC and PIL). The official date of adoption is 16-Jan-2013.

The changes made to the SPC are as follows:

Pneumocystis jirovecii pneumonia replaces Pneumocystis carinii pneumonia

Added to section 4.4:  Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

Added to section 4.8: Cases of interstitial pneumonitis/pneumonitis, pulmonary fibrosis and fatal respiratory failure have been reported very rarely.

Section 4.8 – Now includes text on reported cases of hepatotoxicity including elevations of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis.

Changed to:

Post -Marketing Experience:

Antineoplastic agents, and notably alkylating agents, have been associated with a potential risk of myelodysplastic syndrome (MDS) and secondary malignancies, including leukemia.Very rare cases of MDS and secondary malignancies, including myeloid leukemia have been reported in patients treated with regimens that included Temodal. Prolonged pancytopenia, which may result in aplastic anaemia has been reported very rarely.  Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely.

Cases of interstitial pneumonitis/pneumonitis have been reported very rarely.

Section 10 - date of revision of text updated 

Section 4.3

Changed from:

Temodal is contraindicated in women who are pregnant or breast feeding (see section 4.6).

To:

Temodal is contraindicated in women who are pregnant (see section 4.6).

Section 4.6, Lactation, changed from:

It is not known whether temozolomide is excreted in human milk; thus, Temodal must not be used by women who are breast-feeding.

To:

It is not known whether temozolomide is excreted in human milk; thus, breast-feeding must be discontinued while receiving treatment with Temodal.

The following has also been added to this section:

Male fertility and contraception

Temozolomide can have genotoxic effects. Therefore, men being treated with temozolomide are advised not to father a child during up to 6 months after treatment and to seek advice on cryoconservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with temozolomide.

Section 4.8, Table 5

Blood and lymphatic system disorders: changed to include “grade 3-4” in respect of thrombocytompenia

Section 10 – date of revision of text updated

Section 1

The following strengths have been added – 140mg & 180mg

Section 2

Changed from:

Each Temodal capsule contains 5 mg, 20 mg, 100 mg or 250 mg temozolomide.

Excipient:     5mg contains 132.8 mg of anhydrous lactose.

Excipient:   20mg contains 182.2 mg of anhydrous lactose.

Excipient: 100mg contains 175.7 mg of anhydrous lactose.

Excipient: 250mg contains 154.3 mg of anhydrous lactose.

Change to:

Each capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg temozolomide.

Excipient:     5 mg contains 132.8 mg of anhydrous lactose.

                   20 mg contains 182.2 mg of anhydrous lactose.

                 100 mg contains 175.7 mg of anhydrous lactose.

                 140 mg contains 246 mg of anhydrous lactose.

                 180 mg contains 316.3 mg of anhydrous lactose.

                 250 mg contains 154.3 mg of anhydrous lactose.

Section 3

Changed from:

Hard capsule

The 5mg hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink.

The 20mg hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink.

The 100mg hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink.

The 250mg hard capsules have an opaque white body and cap and are imprinted with black ink.

Changed to:

Hard capsule

The 5 mg hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink.  The cap is imprinted with “Temodal”.  The body is imprinted with “5 mg”, the Schering-Plough logo and two stripes.

The 20 mg hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink.  The cap is imprinted with “Temodal”.  The body is imprinted with “20 mg”, the Schering-Plough logo and two stripes.

The 100 mg hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink.  The cap is imprinted with “Temodal”.  The body is imprinted with “100 mg”, the Schering-Plough logo and two stripes.

The 140 mg hard capsules have an opaque white body, a blue cap, and are imprinted with black ink.

The cap is imprinted with “Temodal”.  The body is imprinted with “140 mg”, the Schering-Plough logo and two stripes.

The 180 mg hard capsules have an opaque white body, an opaque orange cap, and are imprinted with black ink.  The cap is imprinted with “Temodal”.  The body is imprinted with “180 mg”, the Schering-Plough logo and two stripes.

The 250 mg hard capsules have an opaque white body and cap and are imprinted with black ink.

The cap is imprinted with “Temodal”.  The body is imprinted with “250 mg”, the Schering-Plough logo and two stripes.

Section 4.1

Changed from:

Temodal capsules are indicated for the treatment of patients with:

-                 newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment

-                 malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

Changed to:

Temodal is indicated for the treatment of patients with:

-                 newly diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment

-                 malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.

Section 4.2

“Concomitant phase” section, all references to “Temodal” changed to “temozolomide”

Table 1:  heading “(TMZ)” added at end of heading

              “TMZ = temozolomide; CTC = Common Toxicity Criteria.” Removed from end of table

Table 3:  “TMZ = temozolomide; CTC = Common Toxicity Criteria.” Removed from end of table

Penultimate paragraph of section 4.2 changed from:

Temodal capsules must be swallowed whole with a glass of water and must not be opened or chewed. The prescribed dose should be administered using the minimum number of capsules possible.

Changed to:

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

Section 4.4

Paragraph 1, second sentence, “pneumocystis carinii pneumonia” changed to “PCP”

Section headed: Patients with recurrent or progressive malignant glioma:, the following sentence has been removed:

This medicinal product contains lactose; thus, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Section headed: Paediatric use: second sentence changed from:

Experience in older children is very limited (see section 4.2)

Changed to:

Experience in older children and adolescents is very limited (see section 4.2)

The following paragraph has been added at the end of Section 4.4:

Excipients

This medicinal product contains lactose; thus, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicines.

Section 4.5

The last word of paragraph 5 of this section has been changed from “medications” to “medicinal products”

Section 4.8

The following has been added at the start of Section 4.8:

In patients treated with temozolomide, whether in combination with radiotherapy for newly diagnosed glioblastoma multiforme, or monotherapy following radiotherapy for newly diagnosed glioblastoma multiforme, or alone in patients with recurrent or progressive glioma, the very common adverse reactions are similar as follows: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly diagnosed glioblastoma multiforme patients receiving temozolomide concurrent with radiotherapy and also as monotherapy, and commonly in recurrent glioma. Most of the haematologic parameters, as expected, were reported commonly or very commonly in both tables (4 and 5), with frequency of grade 3-4 laboratory findings to follow each table, below.

Under Table 4 the following sentence has been added: “Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.”

Within Table 4 side effects have been updated.

In the first paragraph after Table 4, “Temodal” has been changed to “temozolomide”.

Under Table 5 the following sentence has been added: “Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.”

Within Table 5 side effects have been updated.

Section 6.1

Changed from:

Capsule shells contain:

5mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate

yellow iron oxide (E 172),

indigotin (E 132),

20mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate,

yellow iron oxide (E 172)

100mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate,

red iron oxide (E172).

250mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate

and are imprinted with blackl ink which contains:

shellac,

propylene glycol,

water,

ammonium hydroxide,

potassium hydroxide

black iron oxide (E 172).

Changed to:

Capsule shells contain:

5 mg:

gelatine,

titanium dioxide (E 171),

sodium lauryl sulphate

yellow iron oxide (E 172),

indigo carmine (E 132),

20 mg:

gelatine,

titanium dioxide (E 171),

sodium lauryl sulphate,

yellow iron oxide (E 172)

100 mg:

gelatine,

titanium dioxide (E 171),

sodium lauryl sulphate,

red iron oxide (E172)

140 mg:

gelatine,

titanium dioxide (E 171),

sodium lauryl sulphate,

indigo carmine (E 132)

180 mg:

gelatine,

titanium dioxide (E 171),

sodium lauryl sulphate,

yellow iron oxide (E 172)

red iron oxide (E 172)

250 mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate

and are imprinted with black pharmaceutical ink which contains:

shellac,

propylene glycol,

purified water,

ammonium hydroxide,

potassium hydroxide

black iron oxide (E 172).

Section 6.5

The word “caps” has been changed to “closures”

Section 6.6

The following paragraph has been added to this section:

Any unused product or waste material should be disposed of in accordance with local requirements.”

Section 8

The following has been added:

Temodal 140 mg Capsules       :        EU/1/98/096/009-10

Temodal 180 mg Capsules       :        EU/1/98/096/011-12

Section 10

Date of revision of text updated.

Section 2

Changed from:

Each Temodal capsule contains 5 mg, 20 mg, 100 mg or 250 mg temozolomide.

For excipients, see 6.1.

To:

Each Temodal capsule contains 5 mg, 20 mg, 100 mg or 250 mg temozolomide.

Excipient:     5mg contains 132.8 mg of anhydrous lactose.

Excipient:   20mg contains 182.2 mg of anhydrous lactose.

Excipient: 100mg contains 175.7 mg of anhydrous lactose.

Excipient: 250mg contains 154.3 mg of anhydrous lactose.

For a full list of excipients, see section 6.1.

Section 3

Changed from:

Hard capsule

The hard capsules are white, opaque and imprinted with a specific colour imprinting ink that is unique for each strength.

To:

Hard capsule

The 5mg hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink.

The 20mg hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink.

The 100mg hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink.

The 250mg hard capsules have an opaque white body and cap and are imprinted with black ink.

SECTION 4.2

Section headed Paediatric patients the following sentence has been added at the end of this section:

“There is no clinical experience with use of Temodal in children under the age of 3 years. Experience in older children is very limited (see section 4.4).”

SECTION 4.3

First sentence changed from:

“Temodal is contraindicated in patients who have a history of hypersensitivity to its components or to dacarbazine (DTIC).”

To:

“Hypersensitivity to the active substance, to any of the excipients or to dacarbazine (DTIC).”

SECTION 4.5

The following statement has been added at the beginning of the first paragraph:

“Interaction studies have only been performed in adults”

SECTION 4.7

The following statement has been added at the beginning of the paragraph:

“No studies on the effects on the ability to drive and use machines have been performed.”

SECTION 4.8

The following paragraph has been added before the final paragraph:

“In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169  male subjects for whom nadir neutrophil counts were available and 110 female and 174  male subjects for whom nadir platelet counts were available.  There were higher rates of Grade 4 neutropenia (ANC < 500 cells/µl), 12 % versus 5 %, and thrombocytopenia (< 20,000 cells/µl), 9 % versus 3 %, in women vs. men in the first cycle of therapy. In a 400  subject recurrent glioma data set, Grade 4 neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288  subjects with newly diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.”

The final paragraph has the following sentence added to the end:

“Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely.”

SECTION 6.1

Changed from:

The capsule contains anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate, tartaric acid, stearic acid.  Capsule shells contain gelatine, titanium dioxide, sodium lauryl sulphate and are imprinted with pharmaceutical ink which contains:

5mg - green print – pharmaceutical grade shellac, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172) and indigotin (E 132).

20mg - brown print – pharmaceutical grade shellac, propylene glycol, ammonium hydroxide, potassium hydroxide, titanium dioxide (E 171), black iron oxide (E 172), yellow iron oxide (E 172), brown iron oxide (E 172) and red iron oxide (E 172).

100mg - blue print – pharmaceutical grade shellac, propylene glycol, titanium dioxide (E 171) and indigotin (E 132).

250mg - black print – pharmaceutical grade shellac, propylene glycol, ammonium hydroxide, potassium hydroxide and black iron oxide (E 172).

To:

The capsule contains:

anhydrous lactose,

colloidal anhydrous silica,

sodium starch glycolate,

tartaric acid,

stearic acid. 

Capsule shells contain:

5mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate

yellow iron oxide (E 172),

indigotin (E 132),

20mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate,

yellow iron oxide (E 172)

100mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate,

red iron oxide (E172).

250mg:

gelatine,

titanium dioxide,

sodium lauryl sulphate

and are imprinted with black ink which contains:

shellac,

propylene glycol,

water,

ammonium hydroxide,

potassium hydroxide

black iron oxide (E 172).

SECTION 10  Date of revision of text has been updated