Orion Temozolomide

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Temozolomide 100 mg
Available from:
Orion Laboratories (NZ) Ltd
INN (International Name):
Temozolomide 100 mg
Dosage:
100 mg
Pharmaceutical form:
Capsule
Composition:
Active: Temozolomide 100 mg Excipient: Colloidal silicon dioxide Gelatin Lactose Sodium starch glycolate Stearic acid Tartaric acid Titanium dioxide
Prescription type:
Prescription
Manufactured by:
Perrigo API Ltd
Therapeutic indications:
Treatment of: - Patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as adjuvant treatment - Patients with recurrent high grade glioma, such as glioblastoma multiforme or anaplastic astrocytoma
Product summary:
Package - Contents - Shelf Life: Bottle, glass, - 5 capsules - 3 years from date of manufacture stored at or below 25°C protect from moisture
Authorization number:
TT50-9275b
Authorization date:
2013-04-09

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New Zealand Datasheet

1 PRODUCT NAME

Orion Temozolomide capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Temozolomide 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg capsules.

3 PHARMACEUTICAL FORM

Orion Temozolomide 5 mg capsules have a white opaque capsule with two stripes in green ink

on the cap and with “T 5 mg” in green ink on the body.

Orion Temozolomide 20 mg capsules have a white opaque capsule with two stripes in orange

ink on the cap and with “T 20 mg” in orange ink on the body.

Orion Temozolomide 100 mg capsules have a white opaque capsule with two stripes in pink ink

on the cap and with “T 100 mg” in pink ink on the body.

Orion Temozolomide 140 mg capsules have a white opaque capsule with two stripes in blue ink

on the cap and with “T 140 mg” in blue ink on the body.

Orion Temozolomide 180 mg capsules have a white opaque capsule with two stripes in red ink

on the cap and with “T 180 mg” in red ink on the body.

Orion Temozolomide 250 mg capsules have a white opaque with capsule two stripes in black

ink on the cap and with “T 250 mg” in black ink on the body.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Orion Temozolomide capsules are indicated for the treatment of:

patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and

then as adjuvant treatment.

patients with recurrent high grade glioma, such as glioblastoma multiforme or anaplastic

astrocytoma.

Orion Temozolomide capsules are also indicated as first line treatment for patients with

advanced metastatic malignant melanoma.

4.2 Dosage and method of administration

Anti-emetic

therapy

administered

prior

following

administration

Orion

Temozolomide capsules.

Orion Temozolomide capsules should be administered in the fasting state at least one hour

before a meal. If vomiting occurs after the dose is administered, a second dose should not be

administered that day. Orion Temozolomide capsules must not be opened or chewed, but are to

be swallowed whole with a glass of water. If a capsule becomes damaged, avoid contact of the

powder contents with skin or mucous membrane.

Adults: Newly diagnosed glioblastoma multiforme

Concomitant phase

Concomitant phase consists of Orion Temozolomide capsules administered orally at 75 mg/m

daily for 42 days with focal radiotherapy (60 Gy administered in 30 fractions). The concomitant

phase is followed by the adjuvant phase [temozolomide for 6 cycles.]

Dose reductions are not recommended, however, dose interruptions may occur based on

patient tolerance.

The temozolomide dose can be continued throughout the 42 day concomitant period up to 49

days (if needed due to radiotherapy interruption) if all of the following conditions are met:

absolute neutrophil count ≥ 1.5x10

/ L thrombocyte count ≥ 100x10

/ L common toxicity criteria

(CTC) non-haemotological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).

During concomitant treatment a complete blood count should be obtained weekly. Orion

Temozolomide capsule dosing should be interrupted or discontinued during concomitant phase

according to the haematological and non-haemotological toxicity criteria as noted in Table 1.

Table 1: Temozolomide Dosing Interruption or Discontinuation during Concomitant Focal

Radiotherapy and Temozolomide

Toxicity

TMZ Interruption

a

TMZ Discontinuation

Absolute Neutrophil Count

≥ 0.5 and < 1.5x10

/ L

< 0.5x10

Thrombocyte Count

≥ 10 and < 100x10

/ L

< 10x10

/ L

CTC Non-haematological Toxicity (except

for alopecia, nausea, vomiting)

CTC Grade 2

CTC Grade 3 or 4

: Treatment with concomitant TMZ could be continued when all of the following conditions were met:

absolute neutrophil count ≥ 1.5x10

/ L; thrombocyte count ≥100 x 10

/ L; CTC non-haematological

toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting).

TMZ= Temozolomide; CTC = Common Toxicity Criteria.

Adjuvant Phase

Four weeks after completing the Temozolomide + Radiotherapy phase, Temozolomide is

administered for an additional 6 cycles of adjuvant treatment. Dosage in Cycle 1 (adjuvant) is

150 mg/m

once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2,

the dose is escalated to 200 mg/m

if the CTC non-haematological toxicity for Cycle 1 is Grade

≤ 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥1.5x10

and the thrombocyte count is ≥100x10

/L. If the dose was not escalated at Cycle 2, escalation

should not be done in subsequent cycles. The dose remains at 200 mg/m

per day for the first 5

days of each subsequent cycle except if toxicity occurs.

During treatment a complete blood count should be obtained on day 22 (21 days after the first

dose of Orion Temozolomide capsules). The Orion Temozolomide capsule dose should be

reduced or discontinued according to Table 3. Dose reductions during the adjuvant phase

should be applied according to Tables 2 and 3.

Table 2: Temozolomide Dose Levels for Adjuvant Treatment

Dose Level Dose

Dose (mg/m

2

/day)

Remarks

Reduction for prior toxicity

Dose during Cycle 1

Dose

during

Cycles

absence of toxicity

Table 3: Temozolomide Dose Reduction or Discontinuation during Adjuvant Treatment

Toxicity

Reduce TMZ by 1 Dose Level

a

Discontinue TMZ

Absolute Neutrophil Count

< 1.0 x 10

See footnote b

Thrombocyte Count

< 50 x 10

See footnote b

CTC Non-haematological Toxicity

(except for alopecia, nausea,

vomiting)

CTC Grade 3

CTC Grade 4 b

: TMZ dose levels are listed in Table 2

:TMZ is to be discontinued if dose reduction to < 100 mg/m

is required or if the same Grade 3 non-

haematological toxicity (except for alopecia, nausea, vomiting ) recurs after dose reduction.

TMZ+ Temozolomide, CTC= Common Toxicity Criteria.

Adults:

Recurrent

glioblastoma

multiforme,

anaplastic

astrocytoma

or

malignant

melanoma

In patients previously untreated with chemotherapy, temozolomide is administered orally at a

dose of 200 mg/m

once daily for 5 days per 28-day cycle. In patients previously treated with

chemotherapy, the initial dose is 150 mg/m

once daily, to be increased in the second cycle to

mg/m

daily

providing

absolute

neutrophil

count

(ANC)

1.5x10

thrombocyte count is ≥ 100x10

/L on Day 1 of the next cycle. Dose modifications for Orion

Temozolomide capsules should be based on toxicities according to nadir ANC or platelet

counts.

Children

In patients 3 years of age and older, temozolomide is administered orally at a dose of 200

mg/m

once daily for 5 days per 28-day cycle. Paediatric patients previously treated with

chemotherapy or craniospinal irradiation should receive an initial dose of 150 mg/m

once daily

for 5 days, with escalation to 200 mg/m

once daily at the next cycle if there is no haematologic

toxicity.

Laboratory Parameters for dose modification in recurrent or progressive malignant

glioma or malignant melanoma

Patients treated with temozolomide may experience myelosuppression, including prolonged

pancytopenia, which may result in aplastic anaemia, which is some cases has resulted in a fatal

outcome.

some

cases,

exposure

concomitant

medications

associated

with

aplastic

anaemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates

assessment.

Prior to dosing, the following laboratory parameters must be met: absolute neutrophil count

(ANC) ≥ 1.5x10

/L and platelets ≥ 100x10

/L. During cyclical treatment a complete blood count

must be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and

weekly until ANC is above 1.5x10

/L and platelet count exceeds 100x10

/L. If ANC falls to <

1.0x109/L or the platelet count is < 50x10

/L during any cycle, the next cycle should be reduced

one dose level. Dose levels include 100 mg/m

, 150 mg/m

and 200 mg/m

. The lowest

recommended dose is 100 mg/m

The efficacy of temozolomide for the treatment of recurrent glioblastoma multiforme, in patients

who received the drug as concomitant/ adjuvant treatment has not been established.

patients

with

recurrent

glioblastoma

multiforme/anaplastic

astrocytoma

metastatic

melanoma, Orion Temozolomide capsules can be continued until disease progression or for a

maximum of 2 years.

4.3 Contraindications

Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction to

temozolomide, its components or to dacarbazine (DTIC).

Temozolomide is contraindicated for use during pregnancy (see Use in Pregnancy).

Temozolomide must not be used by breastfeeding women (see Use in Lactation).

Temozolomide is contraindicated in patients with severe myelosuppression.

4.4 Special warnings and precautions for use

Patients who received concomitant temozolomide capsules and radiotherapy in a pilot trial for

the prolonged 42 day schedule were shown to be at particular risk for developing Pneumocystis

carinii pneumonia.

Thus, prophylaxis against Pneumocystis carinii pneumonia is required for all patients receiving

concomitant temozolomide capsules and radiotherapy for the 42 day regimen (with a maximum

of 49 days) regardless of lymphocyte count. If lymphocytopenia occurs Pneumocystis carinii

pneumonia prophylaxis should continue to a lymphocyte count less than or equal to grade 1.

There may be a higher occurrence of PCP when temozolomide is administered during a longer

dosing regimen. However, all patients receiving temozolomide, particularly patients receiving

steroids should be observed closely for the development of PCP regardless of the regimen.

Orion

Temozolomide capsules contain lactose. Patients with rare hereditary problems of

galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a

lactose free diet should take this into consideration. Refer to the full list of excipients under

Further Information.

Antiemetic therapy

Nausea and vomiting are very commonly associated with temozolomide and guidelines are

provided:

Patients with newly diagnosed glioblastoma multiforme:

anti-emetic prophylaxis is recommended prior to the initial dose of concomitant Orion

Temozolomide capsules

anti-emetic prophylaxis is strongly recommended during the adjuvant phase.

Patients with recurrent glioma:

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles

may require anti-emetic therapy.

All Patients

The ability to drive and use machinery may be impaired in patients treated with

Orion

Temozolomide capsules due to fatigue and somnolence.

Use in Patients with Hepatic or Renal Dysfunction

The pharmacokinetics of temozolomide were comparable in patients with normal hepatic

function and in those with mild or moderate hepatic dysfunction. No data are available on the

administration of Orion Temozolomide capsules in patients with severe hepatic dysfunction

(Child’s Class III) or with renal dysfunction. Based on the pharmacokinetic properties of

temozolomide, it is unlikely that dose reductions are required in patients with severe hepatic or

renal dysfunction. However, caution should be exercised when Orion Temozolomide capsules

are administered in these patients.

Hepatic injury, including fatal hepatic failure, has been reported very rarely in patients treated

with temozolomide. Baseline liver function tests should be performed prior to treatment initiation.

If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including

the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests

should be repeated midway during this cycle. For all patients, liver function tests should be

checked after each treatment cycle. For patients with significant liver function abnormalities,

physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur

several weeks or more after the last treatment with temozolomide.

Additionally, hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in

death, has been reported. Patients should be screened for HBV infection before treatment

initiation. Patients with evidence of prior HBV infection should be monitored for clinical and

laboratory signs of hepatitis or HBV reactivation during and for several months following

treatment with temozolomide. Therapy should be discontinued for patients with evidence of

active hepatitis B infection.

Use in Children

There is no clinical experience with the use of Orion Temozolomide capsules in children under

the age of 3 years with glioblastoma multiforme. There is limited experience in children over the

age of 3 years with glioma.

There is no clinical experience in melanoma patients under the age of 18 years.

Use in Elderly Patients

Elderly

patients

(>70

years

age)

appear

increased

risk

neutropenia

thombocytopenia, compared with younger patients.

Carcinogenicity, Mutagenicity and Impairment of Fertility

No long term carcinogenicity studies have been conducted, but evidence of carcinogenic

potential of temozolomide capsules was observed in the three- and six-cycle studies in rats.

Neoplasms observed in the rat studies included mammary carcinoma, keratoacanthoma of the

skin, basal cell adenoma and a variety of mesenchymal neoplasms. These neoplasms occurred

at systemic exposure to temozolomide less than that anticipated clinically. No tumours or

preneoplastic changes were observed in the dog studies of up to six cycles. Considering that

temozolomide is a prodrug of the alkylating agent MTIC, its tumourigenic potential is not

unexpected and has been observed with other alkylating agents, including those producing

MTIC.

Temozolomide was genotoxic in assays for gene mutations (Salmonella typhimurium and

Eschericia coli) and chromosomal changes (human blood lymphocytes).

Pathological lesions of necrosis, degeneration, hypospermatogenesis and presence of syncytial

cells and immature/abnormal spermatozoa in the testes, epididymis and seminal vesicles have

been observed in the mouse, rat and dog at systemic exposure levels to temozolomide well

within the

anticipated

human

exposure.

Decreased

ovarian

weight

was noted

in rats

temozolomide exposure comparable to that anticipated clinically. The reversibility of these

changes has not been investigated, but no evidence of recovery was noted during the 23-day

nontreatment period.

Orion Temozolomide capsules are contraindicated in women who intend to become pregnant,

and effective contraception should be used in both male and female patients during and for a

prolonged period after treatment with temozolomide (see Sections 4.3 and 4.6).

4.5 Interaction with other medicines and other forms of interaction

Administration of temozolomide with ranitidine did not result in clinically significant alterations in

extent

absorption

temozolomide.

Co-administration

dexamethasone,

prochlorperazine,

phenytoin,

carbamazepine,

ondansetron,

H2-receptor

antagonists

phenobarbital did not alter the clearance of temozolomide. Co-administration with valproic acid

was associated with a small but statistically significant decrease in clearance of temozolomide.

Use of temozolomide in combination with other myelosuppressive agents may increase the

likelihood of myelosuppression.

4.6 Fertility, Pregnancy and lactation

Use in Pregnancy (Category D)

There are no studies in pregnant women. In preclinical studies in rats and rabbits administered

mg/m

teratogenicity

and/or

foetal

toxicity

were

demonstrated.

Orion

Temozolomide

capsules, therefore, should not be administered to pregnant women. If use during pregnancy

must be considered, the patient should be apprised of the potential risk to the foetus.

Women of childbearing potential should be advised to avoid pregnancy while they are receiving

Orion Temozolomide capsules and for the 6 months after discontinuation of temozolomide

therapy.

Use in Lactation

It is not known whether temozolomide is excreted in human milk; thus, Orion Temozolomide

capsules should not be used by women who are breast-feeding.

Use in Men

Effective contraception should be used by male patients treated with Orion Temozolomide

capsules. Orion Temozolomide can have genotoxic effects. Therefore, men being treated with

temozolomide are advised not to father a child and to seek advice on cryoconservation of

spermatozoa prior to treatment because of the possibility of irreversible infertility due to therapy

with temozolomide (see Carcinogenicity, Mutagenicity and Impairment of Fertility).

4.7 Effects on ability to drive and use machines

Temozolomide has minor influence on the ability to drive and use machines due to fatigue and

somnolence (see section 4.8).

4.8 Undesirable effects

Newly diagnosed glioblastoma multiforme

Table

4:

Treatment

Emergent

Adverse

Events

with

an

incidence

of

2%

or

greater

observed more frequently in the TMZ arm than the RT arm during the concomitant phase

and corresponding adverse events in the adjuvant phase.

Table 4

Concomitant phase

Adjuvant phase

Adverse event

Radiotherapy Alone

concomitant

n = 285

(%)

RT + TMZ

concomitant

n = 288

(%)

TMZ Adjuvant

Therapy

n = 224

(%)

Musculoskeletal and

connective tissue

disorders

muscle weakness

arthralgia

Nervous system

disorders

headache

neuropathy

aphasia

concentration impaired

paresthesia

balance impaired NOS

consciousness decrease

somnolence

<1

<1

<1

General disorders and

administration site

conditions

fatigue

radiation injury NOS

fever

allergic reaction

taste perversion

face oedema

pain

Ear and labyrinth

disorders

hearing impairment

Gastrointestinal

disorders

nausea

constipation

dyspepsia

diarrhoea

stomatitis

abdominal pain

dysphagia

Vascular disorders

oedema legs

haemorrhage NOS

<1

Renal and urinary

disorders

micturition frequency

urinary incontinence

<1

Blood and the lymphatic

system

thrombocytopenia

lymphopenia

leucopenia

neutropenia

Metabolism and

nutrition disorders

anorexia

vomiting

weight decrease

hyperglycaemia

<1

Skin and subcutaneous

tissue disorders

alopecia

rash

pruritus

Psychiatric disorders

insomnia

Respiratory, thoracic

and mediastinal

dyspnoea

coughing

Investigation

SGPT increased

Patients with recurrent anaplastic astrocytoma, glioblastoma multiforme or malignant

melanoma

Table 5 Frequency of adverse drug reactions reported in clinical trials or spontaneously,

classified according to body system

Adverse Effects in patients with recurrent anaplastic astrocytoma, glioblastoma

multiforme or malignant melanoma

Very Common (10%); Common (1% and <10%)

Neurological

Very common

Common

Fatigue, headache

Somnolence, asthenia, dizziness, paresthesia

Gastrointestinal

Very common

Common

Nausea, vomiting, constipation, anorexia

Diarrhoea, abdominal pain, dyspepsia, taste perversion\

Haematological

Very Common

Common

Thrombocytopenia, neutropenia

Anemia, leucopenia

Dermatological

Common

Rash, alopecia, pruritus, petechiae

Respiratory

Common

Dyspnoea

General

Common

Fever, pain, malaise, weight decrease, rigors

clinical

trials,

most

frequently

occurring

undesirable

effects

were

gastrointestinal

disturbances, specifically nausea (42%) and vomiting (35%). These effects were usually Grade

1 or 2 (mild to moderate in severity) and were either self-limiting or readily controlled with

standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4%. There is

no information on the risk of second malignancies.Severe myelosuppression, predominantly

thrombocytopenia, was dose-limiting and occurred in 7% of all patients. Anaemia was reported

in 5% of patients. Severe neutropenia and leucopenia occurred in 3% and 2% of patients,

respectively.

Laboratory Results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17% of patients

respectively treated for glioma and 20% and 22% respectively of patients with metastatic

melanoma. This led to hospitalisation and/or discontinuation of temozolomide in 8% and 4%

respectively of patients with glioma and 3% and 1.3% respectively of those with melanoma.

Myelosuppression was predictable (usually within the first few cycles, with the nadir between

Day 21 and 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative

myelosuppression was observed. Pancytopenia, leucopenia and anaemia have also been

reported. Lymphopenia has also been reported very commonly.

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 versus 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.

Post-Marketing experience with Temozolomide

During

marketing

temozolomide,

cases

erythema

multiforme,

toxic

epidermal

necrolysis, Stevens-Johnson syndrome and allergic reactions, including anaphylaxis, have also

been

reported

very

rarely.

There

have

been

reported

cases

hepatotoxicity

including

elevations

liver

enzymes,

hyperbilirubinaemia,

cholestasis

hepatitis.Hepatic

injury,

including fatal hepatic failure, has been reported very rarely (see section 4.4).

Rare cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP) and

both primary and reactivated cytomegalovirus (CMV) infection have been reported. Cases of

reactivation of hepatitis B infections, including some cases with fatal outcomes have also been

reported (see section 4.4). Cases of interstitial pneumonitis/pneumonitis and pulmonary fibrosis

have been reported very rarely. Very rare cases of myelodysplastic syndrome (MDS) and

secondary malignancies, including myeloid leukaemia, have also been observed. Prolonged

pancytopenia, which may result in aplastic anaemia has been reported and in some cases has

resulted in a fatal outcome. Diabetes insipidus has also been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m

(total dose per cycle over 5 days) have been

evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported at

any dose but is expected to be more severe at higher doses. An overdose of 2,000 mg per day

for 5 days was taken by one patient and the adverse events reported were pancytopenia,

pyrexia, multi-organ failure and death. There are reports of patients who have taken more than

5 days of treatment (up to 64 days) with adverse events reported including bone marrow

suppression, with or without infection, in some cases severe and prolonged and resulting in

death. In the event of an overdose, haematologic evaluation is

needed. Supportive measures

should be provided as necessary.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A

Temozolomide is an imidazotetrazine alkylating agent with antitumour activity. It undergoes

rapid

chemical

conversion

systemic

circulation

physiological

active

compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is

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