New Zealand - English - Medsafe (Medicines Safety Authority)
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
Orion Temozolomide capsules are also indicated as first line treatment for patients with
advanced metastatic malignant melanoma.
4.2 Dosage and method of administration
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 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
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
Absolute Neutrophil Count
≥ 0.5 and < 1.5x10
≥ 10 and < 100x10
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.
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
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
Reduction for prior toxicity
Dose during Cycle 1
absence of toxicity
Table 3: Temozolomide Dose Reduction or Discontinuation during Adjuvant Treatment
Reduce TMZ by 1 Dose Level
Absolute Neutrophil Count
< 1.0 x 10
See footnote b
< 50 x 10
See footnote b
CTC Non-haematological Toxicity
(except for alopecia, nausea,
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.
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
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
In patients 3 years of age and older, temozolomide is administered orally at a dose of 200
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
for 5 days, with escalation to 200 mg/m
once daily at the next cycle if there is no haematologic
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
anaemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates
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.
melanoma, Orion Temozolomide capsules can be continued until disease progression or for a
maximum of 2 years.
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
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.
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
Nausea and vomiting are very commonly associated with temozolomide and guidelines are
Patients with newly diagnosed glioblastoma multiforme:
anti-emetic prophylaxis is recommended prior to the initial dose of concomitant Orion
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.
The ability to drive and use machinery may be impaired in patients treated with
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
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
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
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
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
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
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
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
observed more frequently in the TMZ arm than the RT arm during the concomitant phase
and corresponding adverse events in the adjuvant phase.
n = 285
RT + TMZ
n = 288
n = 224
balance impaired NOS
General disorders and
radiation injury NOS
Ear and labyrinth
Renal and urinary
Blood and the lymphatic
Skin and subcutaneous
Patients with recurrent anaplastic astrocytoma, glioblastoma multiforme or malignant
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%)
Somnolence, asthenia, dizziness, paresthesia
Nausea, vomiting, constipation, anorexia
Diarrhoea, abdominal pain, dyspepsia, taste perversion\
Rash, alopecia, pruritus, petechiae
Fever, pain, malaise, weight decrease, rigors
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,
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
necrolysis, Stevens-Johnson syndrome and allergic reactions, including anaphylaxis, have also
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/.
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
compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is