ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
TORISEL 30 mg concentrate and diluent for solution for infusion.
2.
Each vial of TORISEL concentrate contains 30 mg temsirolimus.
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentration
of temsirolimus is 10 mg/ml (see section 4.2).
Excipients:
1 vial TORISEL 30 mg concentrate contains 474 mg anhydrous ethanol.
1.8 ml of the diluent, provided contains 358 mg anhydrous ethanol.
For a full list of excipients, see section 6.1.
3.
Concentrate and diluent for solution for infusion (sterile concentrate).
The concentrate is a clear, colourless to light-yellow solution, essentially free from visible particulates.
The diluent is a clear to slightly turbid, light-yellow to yellow solution, essentially free from visible
particulates.
4.
Renal cell carcinoma
TORISEL is indicated for the first-line treatment of patients with advanced renal cell carcinoma
(RCC) who have at least three of six prognostic risk factors (see section 5.1).
Mantle cell lymphoma
TORISEL is indicated for the treatment of adult patients with relapsed and/or refractory mantle cell
lymphoma [MCL] (see section 5.1).
TORISEL must be administered under the supervision of a physician experienced in the use of
antineoplastic medicinal products.
The vial of TORISEL concentrate must first be diluted with 1.8 ml of diluent withdrawn from
the supplied vial to achieve a concentration of temsirolimus of 10 mg/ml. Withdraw the required
amount of the temsirolimus-diluent mixture ( 10 mg/ml) and then inject rapidly into sodium
chloride 9 mg/ml (0.9%) solution for injection.
For instructions on preparation and to help ensure correct dosing, see section 6.6.
Posology
2
Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine)
approximately 30 minutes before the start of each dose of temsirolimus.
Treatment with TORISEL should continue until the patient is no longer clinically benefiting from
therapy or until unacceptable toxicity occurs. No special dose modification is required for any of the
populations that have been studied (gender, elderly).
Renal cell carcinoma
The recommended dose of temsirolimus for advanced renal cell carcinoma administered intravenously
is 25 mg infused over a 30- to 60-minute period once weekly (see section 6.6 for instructions on
dilution, administration and disposal).
Management of suspected adverse reactions may require temporary interruption and/or dose reduction
of temsirolimus therapy. If a suspected reaction is not manageable with dose delays, then temsirolimus
may be reduced by 5 mg/week decrements.
Mantle cell lymphoma
The recommended dosing regimen of temsirolimus for mantle cell lymphoma is 175 mg, infused over
a 30-60 minute period once weekly for 3 weeks followed by weekly doses of 75 mg, infused over a
30-60 minute period. The starting dose of 175 mg was associated with a significant incidence of
adverse events and required dose reductions/delays in the majority of patients. The contribution of the
initial 175 mg doses to the efficacy outcome is currently not known.
Management of suspected adverse reactions may require temporary interruption and/or dose reduction
of temsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is
not manageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should
be reduced according to the dose reduction table below.
Dose Reduction Levels
Dose Reduction Level
Starting Dose
175 mg
Continuing Dose
a
75 mg
-1
75 mg
50 mg
-2
50 mg
25 mg
a
In the MCL Clinical Trial, up to two dose level reductions were allowed per patient.
Temsirolimus Dose Modifications Based on Weekly ANC and Platelet Counts
ANC Platelets Dose of Temsirolimus
≥1.0 x 10
9
/l ≥50 x 10
9
/l
100% of planned dose
<1.0 x 10
9
/l <50 x 10
9
/l
Hold
a
a
Upon recovery to ANC ≥1.0 x 10
9
/l (1000 cells/mm
3
) and platelets to ≥50 x 10
9
/l (50,000 cells/mm
3
), the doses
should be modified to the next lower dose level according to the table above. If the patient cannot maintain
ANC >1.0 x 10
9
/l and platelets >50 x 10
9
/l on the new dose reduction level, then the next lower dose should be
given once the counts have recovered.
Abbreviation: ANC = absolute neutrophil count.
Paediatric population
There is no relevant use of temsirolimus in the paediatric population in the indications treatment of
renal cell carcinoma and treatment of mantle cell lymphoma.
3
Temsirolimus should not be used in the paediatric population for the treatment of neuroblastoma,
rhabdomyosarcoma or high-grade glioma, because of efficacy concerns based on the available data
(see section 5.1).
Elderly population
No specific dose adjustment is necessary.
Renal impairment
No dose adjustment of temsirolimus is recommended in patients with renal impairment. Temsirolimus
should be used with caution in patients with severe renal impairment (see section 4.4).
Hepatic impairment
Temsirolimus should be used with caution in patients with hepatic impairment (see section 4.4).
No dose adjustment of temsirolimus is recommended for patients with advanced renal cell carcinoma
(RCC) and mild to moderate hepatic impairment. For patients with RCC and severe hepatic
impairment, the recommended dose for patients who have baseline platelets ≥ 100 x 10
9
/l is 10 mg IV
once a week infused over a 30-60 minute period (see section 5.2).
Method of administration
TORISEL must be administered by intravenous (IV) infusion. For instructions on dilution and
preparation of the medicinal product before administration, see section 6.6.
Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or to any of the
excipients of TORISEL.
Use of temsirolimus in patients with mantle cell lymphoma with moderate or severe hepatic
impairment is not recommended (see section 4.4).
The incidence and severity of adverse events is dose-dependent. Patients receiving the starting dose of
175 mg weekly for the treatment of MCL must be followed closely to decide on dose
reductions/delays.
Paediatric population
Temsirolimus is not recommended for use in paediatric patients (see sections 4.2, 4.8 and 5.1).
Elderly population
Based on the results of a phase 3 study in renal cell carcinoma, elderly patients (≥ 65 years of age) may
be more likely to experience certain adverse reactions, including oedema, diarrhoea, and pneumonia.
Based on the results of a phase 3 study in mantle cell lymphoma, elderly patients (≥ 65 years of age)
may be more likely to experience certain adverse reactions, including
pleural effusion, anxiety,
depression, insomnia, dyspnoea, leukopaenia, lymphopaenia, myalgia, arthralgia, taste loss, dizziness,
upper respiratory infection, mucositis, and rhinitis.
4
Renal impairment
Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renal
impairment have not been conducted (see sections 4.2 and 5.2). TORISEL has not been studied in
patients undergoing haemodialysis.
Renal failure
Renal failure (including fatal outcomes) has been observed in patients receiving TORISEL for
advanced renal cell cancer and/or with pre-existing renal insufficiency (see section 4.8).
Hepatic impairment
Temsirolimus is cleared predominantly by the liver. Based on an open-label, dose-escalation study in
112 subjects with advanced malignancies and either normal or impaired hepatic function, no dose
adjustment of temsirolimus is recommended for patients with baseline platelet counts ≥ 100x10
9
/l and
advanced renal cell carcinoma (RCC) and mild to moderate hepatic impairment (total bilirubin up to 3
times upper limit of normal [ULN] with any abnormality of AST, or as defined by Child-Pugh Class A
or B). For patients with RCC and severe hepatic impairment (total bilirubin > 3 times ULN with any
abnormality of AST, or as defined by Child-Pugh Class C), the recommended dose for patients who
have baseline platelets ≥ 100 x 10
9
/l is 10 mg IV once a week infused over a 30-60 minute period (see
section 4.2).
Intracerebral bleeding
Patients with central nervous system (CNS) tumours (primary CNS tumours or metastases) and/or
receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding
(including fatal outcomes) while receiving therapy with temsirolimus.
Thrombocytopaenia and neutropaenia
Grades 3 and 4 thrombocytopaenia and/or neutropaenia have been observed in the MCL Clinical Trial
(see section 4.8). Patients on temsirolimus who develop thrombocytopaenia may be at increased risk of
bleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baseline
neutropaenia may be at risk of developing febrile neutropaenia.
Infections
Patients may be immunosuppressed and should be carefully observed for the occurrence of infections,
including opportunistic infections. Among patients receiving 175 mg/week for the treatment of MCL,
infections (including grade 3 and 4 infections) were substantially increased compared to lower doses
and compared to conventional chemotherapy.
Cataracts
Cataracts have been observed in some patients who received the combination of temsirolimus and
interferon-α.
Hypersensitivity/infusion reactions
Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), including
and not limited to flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness,
hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus (see
section 4.8). These reactions can occur very early in the first infusion, but may also occur with
subsequent infusions. Patients should be monitored early during the infusion and appropriate
supportive care should be available. Temsirolimus infusion should be interrupted in all patients with
severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment
5
should be done prior to the continuation of temsirolimus therapy in patients with severe or life-
threatening reactions.
If a patient develops a hypersensitivity reaction during the TORISEL infusion, despite the
premedication, the infusion must be stopped and the patient observed for at least 30 to 60 minutes
(depending on the severity of the reaction). At the discretion of the physician, treatment may be
resumed after the administration of an H
1
-receptor antagonist (diphenhydramine or similar
antihistamine) and a H
2
-receptor antagonist (intravenous famotidine 20 mg or intravenous ranitidine
50 mg) approximately 30 minutes before restarting the TORISEL infusion. Administration of
corticosteroids may be considered; however, the efficacy of corticosteroid treatment in this setting has
not been established. The infusion may then be resumed at a slower rate (up to 60 minutes) and should
be completed within six hours from the time that TORISEL is first added to sodium chloride 9 mg/ml
(0.9%) solution for injection.
Because it is recommended that an H
1
antihistamine be administered to patients before the start of the
intravenous temsirolimus infusion, temsirolimus should be used with caution in patients with known
hypersensitivity to the antihistamine or in patients who cannot receive the antihistamine for other
medical reasons.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative
dermatitis and hypersensitivity vasculitis, have been associated with the oral administration of
sirolimus.
Hyperglycaemia/glucose intolerance/diabetes mellitus
Patients should be advised that treatment with TORISEL may be associated with an increase in blood
glucose levels in diabetic and non-diabetic patients. In the RCC Clinical Trial, a phase 3 clinical trial
for renal cell carcinoma, 26% of patients reported hyperglycaemia as an adverse event. In the MCL
Clinical Trial, a phase 3 clinical trial for mantle cell lymphoma, 11% of patients reported
hyperglycaemia as an adverse event. This may result in the need for an increase in the dose of, or
initiation of, insulin and/or hypoglycaemic agent therapy. Patients should be advised to report
excessive thirst or any increase in the volume or frequency of urination.
Interstitial lung disease
There have been cases of non-specific interstitial pneumonitis, including fatal reports, occurring in
patients who received weekly intravenous TORISEL. Some patients were asymptomatic or had
minimal symptoms with pneumonitis detected on computed tomography scan or chest radiograph.
Others presented with symptoms such as dyspnoea, cough, and fever. Some patients required
discontinuation of TORISEL or treatment with corticosteroids and/or antibiotics, while some patients
continued treatment without additional intervention. It is recommended that patients undergo baseline
radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation
of TORISEL therapy. Periodical follow-up assessments may be considered. It is recommended that
patients be followed closely for occurrence of clinical respiratory symptoms and patients should be
advised to report promptly any new or worsening respiratory symptoms. If clinically significant
respiratory symptoms develop, consider withholding TORISEL administration until after recovery of
symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with
corticosteroids and/or antibiotics may be considered.
Hyperlipaemia
The use of TORISEL was associated with increases in serum triglycerides and cholesterol. In the RCC
Clinical Trial 1, hyperlipaemia was reported as an adverse event in 27% of patients. In the MCL
Clinical Trial, hyperlipaemia was reported as an adverse event in 9.3% of patients. This may require
initiation, or increase, in the dose of lipid-lowering agents. Serum cholesterol and triglycerides should
be tested before and during treatment with TORISEL.
6
Wound healing complications
The use of TORISEL has been associated with abnormal wound healing; therefore, caution should be
exercised with the use of TORISEL in the peri-surgical period.
Concomitant use of temsirolimus with sunitinib
The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting
toxicities (grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were
observed in two out of three patients treated in the first cohort of a phase 1 study at doses of
temsirolimus 15 mg intravenous per week and sunitinib 25 mg oral per day (days 1-28 followed by a
2-week rest).
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Angioneurotic oedema-type reactions (including delayed reactions occurring two months following
initiation of therapy) have been observed in some patients who received temsirolimus and ACE
inhibitors concomitantly (see section 4.5).
Agents inducing CYP3A metabolism
Agents such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s Wort are strong
inducers of CYP3A4/5 and may decrease composite exposure of the active moieties, temsirolimus and
its metabolite, sirolimus. Therefore, for patients with renal cell carcinoma, continuous administration
beyond 5-7 days with agents that have CYP3A4/5 induction potential should be avoided. For patients
with mantle cell lymphoma, it is recommended that coadministration of CYP3A4/5 inducers should be
avoided due to the higher dose of temsirolimus (see section 4.5).
Agents inhibiting CYP3A metabolism
Agents such as protease inhibitors (nelfinavir, ritonavir), antifungals (e.g., itraconazole, ketoconazole,
voriconazole), and nefazodone are strong CYP3A4 inhibitors and may increase blood concentrations
of the active moieties, temsirolimus and its metabolite, sirolimus. Therefore, concomitant treatment
with agents that have strong CYP3A4 inhibition potential should be avoided. Concomitant treatment
with moderate CYP3A4 inhibitors (e.g., aprepitant, erythromycin, fluconazole, verapamil, grapefruit
juice) should only be administered with caution in patients receiving 25 mg and should be avoided in
patients receiving temsirolimus doses higher than 25 mg (see section 4.5). Alternative treatments with
agents that do not have CYP3A4 inhibition potential should be considered (see section 4.5).
Vaccinations
Immunosuppressants may affect responses to vaccination. During treatment with TORISEL,
vaccination may be less effective. The use of live vaccines should be avoided during treatment with
TORISEL. Examples of live vaccines are: measles, mumps, rubella, oral polio, BCG, yellow fever,
varicella, and TY21a typhoid vaccines.
Excipients
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentrate-
diluent mixture contains 35% volume ethanol (alcohol); i.e., up to 0.693 g per 25 mg dose of
TORISEL, equivalent to 17.6 ml beer, 7.3 ml wine per dose. Patients administered the higher dose of
175 mg of TORISEL for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent
to 123 ml beer, 51 ml wine per dose).
Harmful for those suffering from alcoholism.
7
To be taken into account in pregnant or breast-feeding women, children and high-risk groups, such as
patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the
effects of other medicines. The amount of alcohol in this medicinal product may impair your ability to
drive or use machines.
Interaction studies have only been performed in adults.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Angioneurotic oedema-type reactions (including delayed reactions occurring two months following
initiation of therapy) have been observed in some patients who received temsirolimus and ACE
inhibitors concomitantly (see section 4.4).
Agents inducing CYP3A metabolism
Co-administration of TORISEL with rifampicin, a potent CYP3A4/5 inducer, had no significant effect
on temsirolimus C
max
(maximum concentration) and AUC (area under the concentration vs. time
curve) after intravenous administration, but decreased sirolimus C
max
by 65% and AUC by 56%,
compared to TORISEL treatment alone. Therefore, concomitant treatment with agents that have
CYP3A4/5 induction potential should be avoided [e.g., carbamazepine, phenobarbital, phenytoin,
rifampicin, and St. John’s Wort] (see section 4.4).
Agents inhibiting CYP3A metabolism
Co-administration of TORISEL 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no
significant effect on temsirolimus C
max
or AUC; however, sirolimus AUC increased 3.1-fold, and
AUC
sum
(temsirolimus + sirolimus) increased 2.3-fold compared to TORISEL alone. The effect on the
unbound concentrations of sirolimus has not been determined, but is expected to be larger than the
effect on whole-blood concentrations due to the saturable binding to red blood cells. The effect may
also be more pronounced at a 25 mg dose. Therefore, substances that are potent inhibitors of CYP3A4
activity (e.g., nelfinavir, ritonavir, itraconazole, ketoconazole, voriconazole, nefazodone) increase
sirolimus blood concentrations. Concomitant treatment of TORISEL with these agents should be
avoided see section 4.4).
Concomitant treatment with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, clarithromycin,
erythromycin, aprepitant, amiodarone) should only be administered with caution in patients receiving
25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg.
Interaction with medicinal products metabolised by CYP2D6 or CYP3A4
In 23 healthy subjects, the concentration of desipramine, a CYP2D6 substrate, was unaffected when
25 mg of temsirolimus was co-administered. No clinically significant effect is anticipated when
TORISEL is co-administered with agents that are metabolised by CYP2D6 in patients with renal cell
carcinoma. For patients with mantle cell lymphoma, the effect of a 175 or 75 mg temsirolimus dose on
CYP2D6 or 3A4 substrates has not been studied. However, based on in vitro studies in human liver
microsomes, the plasma concentrations achieved after a 175 mg dose of temsirolimus might possibly
lead to inhibition of CYP3A4/5 and CYP2D6 (see section 5.2). Therefore, caution is advised during
concomitant administration of temsirolimus at a dose of 175 mg with medicinal products that are
metabolised via CYP3A4/5 or CYP2D6 and that have a narrow therapeutic index.
Interactions with drugs that are P-glycoprotein substrates
In an
in vitro
study, temsirolimus inhibited the transport of P-glycoprotein (P-gp) substrates with an
IC
50
value of 2 µM.
In vivo
, the effect of P-gp inhibition has not been investigated, but mean C
max
concentrations of temsirolimus are 2.6 µM in MCL patients receiving the 175 mg IV dose of
8
temsirolimus. Therefore, when temsirolimus is co-administered with medications which are P-gp
substrates (e.g. digoxin, vincristine, colchicine, and paclitaxel) close monitoring for adverse events
related to the co-administered drugs should be observed.
Amphiphilic agents
Temsirolimus has been associated with phospholipidosis in rats. Phospholipidosis has not been
observed in mice or monkeys treated with temsirolimus, nor has it been documented in patients treated
with temsirolimus. Although phospholipidosis has not been shown to be a risk for patients
administered temsirolimus, it is possible that combined administration of temsirolimus with other
amphiphilic agents such as amiodarone or statins could result in an increased risk of amphiphilic
pulmonary toxicity.
Women of childbearing potential/ Contraception in males and females
Due to the unknown risk related to potential exposure during early pregnancy, women of childbearing
potential must be advised not to become pregnant while using TORISEL.
Men with partners of childbearing potential should use medically acceptable contraception while
receiving TORISEL (see section 5.3).
Pregnancy
There are no adequate data from the use of temsirolimus in pregnant women. Studies in animals have
shown reproductive toxicity. In reproduction studies in animals, temsirolimus caused
embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated
delays in skeletal ossification) in rats and rabbits. Teratogenic effects (omphalocele) were seen in
rabbits (see section 5.3).
The potential risk for humans is unknown. TORISEL must not be used during pregnancy, unless the
risk for the embryo is justified by the expected benefit for the mother.
Breastfeeding
It is unknown whether temsirolimus is excreted in human breast milk. The excretion of temsirolimus
in milk has not been studied in animals. However, sirolimus, the main metabolite of temsirolimus, is
excreted in milk of lactating rats. Because of the potential for adverse reactions in breast-fed infants
from temsirolimus, breast-feeding should be discontinued during therapy.
Fertility
In male rats, decreased fertility and partly reversible reductions in sperm counts were reported (see
section 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
For patients receiving the higher dose of 175 mg IV of TORISEL for the treatment of MCL, the
amount of ethanol in this medicinal product may impair your ability to drive or use machines (see
section 4.4).
9
Due to the different approved posology for RCC and MCL and the dose-dependency of the frequency
and severity of undesirable effects, adverse drug reactions are listed separately.
Renal cell carcinoma
A total of 626 patients were randomly assigned in a phase 3, three-arm, randomised, open-label study
of Interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α. A total of 616 patients
received treatment: 200 patients received IFN-α weekly; 208 received TORISEL 25 mg weekly, and
208 patients received a combination of IFN-α and TORISEL weekly. Based on the results of the
phase 3 study, elderly patients may be more likely to experience certain adverse reactions, including
face oedema and pneumonia.
The most serious reactions observed with TORISEL are hypersensitivity/infusion reactions (including
some life-threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections,
interstitial lung disease (pneumonitis), hyperlipaemia, intracerebral bleeding, renal failure, bowel
perforation, and wound healing complication.
The most common (≥30%) adverse reactions (all grades) observed with TORISEL include anaemia,
nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), anorexia, oedema
(including facial oedema and peripheral oedema), and asthenia.
Cataracts have been observed in some patients who received the combination of temsirolimus and
interferon-α.
See section 4.4 for additional information concerning serious adverse reactions, including appropriate
actions to be taken if specific reactions occur.
The following list contains adverse reactions seen in RCC Clinical Trial 1. Only events for which there
is at least reasonable suspicion of a causal relationship to intravenous treatment with TORISEL are
listed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions are listed according to the following categories:
Very common: ≥1/10
Common: ≥1/100 to <1/10
Uncommon: ≥1/1,000 to <1/100
Adverse Reactions in RCC Clinical Trial 1
System
Organ Class
Frequency
Adverse Reactions
All
Grades
n (%)
Grade
3 & 4
n (%)
Infections and
infestations
Very common
Bacterial and viral infections
(including infection, cellulitis, herpes
zoster, herpes simplex, bronchitis,
sinusitis, abscess)*
42 (20)
6 (3)
Very common
Urinary tract infection (including
dysuria, haematuria, cystitis, urinary
frequency, urinary tract infection)*
31 (15)
4 (2)
Very common
Pharyngitis
25 (12)
0 (0)
Very common
Rhinitis
20 (10)
0 (0)
Common
Pneumonia
17 (8)
5 (2)
Common
Upper respiratory tract infection
14 (7)
0 (0)
Common
Folliculitis
4 (2)
0 (0)
10
Adverse Reactions in RCC Clinical Trial 1
System
Organ Class
Frequency
Adverse Reactions
All
Grades
n (%)
Grade
3 & 4
n (%)
Blood and
lymphatic system
disorders
Very common
Thrombocytopaenia
28 (14)
3 (1)
Very common
Anaemia
94 (45) 41 (20)
Common
Neutropaenia
15 (7)
6 (3)
Common
Leukopoenia
13 (6)
1 (1)
Common
Lymphopaenia
11 (5)
9 (4)
Immune system
disorders
Common
Allergic/hypersensitivity reactions
18 (9)
0 (0)
Metabolism and
nutrition
disorders
Very common
Hypokalaemia
20 (10)
7 (3)
Very common
Anorexia
66 (32)
6 (3)
Very common
Hyperglycaemia/diabetes mellitus**
53 (26) 22 (11)
Very common
Hypercholesterolaemia
51 (24)
1 (1)
Very common
Hyperlipaemia
57 (27)
8 (4)
Common
Hypophosphataemia
17 (8)
11 (5)
Psychiatric
disorders
Very common
Insomnia
24 (12)
1 (1)
Common
Anxiety
16 (8)
0 (0)
Common
Depression
9 (4)
0 (0)
Nervous system
disorders
Very common
Dysgeusia
31 (15)
0 (0)
Common
Somnolence
14 (7)
3 (1)
Common
Paresthaesia
13 (6)
1 (1)
Common
Dizziness
19 (9)
1 (1)
Common
Ageusia
11 (5)
0 (0)
Uncommon
Intracerebral bleeding
1 (0.5)
1 (0.5)
Eye disorders
Common
Conjunctivitis (including
conjunctivitis, lacrimation disorders)* 15 (7)
1 (1)
Cardiac disorders
Uncommon
Pericardial effusion (including
haemodynamically significant
pericardial effusions requiring
intervention)
2 (1)
1 (1)
Vascular
disorders
Common
Venous thromboembolism (including
deep vein thrombosis, pulmonary
embolus [including fatal outcomes],
thrombosis)*
6 (3)
3 (1)
Common
Hypertension
14 (7)
3 (1)
Common
Thrombophlebitis
2 (1)
0 (0)
Respiratory,
thoracic and
mediastinal
disorders
Very common
Dyspnoea
58 (28)
18 (9)
Very common
Epistaxis
25 (12)
0 (0)
Very common
Cough
54 (26)
2 (1)
Common
Pneumonitis [including fatal
pneumonitis] (see section 4.4)
4 (2)
1 (1)
Common
Pleural effusion
8 (4)
5 (2)
Gastrointestinal
disorders
Very common
Abdominal pain
44 (21)
9 (4)
Very common
Vomiting
40 (19)
4 (2)
Very common
Stomatitis*
42 (20)
3 (1)
Very common
Diarrhoea
57 (27)
3 (1)
Very common
Nausea
77 (37)
5 (2)
Common
Abdominal distension
9 (4)
1 (1)
Common
Oral pain
5 (2)
0 (0)
Common
Gingivitis
5 (2)
0 (0)
Common
Aphthous stomatitis
8 (4)
1 (0)
Uncommon
Bowel perforation
1 (0.5)
1 (0.5)
11
Adverse Reactions in RCC Clinical Trial 1
System
Organ Class
Frequency
Adverse Reactions
All
Grades
n (%)
Grade
3 & 4
n (%)
Skin and
subcutaneous
tissue disorders
Very common
Rash (including rash, pruritic rash,
maculopapular rash, pustular rash)*
88 (42)
10 (5)
Very common
Pruritus
40 (19)
1 (1)
Very common
Acne
21 (10)
0 (0)
Very common
Nail disorder
28 (14)
0 (0)
Very common
Dry skin
22 (11)
1 (1)
Common
Exfoliative dermatitis
16 (8)
0 (0)
Musculoskeletal
and connective
tissue disorders
Very common
Back pain
41 (20)
6 (3)
Very common
Arthralgia
37 (18)
2 (1)
Myalgia (including myalgia, leg
cramps)*
Common
17 (8)
1 (1)
Renal and urinary
disorders
Common
Renal failure [including fatal
outcomes] (see section 4.4)
4 (2)
2 (1)
General disorders
and
administration
site conditions
Very common
Oedema (including oedema, facial
oedema, peripheral oedema)*
72 (35)
7 (3)
Very common
Asthenia
106 (51) 23 (11)
Very common
Pain
59 (28)
11 (5)
Very common
Pyrexia
51 (24)
1 (1)
Very common
Mucositis
39 (19)
2 (1)
Very common
Chest pain
34 (16)
2 (1)
Common
Chills
17 (8)
1 (1)
Common
Impaired wound healing
3 (1)
0 (0)
Investigations
Very common
Blood creatinine increased
30 (14)
6 (3)
Common
Increased aspartate aminotransferase
17 (8)
3 (1)
Common Increased alanine aminotransferase 12 (6) 1 (1)
*Body system totals are not necessarily the sum of the individual adverse events, since a subject may report
two or more different adverse events in the same body system.
**Patients should be advised that treatment with TORISEL may be associated with an increase in blood
glucose levels in diabetic and non-diabetic patients.
Mantle cell lymphoma
A total of 54 patients were treated with 175/75 mg TORISEL in the MCL Clinical Trial, a phase 3,
three-arm, randomised, open-label study of TORISEL comparing 2 different dosing regimens of
temsirolimus with an investigator's choice of therapy in patients with relapsed and/or refractory mantle
cell lymphoma. Based on the results of the phase 3 study, elderly patients (≥65 years) may be more
likely to experience certain adverse reactions, including pleural effusion, anxiety, depression,
insomnia, dyspnoea, leukopaenia, lymphopaenia, myalgia, arthralgia, taste loss, dizziness, upper
respiratory infection, mucositis, and rhinitis.
The most serious reactions observed with TORISEL are thrombocytopaenia, neutropaenia, infections,
interstitial lung disease (pneumonitis), bowel perforation, hypersensitivity reactions, and
hyperglycaemia/glucose intolerance.
The most common (≥30%) adverse reactions (all grades) observed with TORISEL include
thrombocytopaenia, asthenia, anaemia, diarrhoea, bacterial and viral infections*, rash*, pyrexia,
anorexia, epistaxis, mucositis, oedema*, and stomatitis*.
The occurrence of undesirable effects following the dose of 175 mg TORISEL/week for MCL, e.g.
grade 3 or 4 infections or thrombocytopaenia, is associated with a higher incidence than that observed
with either 75 mg TORISEL/week or conventional chemotherapy.
12
*See table below for additional terms included with these adverse reactions.
See section 4.4 for additional information concerning serious adverse reactions, including appropriate
actions to be taken if specific reactions occur.
The following list contains adverse reactions seen in the MCL Clinical Trial. Only events for which
there is at least reasonable suspicion of a causal relationship to intravenous treatment with TORISEL
are listed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions are listed according to the following categories:
Very common: ≥1/10
Common: ≥1/100 to <1/10
Adverse Reactions in MCL Clinical Trial
System
Organ Class
Frequency
Adverse Reactions
All
Grades
n (%)
Grade
3 & 4
n (%)
Infections and
infestations
Very common Bacterial and viral infections
(including infection, cellulitis,
bronchitis, sinusitis, herpes zoster,
herpes simplex)*
23 (43)
8 (15)
Pneumonia (including interstitial
pneumonia)**
Very common
8 (15)
6 (11)
Very common Urinary tract infection (including
dysuria, urinary frequency, urinary
tract infection, urinary urgency)*
8 (15)
0 (0)
Very common Pharyngitis
4 (7)
0 (0)
Very common Upper respiratory tract infection
8 (15)
0 (0)
Common
Sepsis (including sepsis, septic
shock)*
3 (6)
3 (6)
Common
Rhinitis
5 (9)
0 (0)
Common
Folliculitis
1 (2)
0 (0)
Blood and
lymphatic system
disorders
Very common
Thrombocytopaenia**
39 (72)
32 (59)
Very common
Anaemia
28 (52)
11 (20)
Very common
Neutropaenia**
13 (24)
8 (15)
Very common
Leukopaenia
8 (15)
4 (7)
Very common
Lymphopaenia
6 (11)
4 (7)
Immune system
disorders
Common
Allergic/hypersensitivity reactions
1 (2)
0 (0)
Metabolism and
nutrition
disorders
Very common Hypokalaemia
10 (19)
4 (7)
Very common Anorexia
20 (37)
1 (2)
Very common Hyperglycaemia***
6 (11)
6 (11)
Very common Hypercholesterolaemia
7 (13)
0 (0)
Common
Dehydration
3 (6)
2 (4)
Common
Hypophosphataemia
3 (6)
0 (0)
Common
Hyperlipaemia
5 (9)
1 (2)
Common
Hypocalcaemia
5 (9)
1 (2)
Psychiatric
disorders
Very common Insomnia
11 (20)
0 (0)
Very common Anxiety
8 (15)
0 (0)
Common
Depression
5 (9)
0 (0)
Nervous system
disorders
Very common Dysgeusia
8 (15)
0 (0)
Common
Paresthaesia
4 (7)
0 (0)
Common
Dizziness
3 (6)
0 (0)
Common
Ageusia
5 (9)
0 (0)
13
Adverse Reactions in MCL Clinical Trial
System
Organ Class
Frequency
Adverse Reactions
All
Grades
n (%)
Grade
3 & 4
n (%)
Eye disorders
Common
Conjunctivitis
4 (7)
0 (0)
Common
Eye haemorrhage
2 (4)
0 (0)
Vascular
disorders
Common
Thrombosis (including deep venous
thrombosis, thrombosis)*
3 (6)
1 (2)
Common
Hypertension
2 (4)
0 (0)
Respiratory,
thoracic and
mediastinal
disorders
Very common
Dyspnoea
10 (19)
4 (7)
Very common Epistaxis
19 (35)
0 (0)
Very common
Cough
14 (26)
0 (0)
Common
Pneumonitis****
2 (4)
0 (0)
Gastrointestinal
disorders
Very common
Abdominal pain
11 (20)
1 (2)
Very common
Vomiting
9 (17)
0 (0)
Very common
Stomatitis (including aphthous
stomatitis, mouth ulceration,
stomatitis, glossitis, oral pain)*
16 (30)
1 (2)
Very common
Diarrhoea
24 (44)
4 (7)
Very common
Nausea
14 (26)
0 (0)
Common
Bowel perforation
1 (2)
1 (2)
Common
Gastrointestinal haemorrhage
(including gastrointestinal
haemorrhage, rectal haemorrhage)*
6 (11)
2 (4)
Common
Gingivitis
2 (4)
0 (0)
Common
Gastritis
3 (6)
1 (2)
Common
Dysphagia
4 (7)
0 (0)
Skin and
subcutaneous
tissue disorders
Very common
Rash (including rash, pruritic rash,
maculopapular rash, pustular rash,
eczema)*
22 (41)
4 (7)
Very common
Pruritus
14 (26)
2 (4)
Very common
Nail disorder
8 (15)
0 (0)
Very common
Dry skin
7 (13)
0 (0)
Common
Acne
4 (7)
0 (0)
Common
Moniliasis (including moniliasis, oral
moniliasis)*
2 (4)
0 (0)
Common
Fungal dermatitis
1 (2)
0 (0)
Common
Ecchymosis
4 (7)
0 (0)
Musculoskeletal,
connective tissue
and bone
disorders
Very common
Back pain
7 (13)
0 (0)
Very common
Arthralgia
11 (20)
1 (2)
Myalgia (including muscle cramps,
leg cramps, myalgia)*
Very common
9 (17)
0 (0)
General disorders
and
administration
site conditions
Very common
Oedema (including oedema, facial
oedema, peripheral oedema, scrotal
oedema, genital oedema, generalised
oedema)*
19 (35)
1 (2)
Very common
Asthenia
34 (63)
7 (13)
Very common
Pain
15 (28)
1 (2)
Very common
Pyrexia
21 (39)
3 (6)
Very common
Mucositis
19 (35)
3 (6)
Very common
Chills
14 (26)
1 (2)
Common
Chest pain
4 (7)
0 (0)
Investigations
Common
Blood creatinine increased
4 (7)
0 (0)
Common
Increased aspartate aminotransferase
2 (4)
1 (2)
Common
Increased alanine aminotransferase
1 (2)
1 (2)
14
*Body system totals are not necessarily the sum of the individual adverse events since a subject may report two
or more different adverse events in the same body system.
**Grades 3 and 4 (thrombocytopaenia) are defined as 50,000-25,000 platelets/mm
3
and <25,000 platelets/mm
3
,
respectively. Grades 3 and 4 (neutropaenia) are defined as 1000-500 neutrophils/mm
3
and <500 neutrophils/mm
3
,
respectively.
***Patients should be advised that treatment with TORISEL may be associated with an increase in blood glucose
levels in diabetic and non-diabetic patients.
****One case of fatal pneumonitis was reported in a mantle cell lymphoma patient receiving 175/25 mg/week
that is not included in this table.
Serious adverse reactions observed in clinical trials of temsirolimus for advanced renal cell carcinoma,
but not in clinical trials of temsirolimus for mantle cell lymphoma include: anaphylaxis, impaired
wound healing, renal failure with fatal outcomes, and pulmonary embolus.
Adverse reactions for which frequency is undetermined
Angioneurotic oedema-type reactions in some patients who received temsirolimus and ACE-inhibitors
concomitantly.
Post Marketing Experience
There have been reports of Stevens-Johnson syndrome in patients who received TORISEL.
There have been reports of rhabdomyolysis in patients who received TORISEL.
Paediatric population
In a phase 1/2 study, 71 patients (59 patients, aged from 1 to 17 years old, and 12 patients, aged 18 to
21 years) were administered temsirolimus at doses ranging from 10 mg/m
2
to 150 mg/m
2
(see section
5.1).
The adverse reactions reported by the highest percentage of patients were haematologic (anaemia,
leukopaenia, neutropaenia, and thrombocytopaenia), metabolic (hypercholesterolaemia, hyperlipaemia,
hyperglycaemia, increase of serum aspartate amino transferase [AST] and serum alanine
aminotransferase [ALT] plasma levels), and digestive (mucositis, stomatitis, nausea, and vomiting).
There is no specific treatment for TORISEL intravenous overdose. While TORISEL has been safely
administered to patients with renal cancer with repeated intravenous doses of temsirolimus as high as
220 mg/m
2
, in MCL, two administrations of 330 mg TORISEL/week in one patient resulted in grade 3
rectal bleeding and grade 2 diarrhoea.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protein Kinase Inhibitors; ATC code: L01X E09
Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds
to an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the
activity of mTOR that controls cell division.
In vitro
, at high concentrations (10-20 µM), temsirolimus
can bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growth
inhibition was observed. High concentrations resulted in complete cell growth inhibition
in vitro
,
whereas inhibition mediated by FKBP-12/temsirolimus complex alone resulted in approximately 50%
decrease in cell proliferation. Inhibition of mTOR activity results in a G1 growth delay at nanomolar
concentrations and growth arrest at micromolar concentrations in treated tumour cells resulting from
15
selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and
ornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and thereby
control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the
P13 kinase/AKT pathway) that control cell division, is blocked.
In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible
factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to
hypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor
(VEGF). The anti-tumour effect of temsirolimus, therefore, may also in part stem from its ability to
depress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel
development.
Clinical Efficacy
Renal cell carcinoma
The safety and efficacy of TORISEL in the treatment of advanced renal cell carcinoma were studied in
the following two randomised clinical trials:
RCC Clinical Trial 1
RCC Clinical Trial 1 was a phase 3, multi-centre, three-arm, randomised, open-label study in
previously untreated patients with advanced renal cell carcinoma and with 3 or more of 6 pre-selected
prognostic risk factors (less than one year from time of initial renal cell carcinoma diagnosis to
randomisation, Karnofsky performance status of 60 or 70, haemoglobin less than the lower limit of
normal, corrected calcium of greater than 10 mg/dl, lactate dehydrogenase>1.5 times the upper limit of
normal, more than one metastatic organ site). The primary study endpoint was overall survival (OS).
Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical
benefit rate, time to treatment failure (TTF), and quality adjusted survival measurement. Patients were
stratified for prior nephrectomy status within three geographic regions and were randomly assigned
(1:1:1) to receive IFN-α alone (n = 207), TORISEL alone (25 mg weekly; n = 209), or the combination
of IFN-α and TORISEL (n = 210).
In RCC Clinical Trial 1, TORISEL 25 mg was associated with a statistically significant advantage
over IFN-α in the primary endpoint of OS at the 2
nd
pre-specified interim analysis (n = 446 events,
p = 0.0078). The TORISEL arm showed a 49% increase in median OS compared with the IFN-α arm.
TORISEL also was associated with statistically significant advantages over IFN-α in the secondary
endpoints of PFS, TTF, and clinical benefit rate.
The combination of TORISEL 15 mg and IFN-α did not result in a significant increase in overall
survival when compared with IFN-α alone at either the interim analysis (median 8.4 vs. 7.3 months,
hazard ratio = 0.96, p = 0.6965) or final analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.93,
p = 0.4902). Treatment with the combination of TORISEL and IFN-α resulted in a statistically
significant increase in the incidence of certain grade 3-4 adverse events (weight loss, anaemia,
neutropaenia, thrombocytopaenia and mucosal inflammation) when compared with the adverse events
observed in the IFN-α or TORISEL-alone arms.
16
Summary of Efficacy Results in TORISEL RCC Clinical Trial 1
Parameter
TORISEL
n = 209
IFN-
α
n = 207
P-value
a
Hazard ratio
(95% CI)
b
Pre-specified interim analysis
Median overall survival,
Months (95% CI)
10.9 (8.6, 12.7)
7.3 (6.1,
8.8)
0.0078 0.73 (0.58, 0.92)
Final analysis
Median overall survival,
Months (95% CI)
10.9 (8.6, 12.7)
7.3 (6.1,
8.8)
0.0252 0.78 (0.63, 0.97)
Median progression-free
survival by independent
assessment
Months (95% CI)
5.6 (3.9, 7.2)
3.2 (2.2,
4.0)
0.0042 0.74 (0.60, 0.91)
Median progression-free
survival by investigator
assessment
Months (95% CI)
3.8 (3.6, 5.2)
1.9 (1.9,
2.2)
0.0028 0.74 (0.60, 0.90)
Overall response rate by
independent assessment
% (95% CI)
9.1 (5.2, 13.0)
5.3 (2.3,
8.4)
0.1361
NA
CI = confidence interval; NA = not applicable.
a
Based on log-rank test stratified by prior nephrectomy and region.
b
Based on Cox proportional hazard model stratified by prior nephrectomy and region (95% CI are descriptive
only).
c
Based on Cochran-Mantel-Hansel test stratified by prior nephrectomy and region.
In RCC Clinical Trial 1, 31% of patients treated with TORISEL were 65 or older. In patients younger
than 65, median overall survival was 12 months (95% CI 9.9, 14.2) with a hazard ratio of 0.67
(95% CI 0.52, 0.87) compared with those treated with IFN-α. In patients 65 or older, median overall
survival was 8.6 months (95% CI 6.4, 11.5) with a hazard ratio of 1.15 (95% CI 0.78, 1.68) compared
with those treated with IFN-α.
RCC Clinical Trial 2
RCC Clinical Trial 2 was a randomised, double-blind, multi-centre, outpatient trial to evaluate the
efficacy, safety, and pharmacokinetics of three dose levels of TORISEL when administered to
previously treated patients with advanced renal cell carcinoma. The primary efficacy endpoint was
ORR, and OS was also evaluated. One hundred eleven (111) patients were randomly assigned in a
1:1:1 ratio to receive 25 mg, 75 mg, or 250 mg temsirolimus intravenous weekly. In the 25 mg arm
(n = 36), all patients had metastatic disease; 4 (11%) had no prior chemo- or immunotherapy; 17
(47%) had one prior treatment, and 15 (42%) had 2 or more prior treatments for renal cell carcinoma.
Twenty-seven (27, 75%) had undergone a nephrectomy. Twenty-four (24, 67%) were Eastern
Cooperative Oncology Group (ECOG) performance status (PS) = 1, and 12 (33%) were ECOG PS = 0.
For patients treated weekly with 25 mg temsirolimus OS was 13.8 months (95% CI: 9.0, 18.7 months);
ORR was 5.6% (95% CI: 0.7, 18.7%).
Mantle cell lymphoma
The safety and efficacy of intravenous (IV) temsirolimus for the treatment of relapsed and/or
refractory mantle cell lymphoma were studied in the following phase 3 clinical study.
17
c
MCL Clinical Trial
MCL Clinical Trial is a controlled, randomised, open-label, multicenter, outpatient study comparing 2
different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with
relapsed and/or refractory mantle cell lymphoma. Subjects with mantle cell lymphoma (that was
confirmed by histology, immunophenotype, and cyclin D1 analysis) who had received 2 to 7 prior
therapies that included anthracyclines and alkylating agents, and rituximab (and could include
haematopoietic stem cell transplant) and whose disease was relapsed and/or refractory were eligible
for the study. Subjects were randomly assigned in a 1:1:1 ratio to receive temsirolimus IV 175 mg
(3 successive weekly doses) followed by 75 mg weekly (n = 54), temsirolimus IV 175 mg
(3 successive weekly doses) followed by 25 mg weekly (n=54), or the investigator’s choice of
single-agent treatment (as specified in the protocol; n = 54). Investigator's choice therapies included:
gemcitabine (IV: 22 [41.5%]), fludarabine (IV: 12 [22.6%] or oral: 2 [3.8%]), chlorambucil (oral:
3 [5.7%]), cladribine (IV: 3 [5.7%]), etoposide (IV: 3 [5.7%]), cyclophosphamide (oral: 2 [3.8%]),
thalidomide (oral: 2 [3.8%]), vinblastine (IV: 2 [3.8%]), alemtuzumab (IV: 1 [1.9%]), and
lenalidomide (oral: 1 [1.9%]). The primary endpoint of the study was progression-free survival (PFS),
as assessed by an independent radiologist and oncology review. Secondary efficacy endpoints included
overall survival (OS) and objective response rate (ORR).
The results for the MCL Clinical Trial are summarized in the following table. Temsirolimus 175/75
(temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly) led to an improvement in PFS
compared with investigator's choice in patients with relapsed and/or refractory mantle cell lymphoma
that was statistically significant (hazard ratio = 0.44; p-value = 0.0009). Median PFS of the
temsirolimus 175/75 mg group (4.8 months) was prolonged by 2.9 months compared to the
investigator's choice group (1.9 months). Overall survival was similar.
Temsirolimus also was associated with statistically significant advantages over investigator’s choice in
the secondary endpoint of overall response rate (ORR). The evaluations of PFS and ORR were based
on blinded independent radiologic assessment of tumour response using the International Workshop
Criteria.
Summary of Efficacy Results in TORISEL MCL Clinical Trial
Parameter
Temsirolimus
Concentrate
for Injection
175/75 mg
n = 54
Investigator’s
Choice
n = 54
P-value
Hazard Ratio
(97.5% CI)
a
Median
progression-free
survival
b
Months (97.5% CI)
4.8 (3.1, 8.1)
1.9 (1.6, 2.5)
0.0009
c
0.44 (0.25, 0.78)
Objective
response rate
b
% (95% CI)
22.2 (11.1, 33.3)
1.9 (0.0, 5.4)
0.0019
d
NA
Overall survival
Months (95% CI)
12.8 (8.6, 22.3)
10.3 (5.8, 15.8)
0.2970
c
0.78 (0.49, 1.24)
One-year survival
rate
% (97.5% CI)
0.47 (0.31, 0.61) 0.46 (0.30, 0.60)
a
Compared with INV CHOICE based on Cox proportional hazard model.
b
Disease assessment is based on radiographic review by independent radiologists and review of clinical data by
independent oncologists.
c
Compared with INV CHOICE based on log-rank test.
d
Compared with INV CHOICE alone based on Fisher's exact test.
Abbreviations: CI = confidence interval; NA = not applicable.
18
The temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly treatment arm did
not result in a significant increase in PFS when compared with investigator’s choice (median
3.4 vs. 1.9 months, hazard ratio = 0.65, CI = 0.39, 1.10, p = 0.0618).
In the MCL Clinical Trial, there was no difference in efficacy in patients with respect to age, sex, race,
geographic region, or baseline disease characteristics.
Paediatric population
In a phase 1/2 safety and exploratory efficacy study, 71 patients (59 patients, aged from 1 to 17 years,
and 12 patients, aged from 18 to 21 years) received temsirolimus as a 60-minute IV infusion once
weekly in three-week cycles. In part 1, 14 patients aged from 1 to 17 years with advanced
recurrent/refractory solid tumours received temsirolimus at doses ranging from 10 mg/m
2
to
150 mg/m
2
. In part 2, 45 patients aged from 1 to 17 years with recurrent/relapsed rhabdomyosarcoma,
neuroblastoma, or high grade glioma were administered temsirolimus at a weekly dose of 75 mg/m
2
.
Adverse events were generally similar to those observed in adults (see section 4.8).
Temsirolimus was found to be ineffective in paediatric patients with neuroblastoma,
rhabdomyosarcoma, and high-grade glioma (n = 52). For subjects with neuroblastoma, the objective
response rate was 5.3% (95% CI: 0.1%, 26.0%). After 12 weeks of treatment, no response was
observed in subjects with rhabdomyosarcoma or high-grade glioma. None of the 3 cohorts met the
criterion for advancing to the second stage of the Simon 2-stage design.
5.2 Pharmacokinetic properties
Absorption
Following administration of a single 25 mg intravenous dose of temsirolimus in patients with cancer,
mean C
max
in whole blood was 585 ng/ml (coefficient of variation, CV = 14%), and mean AUC in
blood was 1627 ng•h/ml (CV = 26%). For patients receiving 175 mg weekly for 3 weeks followed by
75 mg weekly, estimated C
max
in whole blood at end of infusion was 2457 ng/ml during week 1, and
2574 ng/ml during week 3.
Distribution
Temsirolimus exhibits a polyexponential decline in whole blood concentrations, and distribution is
attributable to preferential binding to FKBP-12 in blood cells. The mean (standard deviation, SD)
dissociation constant (K
d
) of binding was 5.1 (3.0) ng/ml, denoting the concentration at which 50% of
binding sites in blood cells were occupied. Temsirolimus distribution is dose-dependent with mean
(10th, 90th percentiles) maximal specific binding in blood cells of 1.4 mg (0.47 to 2.5 mg). Following
a single 25 mg temsirolimus intravenous dose, mean steady-state volume of distribution in whole
blood of patients with cancer was 172 liters.
Metabolism
Sirolimus, an equally potent metabolite to temsirolimus, was observed as the principal metabolite in
humans following intravenous treatment. During
in vitro
temsirolimus metabolism studies, sirolimus,
seco-temsirolimus and seco-sirolimus were observed; additional metabolic pathways were
hydroxylation, reduction and demethylation. Following a single 25 mg intravenous dose in patients
with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer
half-life of sirolimus.
Elimination
Following a single 25 mg intravenous dose of temsirolimus, temsirolimus mean ± SD systemic
clearance from whole blood was 11.4 ± 2.4 l/h. Mean half-lives of temsirolimus and sirolimus were
19
17.7 hr and 73.3 hr, respectively. Following administration of [
14
C] temsirolimus, excretion was
predominantly via the faeces (78%), with renal elimination of active substance and metabolites
accounting for 4.6% of the administered dose. Sulfate or glucuronide conjugates were not detected in
the human faecal samples, suggesting that sulfation and glucuronidation do not appear to be major
pathways involved in the excretion of temsirolimus. Therefore, inhibitors of these metabolic pathways
are not expected to affect the elimination of temsirolimus.
Model-predicted values for clearance from plasma, after applying a 175 mg dose for 3 weeks, and
subsequently 75 mg for 3 weeks, indicate temsirolimus and sirolimus metabolite trough concentrations
of approximately 1.2 ng/ml and 10.7 ng/ml, respectively.
Temsirolimus and sirolimus were demonstrated to be substrates for P-gp
in vitro
. Possible effects of
inhibition of P-gp on elimination of temsirolimus and sirolimus
in vivo
have not been investigated.
Inhibition of CYP isoforms
In
in vitro
studies in human liver microsomes, temsirolimus inhibited CYP3A4/5, CYP2D6, CYP2C9
and CYP2C8 catalytic activity with Ki values of 3.1, 1.5, 14 and 27 µM, respectively. IC
50
values for
inhibition of CYP2B6 and CYP2E1 by temsirolimus were 48 and 100 µM, respectively. Based on a
whole blood mean C
max
concentration of 2.6 µM for temsirolimus in MCL patients receiving the
175 mg dose there is a potential for interactions with concomitantly administered drugs that are
substrates of CYP3A4/5 and CYP2D6 in patients treated with the 175 mg dose of temsirolimus (see
section 4.5). However, it is unlikely that whole blood concentrations of temsirolimus after IV
administration of temsirolimus will inhibit the metabolic clearance of concomitant drugs that are
substrates of CYP2C9, CYP2C8, CYP2B6 or CYP2E1.
Special Populations
Hepatic impairment
Temsirolimus and sirolimus pharmacokinetics have been investigated in an open-label, dose-escalation
study in 112 patients with advanced malignancies and either normal or impaired hepatic function. For
7 patients with severe hepatic impairment (ODWG, group D) receiving the 10 mg dose of
temsirolimus, the mean AUC of temsirolimus was ~1.7-fold higher compared to 7 patients with mild
hepatic impairment (ODWG, group B). For patients with severe hepatic impairment, a reduction of the
temsirolimus dose to 10 mg is recommended to provide levels of temsirolimus and sirolimus
exposures in blood (AUC
sum
6580 ng·h/ml), which approximate to those following the 25 mg dose
(AUC
sum
7280 ng·h/ml) in patients with normal liver function (see sections 4.2 and 4.4).
Gender, weight, race, age
Temsirolimus and sirolimus pharmacokinetics are not significantly affected by gender. No relevant
differences in exposure were apparent when
data from the Caucasian population was compared
with
either the Japanese or Black population.
In population pharmacokinetic-based data analysis, increased body weight (between 38.6 and
158.9 kg) was associated with a two-fold range of trough concentration of sirolimus in whole blood.
Pharmacokinetic data on temsirolimus and sirolimus are available in patients up to age 79 years. Age
does not appear to affect temsirolimus and sirolimus pharmacokinetics significantly.
Paediatric population
In the paediatric population, clearance of temsirolimus was lower and exposure (AUC) was higher
than in adults. In contrast, exposure to sirolimus was commensurately reduced in paediatric patients,
such that the net exposure as measured by the sum of temsirolimus and sirolimus AUCs (AUC
sum
) was
comparable to that for adults.
20
5.3 Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to or
even lower than clinical exposure levels and with possible relevance to clinical use, were as follows:
pancreatic islet cell vacuolation (rat), testicular tubular degeneration (mouse, rat and monkey),
lymphoid atrophy (mouse, rat and monkey), mixed cell inflammation of the colon/caecum (monkey),
and pulmonary phospholipidosis (rat).
Diarrhoea with mixed cell inflammation of the caecum or colon was observed in monkeys and was
associated with an inflammatory response, and may have been due to a disruption of the normal
intestinal flora.
General inflammatory responses, as indicated by increased fibrinogen and neutrophils, and/or changes
in serum protein, were observed in mice, rats, and monkeys, although in some cases these clinical
pathology changes were attributed to skin or intestinal inflammation as noted above. For some
animals, there were no specific clinical observations or histological changes that suggested
inflammation.
Temsirolimus was not genotoxic in a battery of
in vitro
(bacterial reverse mutation in
Salmonella
typhimurium
and
Escherichia coli
, forward mutation in mouse lymphoma cells, and chromosome
aberrations in Chinese hamster ovary cells) and
in vivo
(mouse micronucleus) assays.
Carcinogenicity studies have not been conducted with temsirolimus; however, sirolimus, the major
metabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects were
reported in mice and/or rats in the carcinogenicity studies conducted: granulocytic leukaemia,
lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma.
Reductions in testicular weights and/or histological lesions (e.g., tubular atrophy and tubular giant
cells) were observed in mice, rats, and monkeys. In rats, these changes were accompanied by a
decreased weight of accessory sex organs (epididymides, prostate, seminal vesicles). In reproduction
toxicity studies in animals, decreased fertility and partly reversible reductions in sperm counts were
reported in male rats. Exposures in animals were lower than those seen in humans receiving clinically
relevant doses of temsirolimus.
6.
6.1 List of excipients
Concentrate:
Anhydrous ethanol
all-
rac-
α-Tocopherol (E 307)
Propylene glycol
Anhydrous citric acid (E 330)
Diluent:
Polysorbate 80 (E 433)
Macrogol 400
Anhydrous ethanol
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, except those mentioned in
section 6.6.
21
TORISEL 30 mg concentrate must not be added directly to aqueous infusion solutions. Direct addition
of TORISEL 30 mg concentrate to aqueous solutions will result in precipitation of medicinal product.
Always dilute TORISEL 30 mg concentrate with 1.8 ml of the supplied diluent before adding to the
infusion solution. The concentrate-diluent mixture may only be administered in sodium chloride
9 mg/ml (0.9%) solution for injection.
TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of
di-(2-ethylhexyl) phthalate extraction (DEHP) from polyvinyl chloride (PVC). This incompatibility
has to be considered during the preparation and administration of TORISEL. It is important that the
recommendations in sections 4.2 and 6.6 be followed closely.
PVC bags and medical devices must not be used for the administration of preparations containing
polysorbate 80, because polysorbate 80 leaches DEHP from PVC.
6.3 Shelf life
2 years.
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent: 24 hours when
stored below 25°C and protected from light.
After further dilution of the concentrate-diluent mixture with sodium chloride 9 mg/ml (0.9%) solution
for injection: 6 hours when stored below 25°C and protected from light.
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
TORISEL 30 mg concentrate:
Clear glass vial (type 1 glass) with butyl rubber stopper and a plastic flip-top closure sealed with
aluminum.
Diluent:
Clear glass vial (type 1 glass) with butyl rubber stopper and a plastic flip-top closure sealed with
aluminum.
Pack size: 1 vial of 1.2 ml of concentrate and 1 vial of 2.2 ml of diluent.
6.6 Special precautions for disposal and other handling
During handling and preparation of admixtures, TORISEL should be protected from excessive room
light and sunlight.
TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of
di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC).
22
Therefore, PVC bags and medical devices must not be used for the preparation, storage and
administration of TORISEL solutions for infusions.
Bags/containers that come in contact with TORISEL must be made of glass, polyolefin, or
polyethylene.
Dilution
TORISEL 30 mg concentrate must be diluted with the supplied diluent before administration in
sodium chloride infusion.
Note: For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg. Each vial
of TORISEL must be diluted according to the instructions below. The required amount of concentrate-
diluent mixture from each vial must be combined in one syringe for rapid injection into 250 ml of
sodium chloride 9 mg/ml (0.9%) solution for injection (see section 4.2).
In preparing the solution, the following two-step process must be carried out in an aseptic manner
according to local standards for handling cytotoxic/cytostatic drugs:
STEP 1
: DILUTION OF TORISEL 30 mg CONCENTRATE WITH THE SUPPLIED DILUENT
•
Withdraw 1.8 ml of the supplied diluent.
•
Inject the 1.8 ml of diluent into the vial of TORISEL 30 mg concentrate.
•
Mix the diluent and the concentrate well by inversion of the vial. Sufficient time should be
allowed for air bubbles to subside. The solution should be a clear to slightly turbid, colourless
to light-yellow to yellow solution, essentially free from visual particulates.
One vial of TORISEL concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is
combined with 1.8 ml of withdrawn diluent, a total volume of 3.0 ml is obtained, and the concentration
of temsirolimus will be 10 mg/ml. The concentrate-diluent mixture is stable below 25°C for up to 24
hours.
STEP 2:
ADMINISTRATION OF CONCENTRATE-DILUENT MIXTURE IN SODIUM
CHLORIDE INFUSION
•
Withdraw the required amount of concentrate-diluent mixture (containing temsirolimus
10 mg/ml) from the vial; i.e., 2.5 ml for a temsirolimus dose of 25 mg.
•
Inject the withdrawn volume rapidly into 250 ml of sodium chloride 9 mg/ml (0.9%) solution
for injection to ensure adequate mixing.
The admixture should be mixed by inversion of the bag or bottle, avoiding excessive shaking, as this
may cause foaming.
The resulting solution should be inspected visually for particulate matter and discolouration prior to
administration, whenever solution and container permit. The admixture of TORISEL in sodium
chloride 9 mg/ml (0.9%) solution for injection should be protected from excessive room light and
sunlight.
Administration
• Administration of the final diluted solution should be completed within six hours from the time that
the TORISEL is first added to sodium chloride 9 mg/ml (0.9%) solution for injection.
• TORISEL is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the
preferred method of administration to ensure accurate delivery of the medicinal product.
23
• Appropriate administration materials must be composed of glass, polyolefin, or polyethylene to avoid
excessive loss of medicinal product and to decrease the rate of DEHP extraction. The administration
materials must consist of non-DEHP, non-PVC tubing with appropriate filter. An in-line
polyethersulfone
filter with a pore size of not greater than 5 microns is recommended for
administration to avoid the possibility of particles bigger than 5 microns being infused. If the
administration set available does not have an in-line filter incorporated, a filter should be added at the
end of the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different
end-filters can be used ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an
in-line and end-filter is not recommended.
• TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP
extraction from PVC. This should be considered during the preparation and administration of
TORISEL following constitution. It is important that the recommendations in section 4.2 be followed
closely.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Wyeth Europa Ltd
Huntercombe Lane South
Taplow, Maidenhead
Berkshire SL6 0PH
United Kingdom
8.
EU/1/07/424/001
9.
Date of first authorisation: 19 November 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency:
http://www.ema.europa.eu
24
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
25
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Wyeth Lederle S.p.A.
Via Franco Gorgone
Zona Industriale
95100 Catania
Italy
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance System
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.4 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted
• When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
• At the request of the European Medicines Agency
26
ANNEX III
LABELLING AND PACKAGE LEAFLET
27
A. LABELLING
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
TORISEL 30 mg concentrate and diluent for solution for infusion.
Temsirolimus.
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 1.2 ml of TORISEL concentrate contains 30 mg temsirolimus.
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentration
of temsirolimus is 10 mg/ml.
3.
LIST OF EXCIPIENTS
The other ingredients in the concentrate are: anhydrous ethanol, all-
rac
-α-tocopherol (E 307),
propylene glycol, anhydrous citric acid (E 330).
The diluent contains: polysorbate 80 (E 433), macrogol 400, anhydrous ethanol.
4.
Concentrate and diluent for solution for infusion:
Contents:
One vial of 1.2 ml TORISEL concentrate.
One vial of 2.2 ml diluent.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after dilution and administration in infusion.
Read the package leaflet before use and for dilution instructions.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Contains ethanol. See leaflet for further information.
29
8.
EXPIRY DATE
EXP
Read the leaflet for the shelf life of the diluted product.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
EU/1/07/424/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
30
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CONCENTRATE VIAL
1.
TORISEL 30 mg concentrate.
Temsirolimus.
I.V. use
2.
METHOD OF ADMINISTRATION
DILUTE BEFORE USE.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1.2 ml
6.
OTHER
Store in a refrigerator (2ºC-8ºC)
Do not freeze.
Keep the vial in the outer carton.
31
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
DILUENT VIAL
1.
Diluent for TORISEL.
I.V. use
2.
METHOD OF ADMINISTRATION
See package leaflet.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
2.2 ml.
6.
OTHER
Contains: polysorbate 80 (E 433), macrogol 400, anhydrous ethanol.
32
B. PACKAGE LEAFLET
33
PACKAGE LEAFLET: INFORMATION FOR THE USER
TORISEL 30 mg concentrate and diluent for solution for infusion
Temsirolimus
Read all of this leaflet carefully before you are given this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effect not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What TORISEL is and what it is used for
2. Before you receive TORISEL
3. How TORISEL is given
4. Possible side effects
5. How to store TORISEL
6. Further information
1.
WHAT TORISEL IS AND WHAT IT IS USED FOR
Your doctor has prescribed TORISEL because you have one of the following types of cancer:
-
Advanced cancer of the kidney (renal cancer).
-
Previously treated mantle cell lymphoma, a type of cancer affecting the lymph nodes
TORISEL is a selective inhibitor of mTOR (mammalian target of rapamycin) that blocks tumour cell
growth and division.
2.
BEFORE YOU RECEIVE TORISEL
Do not use TORISEL
-
If you are allergic (hypersensitive) to temsirolimus, to polysorbate 80 or any of the other
ingredients of TORISEL
-
If you are allergic (hypersensitive) to sirolimus (used to prevent the body from rejecting
transplanted kidneys) since sirolimus is released from temsirolimus in the body.
-
If you have mantle cell lymphoma and liver problems please tell your doctor.
Take special care with TORISEL
-
If you are allergic (hypersensitive) to antihistamines or cannot take antihistamines for other
medical reasons.
-
If you have high cholesterol, TORISEL may elevate triglycerides and/or cholesterol. This may
require treatment with lipid-lowering agents (medicine used to reduce cholesterol in the blood).
-
If you are going to have an operation, if you have had recent major surgery, or if you still have
an unhealed wound following surgery, you should tell your doctor before receiving this
medicine, as TORISEL may increase the risk of problems with wound healing.
-
If you are planning to have a vaccination during treatment with TORISEL, the vaccination may
be less effective. The use of certain vaccinations should be avoided during treatment with
TORISEL.
-
If you have a history of kidney failure or kidney problems.
34
-
Keep this leaflet. You may need to read it again.
-
If you have a history of liver problems.
-
If you are a child or adolescent under 18 years of age, your doctor will consider the potential
benefit to you in relation to any risk.
-
If you are over 65 years of age, you may be more likely to have certain side effects, including
swelling of your face, diarrhoea, pneumonia, anxiety, depression, shortness of breath, decreased
number of white cells in the blood, muscle pain, change in the sense of taste, upper respiratory
infection, fluid around the lungs, sores and inflammation in the mouth and/or the digestive tract
and runny nose, dizziness and infections.
-
If you have tumours in your brain or spinal cord, or are taking medicines to prevent your blood
from clotting (such as warfarin), you may be more likely to have bleeding into your brain.
TORISEL may also
-
increase blood glucose levels and worsen diabetes mellitus. This may result in the need for
insulin and/or oral antidiabetic agent therapy. Tell your doctor if you experience any excessive
thirst or increased frequency and quantity of urination.
-
weaken your immune system; therefore, you may be at risk of getting an infection while you are
taking TORISEL.
-
cause shortness of breath, cough, and fever. Tell your doctor if you experience new or
worsening symptoms.
-
increase the risk of cerebral haemorrhage (bleeding in the brain).
-
cause cataracts when taken with interferon-α (a medicine used in the treatment of hepatitis and
cancer).
-
cause serious allergic reactions. Tell your doctor if you experience difficulty in breathing and/or
swelling of the face.
-
cause a decrease in the number of cells that help blood to clot, which may increase the risk of
bleeding.
Using TORISEL with other medicines
Some medicines can interfere with the breakdown or metabolism of TORISEL. In particular, you
should inform your doctor if you are taking any of the following:
-
protease inhibitors used in the treatment of HIV
-
antibiotics (including rifampicin) or antifungal medicines (including ketoconazole) used to treat
infections
-
nefazodone or selective serotonin re-uptake inhibitors used to treat depression
-
anti-epileptic medicines, including carbamazepine, phenytoin and phenobarbital
-
herbal medicines or natural remedies containing St. John’s Wort (
Hypericum perforatum
) used
to treat mild depression
-
Angiotensin converting enzyme (ACE) inhibitors used to treat high blood pressure or other
cardiovascular problems (such as enalapril, ramipril, lisinopril), amphiphilic medicines used to
treat heart arrhythmias (such as amiodarone), or statins used to treat high cholesterol
Using TORISEL with food and drink
-
Grapefruit juice may increase blood concentrations of TORISEL and should be avoided.
Please tell your doctor if you are taking, or have recently taken, any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
TORISEL has not been studied in pregnant women, and it must not be used during pregnancy. It is
important that you tell your doctor if you are pregnant or are planning to become pregnant before
receiving TORISEL.
35
-
rifabutin used to treat infection in people with HIV and other diseases
Women of childbearing potential must avoid pregnancy by using an effective method of birth control
during treatment with TORISEL. Men with partners of childbearing potential should use medically
acceptable contraception while receiving TORISEL.
Women should not breast-feed during treatment with TORISEL, as this medicine may interfere with
the growth and development of the baby. Ask your doctor for advice before breast-feeding your baby,
as it is not known if TORISEL passes into breast milk.
Driving and using machines
No studies on the ability to drive and use machines have been performed. However, the very common
side effects include feeling or being sick (nausea and vomiting) and difficulty falling or staying asleep.
It is recommended you do not drive immediately after treatment.
For patients receiving the higher dose of TORISEL for the treatment of mantle cell lymphoma,
the amount of alcohol in this medicinal product may impair your ability to drive or use machines.
Important information about some of the ingredients of TORISEL
This medicine contains ethanol (alcohol), equivalent to 17.6 ml beer, 7.3 ml wine per 25 mg dose.
Patients receiving the higher dose of 175 mg of TORISEL for the initial treatment of mantle cell
lymphoma may receive a dose of ethanol equivalent to up to 123 ml beer or 51 ml wine per dose.
Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding
women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of
alcohol in this medicinal product may alter the effects of other medicines.
Children and adolescents
Insufficient data are available in patients under the age of 18 years. The treatment with this medicine is
not recommended in children and adolescents.
3.
HOW TORISEL IS GIVEN
TORISEL will always be prepared and given to you by a doctor or another healthcare professional as
an intravenous infusion (into your vein).
TORISEL 30 mg concentrate must first be diluted with 1.8 ml of withdrawn diluent to achieve a
concentration of 10 mg/ml before administration in sodium chloride 9 mg/ml (0.9%) solution for
injection
(see dilution instructions at the end of the package leaflet).
For renal cancer, the recommended dose is 25 mg infused (as a drip) over a 30- to 60-minute period
once weekly.
For mantle cell lymphoma, the recommended dosing is 175 mg infused (as a drip) over a
30- to 60-minute period once weekly for 3 weeks followed by single weekly doses of 75 mg infused
(as a drip) over a 30- to 60-minute period.
You should receive an injection of antihistamine (to try to prevent allergic reaction to TORISEL)
directly into your vein approximately 30 minutes before your dose of TORISEL.
Treatment with TORISEL should continue until you are no longer benefiting from therapy or until
unacceptable side effects occur.
36
If too much TORISEL is given or you miss a dose
As this medicine is prepared and given by a healthcare professional, it is unlikely you will be given too
much.
If you are concerned about this, or think you may have missed a dose, tell your doctor immediately.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TORISEL can cause side effects, although not everybody gets them. Side effects
may be more pronounced during the higher dose of 175 mg / week during initial treatment for mantle
cell lymphoma.
Very common serious side effects observed in more than 1 in 10 patients treated with TORISEL
are:
-
Decreased number of white cells in the blood, which may increase your risk of infection.
-
Increased blood glucose levels in diabetic and non-diabetic patients.
-
Decreased number of cells in the blood that help the blood to clot, which may increase the risk
of bleeding**.
Common serious side effects observed in more than 1 in 100 patients treated with TORISEL are:
-
Blood clots in the veins.
-
Allergic (hypersensitivity)/infusion reactions (including some life-threatening and rare fatal
reactions [rare is less than 1 in 1,000 patients]). You should inform your doctor immediately if
you have symptoms of angioedema, such as swollen face, tongue or pharynx, and difficulty in
breathing.
-
Perforation of the gut (mantle cell lymphoma)*.
-
Inflammation of the lungs.
-
Kidney failure or kidney problems.
-
Problems with wound healing.
-
Pleural effusion (fluid around the lungs).
The following side effects and frequencies are those that have been seen in patients treated with
TORISEL:
Very Common side effects occurring in more than 1 in 10 patients are:
General feeling of weakness, chills**, swelling due to fluid retention, pain (including abdominal, back,
chest and joint pain), feeling or being sick (nausea and vomiting), diarrhoea, fever, sore throat, sores
and inflammation in the mouth and/or the digestive tract, cough, upper respiratory infections**,
pneumonia**, nose bleed, runny nose, rash, itching, nail disorder, acne, dry skin, anorexia, shortness
of breath, low levels of potassium in the blood (which may cause muscle weakness), low red blood cell
count, decreased number of white blood cells**, decreased number of lymphocytes**, high blood
sugar, high cholesterol and other blood fats, abscess, infections, urinary tract infections, abnormal
kidney function (including kidney failure), change in the sense of taste, difficulty falling or staying
asleep, anxiety**, muscle pain**.
Common side effects occurring in less than 1 out of 10 patients, but more than 1 per 100
patients, are:
Gum redness and swelling, mouth pain (including sores inside the mouth), stomach bloating, high
blood pressure, redness and swelling of the tissues around the eye, including watery eye disorder, taste
loss, redness and swelling of the follicles in the skin, allergic (hypersensitivity) reactions, severe
scaling of the skin, and problems with healing after surgery, increased blood clotting (including
thrombosis of the veins, embolism in the lung), inflammation of the lung, infection in the blood,
37
-
Increased blood levels of cholesterol and triglycerides.
dehydration, depression, sleepiness, numbness and tingling of the skin, dizziness, perforation of the
gut*, bleeding from the stomach or intestines, inflammation of the lining of the stomach, trouble with
swallowing, eye or skin bleeding (bruising), yeast infection, fungal infection of the skin, and blood
tests that show changes in the way the liver or kidney are working, low levels of phosphate in the
blood, low levels of calcium in the blood.
*occurred as uncommon for renal cell carcinoma
**occurred as common for renal cell carcinoma
Uncommon side effects occurring in less than 1 out of 100 patients, but more than 1 per
1,000 patients are:
Pericardial effusion (fluid around the heart that may require drainage and can affect the pumping of
blood).
Bleeding into the brain in patients with brain tumours or who are on blood thinners
Side effects for which frequency has not been determined are:
Swelling of the face, lips, tongue, and throat, possibly causing difficulty breathing.
Serious reactions of the skin and/or mucous membranes which may include painful blisters and fever
(
Stevens-Johnson syndrome
).
Unexplained muscle pain, tenderness or weakness which could indicate muscle damage
(
rhabdomyolysis
)
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE TORISEL
Keep out of the reach and sight of children.
Do not use TORISEL after the expiry date, which is stated on the vial label and carton. The first two
numbers indicate the month; the next four numbers indicate the year.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the mixture may
be stored for up to 24 hours below 25°C and protected from light prior to further dilution.
After further dilution of the concentrate-diluent mixture with sodium chloride 9 mg/ml (0.9%) solution
for injection, the solution may be stored for up to 6 hours below 25°C and protected from light.
6.
FURTHER INFORMATION
What TORISEL contains
The active substance is temsirolimus.
38
Each vial of TORISEL concentrate contains 30 mg of temsirolimus.
The other ingredients in TORISEL are anhydrous ethanol, all-
rac-
α-tocopherol (E 307), propylene
glycol and anhydrous citric acid (E 330). The diluent contains polysorbate 80 (E 433), macrogol 400
and anhydrous ethanol.
What TORISEL looks like and contents of the pack
TORISEL is a concentrate for infusion supplied with a diluent.
The concentrate is a clear, colourless to light-yellow solution. The diluent is a clear to slightly turbid,
light-yellow to yellow solution. The solutions are essentially free from visable particulates.
Each pack of TORISEL contains one vial of 1.2 ml concentrate and one vial of 2.2 ml diluent.
Marketing Authorisation Holder
Wyeth Europa Ltd
Huntercombe Lane South
Taplow, Maidenhead
Berkshire SL6 0PH
United Kingdom
Manufacturer
Wyeth Lederle S.p.A.
Via Franco Gorgone
Zona Industriale
95100 Catania, Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer S.A./ N.V.
Tél/Tel: +32 (0)2 554 62 11
Magyarország
Pfizer Kft.
Tel.: +36 1 488 3700
Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111
Malta
Vivian Corporation Ltd.
Tel: +35621 344610
Danmark
Pfizer ApS
Tlf: +45 44 201 100
Nederland
Wyeth Pharmaceuticals B.V.
Tel: +31 23 567 2567
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Polska
Pfizer Polska Sp. z o.o.,
Tel: +48 22 335 61 00
España
Pfizer, S.A.
Tel: +34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 55 00
France
Pfizer
Tél:
+33 (0)1 58 07 34 40
Slovenská republika
Pfizer Luxembourg SARL,
organizačná zložka
Tel: +421 2 3355 5500
Ireland
Wyeth Pharmaceuticals
Suomi/Finland
Pfizer Oy
39
Tel: +353 1 449 3500
Puh/Tel: +358 (0)9 430 040
Italia
Wyeth Lederle S.p.A.
Tel: +39 06 927151
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Ελλάδα
Pfizer Hellas A.E.
Tηλ: +30 2 10 67 85 800
United Kingdom
Wyeth Pharmaceuticals
Tel: +44 845 367 0098
Κύπρος
Wyeth Hellas (Cyprus Branch) AEBE
Tηλ: +357 22 817690
България/Eesti/Latvija/Lietuva/Slovenija
Wyeth Whitehall Export GmbH
Teл./
Tel/Tãlr: +43 1 89 1140
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu There are also links to other websites about rare diseases and treatments.
40
Ísland
Icepharma hf.
Sími: +354 540 8000
Norge
Pfizer AS
Tlf: +47 67 526 100
__________________________________________________________________________________
The following information is intended for medical or healthcare professionals only:
During handling and preparation of admixtures, TORISEL should be protected from excessive room
light and sunlight.
Bags/containers that come in contact with TORISEL must be made of glass, polyolefin, or
polyethylene.
Polyvinyl chloride (PVC) bags and medical devices must not be used for the administration of
preparations containing polysorbate 80, because polysorbate 80 leaches di-2-ethylhexylphthalate
(DEHP) from PVC.
Dilution
TORISEL 30 mg concentrate must be diluted with 1.8 ml of withdrawn diluent before
administration in sodium chloride 9 mg/ml (0.9%) solution for injection.
Note: For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg. Each vial
of TORISEL must be diluted according to the instructions below. The required amount of concentrate-
diluent mixture from each vial must be combined in one syringe for rapid injection into 250 ml of
sodium chloride 9 mg/ml (0.9%) solution for injection.
In preparing the solution, the following two-step process must be carried out in an aseptic manner
according to local standards for handling cytotoxic/cytostatic drugs:
STEP 1
: DILUTION OF CONCENTRATE WITH THE SUPPLIED DILUENT
•
Withdraw 1.8 ml of the supplied diluent.
•
Inject the 1.8 ml of extracted diluent into the vial of TORISEL 30 mg concentrate.
•
Mix the diluent and the concentrate well by inversion of the vial. Sufficient time should be
allowed for air bubbles to subside. The solution should be a clear to slightly turbid, colourless
to light-yellow to yellow solution, essentially free from visual particulates.
One vial of TORISEL 30 mg concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate
is combined with 1.8 ml of withdrawn diluent, a total volume of 3.0 ml is obtained and the
concentration of temsirolimus will be 10 mg/ml. The concentrate-diluent mixture is stable below 25°C
for up to 24 hours.
STEP 2
: ADMINISTRATION OF CONCENTRATE-DILUENT MIXTURE IN SODIUM
CHLORIDE INFUSION
•
Withdraw the required amount of concentrate-diluent mixture (which contains temsirolimus
10 mg/ml) from the vial; i.e., 2.5 ml for a temsirolimus dose of 25 mg.
•
Inject the withdrawn volume rapidly into 250 ml of sodium chloride 9 mg/ml (0.9%) solution
for injection to ensure adequate mixing.
The admixture should be mixed by inversion of the bag or bottle, avoiding excessive shaking, as this
may cause foaming.
The resulting solution should be inspected visually for particulate matter and discolouration prior to
administration, whenever solution and container permit. The admixture of TORISEL in sodium
chloride 9 mg/ml (0.9%) solution for injection should be protected from excessive room light and
sunlight.
For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg.
41
Administration
• Administration of the final diluted solution should be completed within six hours from the time that
the TORISEL is first added to sodium chloride 9 mg/ml (0.9%) solution for injection.
• TORISEL is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the
preferred method of administration to ensure accurate delivery of the medicinal product.
• Appropriate administration materials must be composed of glass, polyolefin, or polyethylene to avoid
excessive loss of medicinal product and to decrease the rate of DEHP extraction. The administration
materials must consist of non-DEHP, non-PVC tubing with appropriate filter. An in-line
polyethersulfone filter with a pore size of not greater than 5 microns is recommended for
administration to avoid the possibility of particles bigger than 5 microns being infused. If the
administration set available does not have an in-line filter incorporated, a filter should be added at the
end of the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different
end-filters can be used ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an
in-line and end-filter is not recommended.
• TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP
extraction from PVC. This incompatibility has to be considered during the preparation and
administration of TORISEL. It is important that the recommendations in sections 4.2 and 6.6 in the
SPC be followed closely.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
42
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/torisel.html
Copyright © 1995-2021 ITA all rights reserved.