Consumer medicine information

Torisel

Temsirolimus

BRAND INFORMATION

Brand name

Torisel

Active ingredient

Temsirolimus

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Torisel.

What is in this leaflet

This leaflet answers some of the common questions about TORISEL. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TORISEL against the benefits it is expected to provide.

If you have any concerns about using TORISEL, ask your doctor or pharmacist. Your doctor and pharmacist have more information.

Keep this leaflet with the medicine You may need to read it again.

What Torisel is used for

TORISEL is a selective inhibitor of mTOR (mammalian target of rapamycin) that blocks tumour cell growth and division.

Clinical studies have shown that TORISEL can slow the growth of advanced cancer of the kidney and a cancer of the lymph nodes known as mantle cell lymphoma.

Your doctor may have prescribed TORISEL for another reason.

TORISEL is not recommended for use in children (under the age of 18), as there is not enough information on its effects in this age group.

Ask your doctor if you have any questions why TORISEL has been prescribed for you.

TORISEL is available only with a doctor's prescription. It is not habit-forming.

Before you are given TORISEL

When you must not be given TORISEL

Do not have TORISEL if you have an allergy to temsirolimus or any of the other ingredients in TORISEL. Signs of allergy include a skin rash, itching, shortness of breath and/or a swollen face, lips, tongue or other parts of the body.

Do not have TORISEL if you have moderate or severe liver disease. TORISEL may cause your liver problems to worsen.

If you are not sure whether any of the above conditions apply to you, ask your doctor. Do not have TORISEL if you are pregnant or think you are pregnant or you are breast-feeding. TORISEL may cause harm to your unborn child if taken during pregnancy.

It is not known if TORISEL passes into breast milk or what affect it might have on the baby.

Do not have TORISEL after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If this is the case, take the pack back to your pharmacist.

If you are not sure whether you should have TORISEL, contact your doctor.

Before you are given TORISEL

You must tell your doctor:

  • If you are allergic to sirolimus.
    The active ingredient in TORISEL is very similar to sirolimus, the active ingredient in RAPAMUNE (a medicine used to prevent organ rejection in patients who have had a kidney transplant). If you have had an allergic reaction after taking RAPAMUNE then you may be at increased risk of having an allergic reaction to TORISEL.
  • If you are allergic to antihistamines or cannot take antihistamines for some other medical reason.
    Before you receive TORISEL you may be given an antihistamine to reduce the chance of having an allergic reaction. It is important that you tell your doctor if you cannot have antihistamines.
  • If you have or have ever had problems with your liver.
    You may need extra tests to check your liver is working properly before you are given TORISEL and periodically thereafter. TORISEL may cause your liver problems to worsen. It is important to tell your doctor if you experience any yellowing of your skin or eyes (jaundice) or changes in the colour of your urine.
  • If you have or think that you may have diabetes.
    TORISEL may increase blood glucose levels. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycaemic agent therapy. Tell your doctor if you experience any excessive thirst or increased frequency of urination.
  • If you have high blood fat levels (triglycerides)
    TORISEL has been known to increase blood fat levels. If your blood levels are already high your doctor may start you on or increase the dose of, a blood fat lowering drug.

If you have not told your doctors about any of these things, tell them before you start taking TORISEL.

Taking Other Medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and TORISEL may interfere with each other. These include:

  • Antibiotics such as rifampicin, clarithromycin, telithromycin and rifabutin
  • Antifungal medicines such as ketoconazole and itraconazole
  • Epilepsy medicines such as carbamazepine, barbiturates and phenytoin
  • Protease inhibitors such as atazanavir, nelfinavir, saquinavir ritonavir and indinavir, which are used to treat HIV/AIDS
  • Medicines used to treat high blood pressure, which are called ACE inhibitors
  • A combination of ACE inhibitors and/or calcium channel blockers, which are medicines to treat high blood pressure or heart disease.
  • Medicines used to treat depression, which are called selective serotonin reuptake inhibitors (SSRIs)
  • sunitinib, which is used to treat kidney cancer
  • interferon alpha which is used to treat cancer
  • St. John's wort.

Your doctor or pharmacist has information on medicines to be careful with or avoid while you are using TORISEL.

How TORISEL is given

Follow all directions given to you by your doctor or pharmacist.

TORISEL will always be prepared and given to you by a doctor or another healthcare professional.

TORISEL is given intravenously (into your vein).

The recommended dose of TORISEL for advanced cancer of the kidney is 25 mg infused over a 30- to 60-minute period once weekly. You may be given an antihistamine before your dose of TORISEL.

The recommended dose of TORISEL 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.

How long will you receive TORISEL

Your doctor will continue to give you TORISEL for as long as you are receiving some benefit.

Do not stop having TORISEL without first talking to your doctor.

If you miss a dose of TORISEL

If you are concerned that you may have missed a dose, tell your doctor immediately.

Overdose

If you are concerned that you may have been given too much TORISEL, tell your doctor immediately.

While you are receiving TORISEL

Things you must do

If you become pregnant while using TORISEL, tell your doctor immediately. It should not be used while you are pregnant.

Women: before starting TORISEL you must be using effective contraception methods and you must continue contraception for 12 weeks after treatment has stopped. If you are unsure, or think you may have become pregnant, talk to your doctor or pharmacist. Discuss contraceptive options with your doctor.

Men: tell your doctor or pharmacist if your partner intends to become pregnant while you are using TORISEL or shortly after you have stopped receiving TORISEL.

TORISEL may cause birth defects if either the male or female is using it at the time of contraception. It is recommended that you use some kind of birth control while you are receiving TORISEL and for at least 12 weeks after the last dose.

Tell your doctor well in advance of any expected hospitalisation or surgery. If you go to hospital unexpectedly, tell the doctor who admits you that you are using TORISEL. TORISEL has been associated with abnormal wound healing.

Tell any other doctor, dentist or pharmacist who treats you that you are taking TORISEL.

Tell your doctor you are receiving TORISEL if you also want to be vaccinated. TORISEL may affect your response to vaccination.

Tell your doctor if you are taking any medicines that suppress your immune system, including corticosteroids.

Your doctor may prescribe antibiotics for you.

It is important to take the antibiotics as directed by your doctor, even if you do not feel sick.

Follow the following hygiene procedures whilst using TORISEL

TORISEL is used to fight cancer, and the breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomit and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period by:

  • Flushing the toilet twice to dispose of any body fluids and waste
  • Wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
  • Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
  • Place soiled disposable nappies and other pads in a plastic, seal and dispose into the garbage.
  • For sexual intercourse, use a barrier method such as a condom.

Things you must not do

Do not stop having TORISEL without first checking with your doctor.

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are taking TORISEL.

All medicines have side effects. Often they are not serious but sometimes they can be. You may need medical treatment if you get some side effects.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing.

Tell your doctor if you experience any of the following:

  • General feeling of weakness
  • Rash
  • Sore, red mouth
  • Swelling due to fluid retention
  • Nausea
  • Loss of appetite

These are the most common side effects of TORISEL.

TORISEL may also cause the following side effects:

  • Pain (including abdominal, joint, back and chest pain)
  • Fever
  • Diarrhoea
  • Vomiting
  • Cough
  • Sore throat
  • Infections, including urinary tract infections or upper respiratory tract infections
  • Pneumonia
  • Abscess
  • Shortness of breath
  • Nose bleed
  • Runny nose
  • Itching
  • Nail disorder
  • Acne
  • Dry skin
  • Change in the sense of taste
  • Constipation
  • Chills
  • Gum inflammation
  • Conjunctivitis
  • Twitching or abnormal heart rhythm
  • Increased thirst
  • Increased frequency of urination
  • High blood sugar
  • Abnormal kidney function
  • Abnormal liver function
  • High blood pressure
  • Low levels of potassium in the blood (which may cause muscle weakness)
  • Interstitial lung disease
  • High cholesterol and triglyceride (blood fat) levels
  • Perforation of the bowel
  • Impaired healing of wounds
  • Cataracts
  • Blood disorders
  • Blood clots
  • Temporary paralysis or weakness of muscles
  • Yellowing of skin and eyes (jaundice)

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Product Description

What it looks like

Each carton of TORISEL contains two vials. One vial contains the active ingredient. The other contains the diluent.

Ingredients

The active ingredient is temsirolimus.

The following inactive ingredients are also found in TORISEL:

TORISEL Concentrate for Injection.

  • Absolute ethanol
  • dl-Alpha-tocopherol
  • Propylene glycol
  • Citric acid

The diluent contains:

  • Polysorbate 80
  • Macrogol 400
  • Absolute ethanol.

Storage

Keep out of the reach and sight of children.

Store in a refrigerator (2°C-8°C).

Keep the vial in the outer carton in order to protect from light.

Do not freeze.

Do not use this medicine after the expiry date stated on the vial label and carton. The first two numbers indicate the month; the next four numbers indicate the year.

Infusion solutions should be discarded immediately after dilution, and any unused medicine should be discarded.

Manufacturer

TORISEL is supplied in Australia by

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number 1800 675 229

Australian Registration Number:
TORISEL 25 mg
AUST R 133125

This leaflet was prepared in April 2020.

® Registered Trademark

© Pfizer Australia Pty Ltd

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Torisel

Active ingredient

Temsirolimus

Schedule

S4

 

1 Name of Medicine

Temsirolimus.

6.7 Physicochemical Properties

Temsirolimus is a white to off white powder. It is nonhygroscopic. Temsirolimus is insoluble in water and soluble in ethanol. It has no ionisable functional groups and its solubility is independent of pH.
Temsirolimus is the 2,2-bis(hydroxymethyl) propionic acid ester of sirolimus, a macrocyclic lactone produced by Streptomyces hygroscopicus.
The chemical name is: (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,10,12, 13,14,21,22,23,24,25,26,27,32,33,34,34a- hexadecahydro-9,27- dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4- hydroxy-3- methoxycyclohexyl]-1- methylethyl]-10,21- dimethoxy-6,8,12,14,20,26- hexamethyl-23,27- epoxy-3H- pyrido [2,1-c][1,4] oxaazacyclohentriacontine- 1,5,11,28,29(4H,6H,31H)- pentone 4' -[2,2-bis(hydroxymethyl)propionate]; or rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate].

Chemical structure.

The structural formula of temsirolimus is shown below:
Molecular Formula: C56H87NO16.
Molecular Weight: 1030.3.

CAS number.

162635-04-3.

2 Qualitative and Quantitative Composition

Each vial of Torisel (temsirolimus) concentrate for injection contains 30 mg temsirolimus.
Each vial of diluent contains ethanol absolute 438 mg, macrogol-400 941 mg and polysorbate 80, 880 mg.

Excipient(s) with known effect.

Torisel vial: ethanol absolute.
Diluent vial: ethanol absolute.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Temsirolimus concentrate for injection vial.

Concentrate for injection.

Diluent vial.

Solution for injection.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). In humans, sirolimus is a major metabolite of temsirolimus that was equipotent to temsirolimus at inhibiting mTOR phosphorylation, and at inhibiting cell proliferation or tumour cell growth both in tissue culture and in nude mouse xenograft models. Temsirolimus binds to an intracellular protein (FKBP-12), and the protein drug complex binds and inhibits the activity of mTOR that controls cell proliferation. Inhibition of mTOR activity results in a G1 growth arrest in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc and ornithine decarboxylase. Temsirolimus exerts its effect by binding in a complex with FKBP-12 and mTOR. When mTOR is bound in this complex, its ability to phosphorylate, and thereby control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the PI3 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 antitumour 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.

Concentration effect relationship.

The effect of temsirolimus intravenous treatment on the inhibition of phosphorylation of S6 ribosomal protein in circulating lymphocytes was examined in 30 healthy subjects. Data indicate that inhibition of protein phosphorylation was rapid and dose dependent. Following a single 25 mg intravenous dose of temsirolimus, 20% and 50% of inhibition of S6 ribosomal protein was shown for at least 8 days and 3 days, respectively.

Clinical trials.

Renal cell carcinoma.

The safety and efficacy of Torisel in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomised clinical trials.

Study 1.

Study 1 was a phase 3, multicentre, 3 arm, randomised, open label study in previously untreated patients with advanced renal cell carcinoma (RCC) and with 3 or more of 6 preselected risk factors indicating a poor prognosis (less than 1 year from time of initial RCC 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 1 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 3 geographic regions and were randomly assigned (1:1:1) to receive interferon alpha (IFN-α) alone (n = 207), Torisel alone (25 mg weekly; n = 209), or the combination of IFN-α and Torisel (n = 210).
The combination arm did not exhibit a positive clinical benefit risk ratio compared to IFN-α. Treatment with the combination of Torisel 15 mg and IFN-α resulted in a statistically significant increase in the incidence of certain grade 3-4 adverse events (weight loss, hyperlipidaemia, anaemia, neutropenia, thrombocytopenia and mucosal inflammation) when compared to the adverse events observed in the IFN-α or Torisel 25 mg alone arms. The combination of Torisel 15 mg and IFN-α did not result in a significant increase in OS when compared to IFN-α alone (median 8.4 vs. 7.3 months, hazard ratio = 0.96, p = 0.6965).
Information on the Torisel 25 mg alone and IFN-α alone arms is described in this section. The demographic and disease characteristics of the study population are shown in Table 6. Baseline demographic and disease characteristics were well balanced across treatment arms.
In study 1, Torisel was associated with a statistically significant advantage over IFN-α in the primary endpoint of OS (time from randomisation to death). The Torisel arm showed a 49% increase in median OS compared with the IFN-α arm.
Figure 1 is a Kaplan-Meier plot of OS in study 1. Torisel was also associated with statistically significant advantages over IFN-α in the secondary endpoints of PFS (time from randomisation to disease progression or death, censored at the last tumour evaluation date); TTF (time from randomisation to disease progression, death, withdrawal from treatment due to an adverse event, withdrawal of voluntary consent or loss to follow-up) and clinical benefit rate (complete response, partial response or stable disease for > 24 weeks). The evaluations of PFS, ORR and clinical benefit rate were based on blinded independent radiologic assessment of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) based criteria. TTF utilised the investigator's assessment of progression. Efficacy results are summarised in Table 7.
In clinical study 1, 31% of patients treated with Torisel were 65 years or older. In patients younger than 65, median OS for patients treated with Torisel was 12 months (95% CI 9.9-14.5) with hazard ratio of 0.62 (95% CI 0.47-0.82), compared with IFN-α. In patients 65 years or older, median OS was 8.6 months (95% CI 6.4-11.5) with hazard ratio of 1.08 (95% CI 0.71-1.63) compared to those treated with IFN-α.

Quality adjusted survival.

Quality adjusted survival was compared across treatment groups using the quality adjusted time without symptoms and toxicities (Q-TWiST) approach. Survival was value weighted by the patient based on presence or absence of toxicity or progression by completing the EuroQoL 5D (EQ-5D) scale at baseline, weeks 12 and 32, when a grade 3 or 4 toxicity was reported, upon relapse or progression, or upon withdrawal from the study. Torisel is associated with a statistically significant increase in quality adjusted survival (Q-TWiST) time of an estimated 1.3 months (7.0 vs. 5.7 months, 23%) as compared to IFN-α.

Study 2.

Study 2 was a randomised, double blind, multicentre, outpatient trial to evaluate the efficacy, safety and pharmacokinetics of three dose levels of Torisel when administered to previously treated patients with advanced RCC. The primary efficacy endpoint was ORR. Clinical benefit rate, PFS and OS were also evaluated. PFS was defined as time from the first dose of Torisel to disease progression or death. One hundred eleven (111) patients were randomly assigned in a 1:1:1 ratio to receive 25 mg, 75 mg or 250 mg Torisel IV weekly. In the 25 mg arm, 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 RCC. 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 IV Torisel, the median OS was 13.8 months (95% CI: 9.0, 18.7 months); median PFS was 6.3 months (95% CI: 3.6, 7.8 months); ORR was 5.6% (95% CI: 0.7, 18.7%) and clinical benefit rate was 52.8% (95% CI: 35.5, 69.6%).

Mantle cell lymphoma.

The safety and efficacy of IV temsirolimus for the treatment of relapsed and/or refractory mantle cell lymphoma was studied in the following phase 3 clinical study.

Study 3.

Study 3 is a controlled, randomised, open label, multicenter, outpatient study comparing 2 different dosing regimens of Torisel 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 Torisel 175/75 (temsirolimus IV 175 mg (3 successive weekly doses) followed by 75 mg weekly (n = 54)), Torisel 175/25 (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).
The primary endpoint of the study was PFS. Secondary endpoints included OS and ORR. ORR was assessed using the international workshop modified response criteria for non-Hodgkin's lymphoma. PFS and ORR were assessed by blinded independent radiologists and oncologists.
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 median treatment time was 12 weeks for Torisel 175/75, 14 weeks for Torisel 175/25 and 5 weeks for investigator's choice. Torisel 175/75 significantly increased tumour response and progression free survival compared with investigator choice (see Table 8). Torisel 175/25 did not differ significantly from investigator choice. The study was not powered to assess differences in OS.

5.2 Pharmacokinetic Properties

Absorption.

Following administration of a single 25 mg intravenous dose of temsirolimus in patients with cancer, mean Cmax in whole blood was 585 nanogram/mL (coefficient of variation, CV = 14%), and mean AUC in blood was 1627 nanogram.h/mL (CV = 26%).

Distribution.

Temsirolimus exhibits a polyexponential decline in whole blood concentrations and distribution and is attributable by preferential binding to FKBP-12 in blood cells. The mean (standard deviation, SD) dissociation constant (Kd) of binding was 5.1 (3.0) nanogram/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 intravenous dose, mean steady-state volume of distribution in whole blood of patients with cancer was 172 litres. Plasma protein binding is approximately 89%.

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, secotemsirolimus and secosirolimus, were observed; additional metabolic pathways were hydroxylation, reduction and demethylation. Sirolimus and temsirolimus are metabolised predominantly by CYP3A4. 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.

Excretion.

Following a single 25 mg intravenous dose of temsirolimus in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. Mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively. Following administration of [14C]-labelled temsirolimus, excretion was predominantly via the faeces (78%), with renal elimination of drug and metabolites accounting for 4.6% of the administered dose.

Special populations.

Elderly.

In population pharmacokinetic based data analyses, age did not have a significant effect on the disposition of temsirolimus or sirolimus metabolite.

Paediatric.

There are no data available for paediatric patients.

Gender.

In population pharmacokinetic based data analyses, gender did not have a significant effect on the disposition of temsirolimus or sirolimus metabolite.

Patients with renal impairment.

Temsirolimus elimination through kidneys is low. Since differences in creatinine clearance do not affect temsirolimus disposition, no change in temsirolimus intravenous treatment regimen is required for patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Patients with hepatic insufficiency or hepatic impairment.

Temsirolimus is cleared predominantly by the liver. No data are currently available regarding the influence of hepatic dysfunction and/or hepatic metastases on temsirolimus disposition.
Temsirolimus is contraindicated in patients with bilirubin > 1.5 x ULN (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Effects of food.

The effect of food on exposure following an intravenous dose of temsirolimus was not examined.

5.3 Preclinical Safety Data

Genotoxicity.

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.

Carcinogenicity studies have not been conducted with temsirolimus. However, sirolimus, the major metabolite of temsirolimus in humans, was carcinogenic in mice and rats. Increased incidences of lymphoma, hepatocellular adenoma and carcinoma in mice, and testicular adenoma in rats were reported following oral dosing of sirolimus in carcinogenicity studies.

4 Clinical Particulars

4.1 Therapeutic Indications

Renal cell carcinoma.

Torisel is indicated for the treatment of advanced renal cell carcinoma.

Mantle cell lymphoma.

Torisel is indicated for the treatment of patients with relapsed and/or refractory mantle cell lymphoma.

4.3 Contraindications

Torisel is contraindicated in patients with a known hypersensitivity to temsirolimus or any component of this formulation.
Torisel is contraindicated in patients with bilirubin > 1.5 x ULN (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

4.4 Special Warnings and Precautions for Use

Hypersensitivity/infusion reactions.

Hypersensitivity/infusion reactions (including some life threatening and rare fatal reactions), including but not limited to flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. 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 should be done prior to the continuation of temsirolimus therapy in patients with severe or life threatening reactions.
Sirolimus is the major metabolite of temsirolimus, therefore, Torisel should be administered with caution in patients with a known hypersensitivity to sirolimus.
Because it is recommended that an H1 antihistamine be administered to patients before the start of the intravenous Torisel infusion, Torisel should be used with caution in patients with known hypersensitivity to an antihistamine or patients who cannot receive an antihistamine for other medical reasons.
If a patient develops a hypersensitivity reaction during the Torisel infusion despite the premedication, the infusion should be stopped and the patient should be 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 with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Torisel infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).

Hyperglycaemia/glucose intolerance.

The use of Torisel in renal cell carcinoma patients was associated with increases in serum glucose. In study 1, a phase 3 clinical trial for renal cell carcinoma, 26% of patients reported hyperglycaemia as an adverse event. In study 3, 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 oral hypoglycaemic agent therapy. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Infections.

Patients may be immunosuppressed and should be carefully observed for the occurrence of infections, including opportunistic infections. Cases of Pneumocystis jiroveci pneumonia (PJP), some with fatal outcomes, have been reported in patients who received temsirolimus, many of whom also received corticosteroids or other immunosuppressive agents. For patients who require concomitant use of corticosteroids or other immunosuppressive agents, prophylaxis of PJP may be considered.

Interstitial lung disease.

There have been cases of nonspecific 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 temsirolimus therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.
It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms.
If clinically significant respiratory symptoms develop, consider withholding temsirolimus administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Opportunistic infections such as PJP should be considered in the differential diagnosis. Empiric treatment with corticosteroids and/or antibiotics may be considered. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.

Hyperlipidaemia.

The use of Torisel was associated with increases in serum triglycerides and cholesterol. In study 1, hyperlipidaemia was reported as an adverse event (including elevated triglycerides and/or cholesterol) in 27% of patients. In study 3, hyperlipidaemia 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.

Bowel perforation.

Cases of bowel perforation (including fatal outcomes) have occurred in patients who received Torisel.

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 perisurgical period.

Intracerebral bleeding.

Patients with central nervous system 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 Torisel.

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.

Thrombocytopenia and neutropenia.

Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed in study 3 (mantle cell lymphoma).

Cataracts.

Cataracts have been observed in some patients who received the combination of Torisel and IFN-α.

Vaccinations.

The use of live vaccines should be avoided during treatment with Torisel. Examples of live vaccines are measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin (BCG), yellow fever, varicella, and TY21a typhoid vaccines.

Use in hepatic impairment.

Torisel was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 1). Patients with moderate and severe hepatic impairment had increased rates of adverse events and deaths, including deaths due to progressive disease, during the study.
Torisel is contraindicated in patients with bilirubin > 1.5 x ULN due to increased risk of death, including deaths due to progression of underlying cancer (see Section 4.3 Contraindications).
Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. Assessment of AST and bilirubin levels is recommended before initiation with temsirolimus and periodically thereafter.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Use in patients with renal impairment; Section 4.4 Special Warnings and Precautions for Use, Renal failure.

Use in the elderly.

Based on the results of a phase 3 study for renal cell carcinoma, elderly patients may be more likely to experience certain adverse reactions, including oedema, diarrhoea, and pneumonia. Based on the results of a phase 3 study for mantle cell lymphoma, elderly patients may be more likely to experience certain adverse reactions, including anxiety, depression, dyspnoea, leukopenia, myalgia, taste loss, and upper respiratory infection.
Overall survival in a subset of patients 65 years of age or older (n = 64) treated with Torisel was shorter than that observed with patients under 65 years of age and was not significantly different from INF-α (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The clinical relevance of this subgroup analysis is unclear.
No specific dose adjustment is recommended for elderly patients.

Paediatric use.

The safety and effectiveness of Torisel in paediatric patients have not been established.

Effects on laboratory tests.

Not applicable.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Temsirolimus and its active metabolite sirolimus are metabolised predominately by CYP3A4/5.

Agents inducing CYP3A metabolism.

Agents such as carbamazepine, phenytoin, barbiturates, rifabutin, rifampicin and St John's wort are strong inducers of CYP3A4/5 and may decrease composite exposures of the active moieties, temsirolimus and its metabolite, sirolimus. Therefore, concomitant treatment with agents that have CYP3A4/5 induction potential should be avoided. If alternative treatment cannot be administered, a weekly intravenous dose up to 50 mg should be considered. 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.
Coadministration of Torisel with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus maximum concentration (Cmax) and AUC after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56%, and AUCsum (composite of temsirolimus AUC plus sirolimus AUC) by 41% compared to Torisel treatment alone.

Agents inhibiting CYP3A metabolism.

Agents such as protease inhibitors (such as atazanavir, indinavir, nelfinavir, ritonavir and saquinavir), antifungals (such as itraconazole and ketoconazole), and macrolide antibiotics (such as clarithromycin and telithromycin) 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 CYP3A4 inhibition potential should be avoided. Concomitant treatment with moderate CYP3A4 inhibitors should only be administered with caution in patients receiving 25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg.
Alternative treatments with agents that do not have CYP3A4 inhibition potential should be considered.
Coadministration of Torisel with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and AUCsum increased 2.3-fold compared to Torisel alone. Substances that are potent inhibitors of CYP3A4 activity increase sirolimus blood concentrations.

Interactions with drugs metabolised by CYP2D6.

In 23 healthy subjects the concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of Torisel was coadministered. In 36 patients with MCL, including 4 poor metabolisers, the effect of CYP2D6 inhibition after administration of a single dose of 175 mg and 75 mg temsirolimus was investigated. Population PK analysis based on sparse sampling indicated no clinically significant interaction effect on desipramine AUC and Cmax in plasma. No clinically significant effect is anticipated when Torisel is coadministered with agents that are metabolised by CYP2D6.

Interactions with drugs metabolised by CYP3A4/5.

Patients with RCC.

The effect of a 25 mg dose of temsirolimus on CYP3A4/5 substrates has not been studied. In vitro studies in human liver microsomes and simulation using physiologically based PK modelling indicate that the blood concentrations achieved after 25 mg dose of temsirolimus may increase the AUC and Cmax of midazolam, a CYP3A4/5 substrate, by 28% and 9% respectively. No clinically significant effect is anticipated when temsirolimus at a dose of 25 mg is coadministered with agents that are metabolised by CYP3A4/5.

Patients with MCL.

The effect of a 175 mg or 75 mg temsirolimus dose on CYP3A4/5 substrates has not been studied. However, in vitro studies in human liver microsomes and simulations using physiologically based PK models indicate that the blood concentrations achieved after a 175 mg dose of temsirolimus may increase the AUC and Cmax of midazolam by 182% and 40%, respectively. PK modelling at a 75 mg dose of temsirolimus was not studied. Therefore, caution is advised during concomitant administration of Torisel to patients with MCL with medicinal products that are metabolised predominantly via CYP3A4/5 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 digoxin, a P-glycoprotein (P-gp) substrate, with an IC50 value of 2 microM. Clinical implications related to concomitant administration of P-gp substrates are not known.

Concomitant use of Torisel with sunitinib.

The combination of Torisel 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 I study at doses of Torisel 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 Torisel and ACE inhibitors concomitantly.

Concomitant use of ACE inhibitors and/or calcium channel blockers.

An increased risk of angioedema is possible in patients taking mTOR inhibitors in combination with ramipril and/or amlodipine. Caution should be used when temsirolimus is given concomitantly with an ACE inhibitor (e.g. ramipril) or a calcium channel blocker (e.g. amlodipine).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In male rats, fertility was decreased at doses ≥ 0.5 mg/kg/day PO. Exposure (AUC; normalised for the frequency of administration) at this dose was below that expected at the maximum recommended human dose. Fertility was absent at 5 mg/kg/day. These effects on male fertility were accompanied by testicular tubular degeneration, decreased sperm concentration and motility, and decreased reproductive organ weights at dosages ≥ 0.5 mg/kg/day.
In female rats given temsirolimus for 2 weeks prior to mating until gestation day 6, there were increased incidences of pre and post-implantation losses at dosages ≥ 0.7 mg/kg/day PO, resulting in decreased numbers of live foetuses which was considerably less than the maximum recommended dose on an AUC basis.
(Category D)
There are no adequate and well controlled studies in pregnant women using Torisel.
In oral developmental toxicity studies in rats, there was increased embryo/foetal mortality and decreased foetal growth at dosages ≥ 0.45 mg/kg/day. Exposure at this dose was considerably below that expected at the maximum recommended human dose on an AUC basis.
In oral developmental toxicity studies in rabbits, there was increased embryo/foetal mortality and decreased foetal growth at dosages ≥ 0.6 mg/kg/day. Exposure at this dose was considerably below that expected at the maximum recommended human dose on an AUC basis.
Women of childbearing age should use medically acceptable contraception during (and up to 12 weeks after) treatment.
Torisel should not be used during pregnancy.
If a patient becomes pregnant during treatment with Torisel, she and her treating physician should have a thorough discussion of the diagnosis, alternative options and the potential risks of Torisel to the developing foetus.
In addition, men should be adequately counselled prior to starting treatment with Torisel and need to understand the possible danger of taking a drug whose effects on the foetus or sperm are unknown. Men with partners of childbearing potential should use medically acceptable contraception throughout treatment and are recommended to continue this for 12 weeks after the last dose of Torisel.
There is no information available for labour and delivery.
 Lactation studies of intravenous Torisel have not been conducted.
It is not known whether temsirolimus is excreted into human milk. Because many drugs are excreted in human milk, and because the effects of temsirolimus excretion in human milk have not been studied, women should be advised against breastfeeding while receiving Torisel.

4.8 Adverse Effects (Undesirable Effects)

The following serious adverse reactions have been associated with Torisel in clinical trials and are discussed in greater detail (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity/infusion reactions.
Hepatic impairment.
Hyperglycaemia/glucose intolerance.
Infections.
Interstitial lung disease.
Hyperlipidaemia.
Bowel perforation.
Wound healing complications.
Thrombocytopenia and neutropenia.
Renal failure.
The most common (≥ 30%) adverse reactions observed with Torisel are rash, asthenia, mucositis, nausea, oedema and anorexia. The most common (≥ 30%) laboratory abnormalities observed with Torisel are anaemia, hyperglycaemia, hyperlipaemia, hypertriglyceridaemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphataemia, thrombocytopenia, elevated AST, and leukopenia.

Clinical trials experience.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Renal cell carcinoma.

In the phase 3 randomised, open label study of interferon alpha (IFN-α) alone, Torisel alone, and Torisel and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Torisel 25 mg weekly, and 208 patients received a combination of Torisel and IFN-α weekly (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Treatment with the combination of Torisel 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.
Table 2 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Torisel 25 mg alone or IFN-α alone are listed. Table 3 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison.
The following selected adverse reactions were reported less frequently (< 10%).

Gastrointestinal disorders.

Fatal bowel perforation (0.5%), abdominal distension (4.3%), dysphagia (3.4%), mouth pain (2.4%), gingivitis (2.4%), gastritis (1.0%), gastrointestinal haemorrhage (1.0%), haemorrhoidal haemorrhage (1.0%), lip haemorrhage (0.5%), mouth haemorrhage (0.5%), rectal haemorrhage (1.0%).

Eye disorders.

Conjunctivitis (including lacrimation disorder) (7.7%).

Immune system.

Allergic/hypersensitivity reactions (9%).
Angioneurotic oedema type reactions have been observed in some patients who received Torisel and ACE inhibitors concomitantly.

Infections.

Rhinitis (9.6%), pneumonia (8%); upper respiratory tract infection occurred in 14 patients (7%), flu syndrome (3.4%), oral moniliasis (2.4%), sinusitis (1.9%), folliculitis (1.9%), wound infection/postoperative wound infection (1.0%), laryngitis (1.0%), fungal infection/fungal dermatitis (1.0%), sepsis (0.5%).

General disorders and administration site conditions.

Diabetes mellitus (4.8%), dehydration (4.8%), impaired wound healing (1.4%), generalised oedema (0.5%).

Respiratory, thoracic and mediastinal disorders.

Pleural effusion (3.8%), interstitial lung disease (2.9%), including rare fatalities.

Vascular.

Hypertension (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%); thrombophlebitis (1%), pericardial effusion (1%).

Nervous system disorders.

Dizziness (9.1%), anxiety (7.7%), somnolence (6.7%), paraesthesia (6.3%), convulsion (0.5%).

Mantle cell lymphoma.

Fifty-four patients were treated with Torisel 175/75 in the initial treatment period in study 3, a randomised, open label trial comparing two Torisel dosing regimens with an investigator's choice regimen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). During an additional 40 months of safety follow-up, patients who had previously discontinued therapy or were receiving either investigator's choice regimen or Torisel 175/25 were eligible to crossover to Torisel 175/75 treatment. In this safety population Torisel 175/75 n = 57, Torisel 175/25 n = 56, and investigator's choice regimen n = 54.
All treatment groups in the safety population experienced a high incidence of adverse events (over 95%). During the high dose part of Torisel treatment (first three doses), approximately half the subjects had a dose reduction and two-thirds a dose delay. The dose delay was mostly 1-3 days. Table 4 lists the common events (incidence ≥ 10%) that were considerably more frequent with Torisel 175/75 than investigator choice therapy. Of the common events, only neutropenia (41% vs. 26%), leukopenia (41% vs. 18%), oedema (13% vs. 5%), dyspnoea (30% vs. 23%), constipation (19% vs 16%), lymphopenia (19% vs. 12%) and sweating (13% vs. 2%) were considerably more frequent in the investigator choice group than the Torisel 175/75 group.
In the safety population, there was a higher incidence of severe (grade 3-4) adverse events, serious adverse events and deaths within 14 days of last dose in the Torisel groups than in the investigator choice group. For severe adverse events, the incidences were 95%, 88% and 76% for Torisel 175/75, Torisel 175/25 and investigator choice, respectively. For serious adverse events, the incidences were 60%, 61% and 28% and for deaths, 7%, 4% and 2%. Serious reactions with Torisel were fever, diarrhoea, infection, general physical health deterioration, thrombocytopenia, neutropenia, infection, interstitial lung disease (pneumonitis), bowel perforation, hypersensitivity and hyperglycaemia/glucose intolerance.
Deaths due to adverse events occurred in two (4%) temsirolimus 175/75 patients and three (6%) temsirolimus 175/25 patients. There were no deaths due to adverse events in patients receiving investigator choice. Three deaths in the Torisel groups were considered possibly related to the drug, one each due to duodenal perforation, sepsis and pneumonitis. The treatment and observation periods for temsirolimus were considerably longer than for investigator choice (median 12-14 weeks vs. 5 weeks for treatment), which would account for some of the difference in adverse event profiles.
The incidence of thrombocytopenia with Torisel 175/75 was 79% compared with 54% with investigator choice. Both the drug and the underlying disease are likely to be contributing factors. The majority of cases of thrombocytopenia were severe. Minor bleeding, in particular epistaxis, was common and more frequent in this trial than in renal carcinoma patients.
Adverse events of higher incidence with Torisel in this trial compared with previous experience in the lower dose renal carcinoma trial were thrombocytopenia, neutropenia, infection, diarrhoea, asthenia and pneumonitis.
Elderly patients (≥ 65 years) may be more likely to experience certain adverse reactions with Torisel including anxiety, depression, dyspnoea, leukopenia, myalgia, taste loss and upper respiratory infection.
Table 5 contains the incidence of ADRs occurring at all frequencies and the incidence of grade 3 and 4 ADRs for the Torisel 175/75 mg treatment group in study 3. The information in the table is based on the MedDRA dictionary. The frequency categories are very common: ≥ 1/10 and common: ≥ 1/100 to < 1/10.
Serious adverse reactions observed in clinical trials of Torisel for renal cell carcinoma but not in clinical trials of Torisel for mantle cell lymphoma include: anaphylaxis, impaired wound healing, renal failure with fatal outcomes, pericardial effusion (including haemodynamically significant pericardial effusions requiring intervention), convulsions, and pulmonary embolus.

Post-marketing experience.

Additional adverse events reported from worldwide marketing experience with Torisel, occurring under circumstances where causal relationship with Torisel is uncertain. The events are listed using the CIOMS frequency categories as follows: very common (≥ 10%); common (≥ 1%); uncommon (≥ 0.1%, < 1%); rare (≥ 0.01%, < 0.1%); very rare (< 0.01%).

Cardiac disorders.

Uncommon: pericardial effusion (including haemodynamically significant pericardial effusions requiring intervention).

Respiratory, thoracic and mediastinal disorders.

Common: pleural effusion.

Nervous system disorders.

Uncommon: convulsion.

Musculoskeletal and connective tissue disorders.

Common: myalgia (including myalgia, leg cramps).

Infections and infestations.

Rare: Pneumocystis jiroveci pneumonia, some with fatal outcomes (see Section 4.4 Special Warnings and Precautions for Use).
The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson syndrome, pancreatitis, cholecystitis, and cholelithiasis.
Angioneurotic oedema type reactions have been reported in patients who received temsirolimus, including in some patients who received temsirolimus and ACE inhibitors concomitantly.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. No special dosage modification is required for any of the populations that have been studied (e.g. gender, elderly).

Renal cell carcinoma.

The recommended dose of Torisel for advanced renal cell carcinoma is 25 mg, infused over a 30-60 minute period once a week.
Management of suspected drug reactions may require temporary interruption and/or dose reduction of Torisel therapy. If a suspected reaction is not manageable with dose delays, then temsirolimus concentrate for injection 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.
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 as follows: if the reaction occurs during the 175 mg dosing, the 175 mg weekly dose should be reduced to 75 mg weekly. Thereafter, the dose may be reduced by 25 mg/week decrements, to a minimum of 25 mg weekly.

Instructions for intravenous administration.

Torisel and diluent must be stored under refrigeration at 2°C-8°C and protected from light. During handling and preparation of admixtures, Torisel should be protected from excessive room light and sunlight.
Torisel and diluent should be inspected visually for particulate matter and discoloration prior to administration. Bags/containers that come in contact with Torisel must be made of glass, polyolefin, or polyethylene.
Do not use if particulates are present. Use a new vial.

Premedication.

Patients should receive prophylactic medication of an intravenous antihistamine approximately 30 minutes before the start of each dose of Torisel infusion. If a hypersensitivity/infusion reaction develops during the Torisel infusion, the infusion should be stopped.
Upon adequate resolution and at the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (or equivalent), if not previously administered, and/or an H2-receptor antagonist (such as intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Torisel infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).

Dilution.

Note.

For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg. Each vial of Torisel should be diluted according to the instructions below. The required contents from each vial should be combined in one syringe for injection into 250 mL of 0.9% sodium chloride injection.
The diluted solution (concentrate and diluent) should be inspected visually for particulate matter and discolouration.
In preparing the temsirolimus administration solution, follow this two step dilution process in an aseptic manner.

Step 1.

Inject 1.8 mL of supplied diluent into the vial of Torisel concentrate for injection. Mix well by inversion of the vial. One vial of Torisel concentrate contains 30 mg of temsirolimus. When the 1.2 mL vial of concentrate is combined with 1.8 mL of diluent, a total volume of 3.0 mL is obtained, and the concentration of temsirolimus is 10 mg/mL.
Allow sufficient time for air bubbles to subside from the Torisel concentrate diluent mixture. The resulting solution is clear to slightly turbid, colourless to light yellow to yellow, essentially free from visual particulates. Only 2.5 mL of solution, containing 25 mg temsirolimus, should be extracted from the vial.
The Torisel concentrate diluent mixture is chemically stable when stored at controlled room temperature 20°C to 25°C for up to 24 hours. However, to reduce microbiological hazard the mixture should be used as soon as possible after preparation.

Step 2.

Withdraw the required amount of Torisel concentrate for injection/diluent mixture from step 1 (10 mg/mL) and inject rapidly into 250 mL of 0.9% sodium chloride injection to ensure adequate mixing. Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.
The final diluted solution in the bag or bottle should be inspected visually for particulate matter.

Administration.

Administration of the final diluted infusion solution should be completed within six hours from the time that the concentrate diluent mixture is added to the sodium chloride injection.
The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the drug.
Appropriate administration materials must be composed of glass, polyolefin, or polyethylene to avoid excessive loss of drug and to decrease the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction. The administration materials must consist of non-DEHP nonpolyvinyl chloride (PVC) tubing with the appropriate filter. It is important that the recommendations in this section be followed closely.
An inline 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 inline 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 inline and end filter is not recommended.
Torisel, when constituted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Torisel, including storage time elapsed in a PVC container following constitution.
Infusion sets and bags made of soft plastic such as ethylene vinyl acetate should not be used due to the potential to lose drug over time.
It is important that the recommendations (see Section 4.2 Dose and Method of Administration) are followed closely.

Use in patients with renal impairment.

Following a 25 mg intravenous dose of [14C]-labelled temsirolimus in healthy subjects, renal elimination of total radioactivity was 4.6% of the administered dose. Renal elimination is a minor pathway; therefore, renal impairment is not expected to markedly influence drug exposure and no dosage adjustment of Torisel is required in patients with renal impairment. Studies in patients with varying renal impairment have not been conducted.
Torisel has not been studied in patients undergoing haemodialysis.

Use in patients with hepatic impairment.

Temsirolimus is contraindicated in patients with bilirubin > 1.5 x ULN due to increased risk of death, including deaths due to progression of underlying cancer (see Section 4.3 Contraindications).
Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. Assessment of AST and bilirubin levels is recommended before initiation of temsirolimus and periodically thereafter.

Use in children.

The safety and effectiveness of Torisel in paediatric patients have not been established.

Use in elderly patients.

No specific dose adjustment is recommended for elderly patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Compatibilities, incompatibilities.

Torisel concentrate for injection should not be added directly to aqueous infusion solutions. Direct addition of Torisel concentrate for injection to aqueous solutions will result in precipitation of drug. Always combine Torisel concentrate for injection with diluent for Torisel concentrate for injection before adding to infusion solutions. It is recommended that Torisel be administered in 0.9% sodium chloride injection after combining with diluent. The stability of temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of temsirolimus in sodium chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases and thus, combinations of temsirolimus with agents capable of modifying solution pH should be avoided.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

There is no specific treatment for temsirolimus overdose, however, temsirolimus has been safely administered to patients with cancer with repeated intravenous doses as high as 220 mg/m2.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Temsirolimus concentrate for injection vial.

Ethanol absolute, dl-alpha-tocopherol, propylene glycol, citric acid.

Diluent vial.

Polysorbate 80, macrogol 400, ethanol absolute.

6.2 Incompatibilities

Torisel Concentrate for Injection should not be added directly to aqueous infusion solutions. Direct addition of Torisel Concentrate for Injection to aqueous solutions will result in precipitation of drug. Always combine Torisel Concentrate for Injection with diluent for Torisel Concentrate for Injection before adding to infusion solutions. It is recommended that Torisel be administered in 0.9% sodium chloride injection after combining with diluent. The stability of temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of temsirolimus in sodium chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Components.

Torisel concentrate for injection and diluent should be protected from excessive room light and sunlight during handling and preparation of admixtures. Torisel concentrate for injection should be inspected visually for particulate matter and discoloration following reconstitution and prior to administration. Bags/containers that come in contact with Torisel concentrate for injection must be made of glass, polyolefin, or polyethylene.
Torisel concentrate for injection must be refrigerated (2°C to 8°C) and protected from light. Torisel concentrate for injection is stable for 36 months under these storage conditions.
Diluent for Torisel concentrate for injection is stable for 36 months when stored below 25°C. The diluent may be stored at controlled room temperature until packaged with product, at which time it is refrigerated and protected from light.
The drug concentrate diluent mixture is stable for up to 24 hours at controlled room temperature 20°C to 25°C.

Admixtures.

Once the concentrate is combined with the provided diluent, inject the mixture rapidly into 0.9% sodium chloride injection. To reduce microbiological hazard, use as soon as practical after preparation. Administration of the final diluted infusion solution should be completed within six hours from the time that the drug solution/diluent mixture is added to the sodium chloride injection. If storage is necessary, store at room temperature and protect from excessive light and sunlight.
Torisel is for single use in one patient only. Discard any residue.

6.5 Nature and Contents of Container

Each carton of Torisel contains two vials. One vial, which has a lime coloured flip-top seal, contains the temsirolimus concentrate and the other, which has a white coloured flip-top seal, contains the diluent. Both vials contain a small overfill to allow administration of 25 mg of temsirolimus.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes