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Changes to Torisel SmPC
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New text in red
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 vial contains:
30 mg temsirolimus in a resolved in 1.2 ml total volume.
When diluted, the solution contains 10 mg/ml of temsirolimus
(see section 6.6).
Excipients:
Each vial of concentrate contains 474 mg anhydrous ethanol, and each vial of the diluent, provided contains 358 mg anhydrous ethanol.
For a full list of excipients, see section 6.1.
1 vial TORISEL 25 mg/ml concentrate contains:
30 mg temsirolimus dissolved in a total volume of 1.2 ml
Therefore, 1 ml of TORISEL concentrate contains 25 mg temsirolimus.
After dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent, the concentration of temsirolimus is 10 mg/ml.
Excipients:
1 vial TORISEL 25 mg/ml concentrate contains 474 mg anhydrous ethanol.
1 vial of the diluent, provided contains 358 mg anhydrous ethanol.
For a full list of excipients, see section 6.1.
4.2 Posology and method of administration
TORISEL must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.
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).
Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus.
TORISEL must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.
The total volume (1.2 ml) of 1 vial TORISEL 25 mg/ml concentrate must be diluted with 1.8 ml of withdrawn diluent to achieve a concentration of temsirolimus of 10 mg/ml. Withdraw the required amount of the temsirolimus 10 mg/ml mixture and then inject rapidly into sodium chloride 9 mg/ml (0.9%) solution for injection.
For instructions on preparation, see section 6.6.
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).
Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus.
4.4 Special warnings and precautions for use
Renal impairment
As temsirolimus is not eliminated by the kidneys, studies in patients with varying renal impairment have not been conducted (see section 4.2). TORISEL has not been studied in patients undergoing haemodialysis.
Renal impairment
Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renal impairment have not been conducted (see section 4.2 and 5.2). TORISEL has not been studied in patients undergoing haemodialysis.
Hypersensitivity
Hypersensitivityreactions, including anaphylactic reactions, have been associated with the administration of TORISEL (see section 4.8).
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 with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or H2-receptor antagonist (intravenous famotidine 20 mg or 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).
Because it is recommended that an H1 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.
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 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 H1-receptor antagonist (diphenhydramine or similar antihistamine) and a H2-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 H1 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.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Angioneurotic oedema-type reactions have been observed in some patients who received temsirolimus and ACE inhibitors concomitantly.
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).
4.5 Interaction with other medicinal products and other forms of interaction
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).
P-glycoprotein
Temsirolimus is an inhibitor of P-glycoprotein in vitro. In vivo, the effect of inhibition has not been investigated.
Interactions with drugs that are P-glycoprotein substrates
In an in vitro study, temsirolimus inhibited the transport of P-glycoprotein substrates with an IC50 value of 2 µM. The clinical relevance of this finding is not known.
4.6 Pregnancy and lactation
The potential risk for humans is unknown. TORISEL should not be used during pregnancy.
Due to the unknown risk related to potential exposure during early pregnancy, women of childbearing potential should be advised not to become pregnant while using TORISEL.
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.
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.
A total of 616 patients were treated with TORISEL in a phase 3, three-arm, randomised, open-label study of Interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN‑α. Two hundred 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 reactions, hyperglycaemia/glucose intolerance, infections, interstitial lung disease, 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 oedema, facial oedema, peripheral oedema), and asthenia.
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, 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.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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Nervous system disorders
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Very common
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Dysgeusia
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31 (15)
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0 (0)
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Common
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Ageusia
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11 (5)
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0 (0)
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Uncommon
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Intracerebral bleeding
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1 (0.5)
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1 (0.5)
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Uncommon
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Convulsions
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1 (1)
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1 (1)
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Nervous system disorders
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Very common
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Dysgeusia
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31 (15)
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0 (0)
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Common
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Ageusia
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11 (5)
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0 (0)
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Uncommon
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Intracerebral bleeding
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1 (1)
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1 (1)
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Cardiac disorders
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Uncommon
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Pericardial effusion (including haemodynamically significant pericardial effusions requiring intervention)
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2 (1)
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1 (1)
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Respiratory, thoracic and mediastinal disorders
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Very common
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Dyspnoea
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58 (28)
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18 (9)
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Very common
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Epistaxis
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25 (12)
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0 (0)
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Very common
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Cough
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54 (26)
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2 (1)
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Common
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Pneumonitis [including fatal pneumonitis] (see section 4.4),
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4 (2)
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1 (1)
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Respiratory, thoracic and mediastinal disorders
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Very common
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Dyspnoea
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58 (28)
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18 (9)
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Very common
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Epistaxis
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25 (12)
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0 (0)
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Very common
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Cough
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54 (26)
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2 (1)
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Common
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Pneumonitis [including fatal pneumonitis] (see section 4.4)
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4 (2)
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1 (1)
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Common
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Pleural effusion
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8 (4)
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5 (2)
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5.1 Pharmacodynamic properties
Pharmacotherapeutic group: {group} ATC code: {code} [proposed: under application]
Pharmacotherapeutic group: Protein Kinase Inhibitors; ATC code: L01X E09
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
TORISEL solution for infusion should not be added directly to aqueous infusion solutions. Direct addition of TORISEL to aqueous solutions will result in precipitation of medicinal product.
Always dilute TORISEL concentrate for solution for infusion with the supplied diluent before adding to infusion solutions. TORISEL may only be administered in sodium chloride 9 mg/ml (0.9%) solution for injection after combining with diluent .
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 should be considered during the preparation and administration of TORISEL, including storage time elapsed in a PVC container following constitution. It is important that the recommendations in section 4.2 and be followed closely.
PVC bags and medical devices should not be used for the administration of preparations containing polysorbate 80, because polysorbate 80 leaches DEHP from PVC.
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
TORISEL 25 mg/ml concentrate for solution for infusion must not be added directly to aqueous infusion solutions. Direct addition of TORISEL 25 mg/ml concentrate to aqueous solutions will result in precipitation of medicinal product.
Always dilute TORISEL 25 mg/ml concentrate for solution for infusion with the supplied diluent before adding to infusion solutions. TORISEL may only be administered in sodium chloride 9 mg/ml (0.9%) solution for injection after the initial dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent.
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
After dilution of concentrate with the diluent: 24 hours when stored below 25°C and protected from light.
After first dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent: 24 hours when stored below 25°C and protected from light.
6.5 Nature and contents of container
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 1.8 ml of diluent.
TORISEL 25 mg/ml 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 TORISEL 25 mg/ml 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.
Bags/containers that come in contact with TORISEL must be made of glass, polyolefin, or polyethylene.
PVC bags and medical devices should not be used for the , administration of preparations containing polysorbate 80, because polysorbate 80 leaches DEHP from PVC.
Dilution
torisel 25 mg/ml In preparing the solution, the following two-step process should be carried out in an aseptic manner:
Torisel 25 mg/ml
- 1.8 ml of the supplied diluent should be injected into the vial of Torisel 25 mg/ml and mixed 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 contains 1.2 ml of concentrate containing 30 mg of temsirolimus. When the 1.2 ml concentrate is combined with 1.8 ml of 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.
- The required amount of concentrate-diluent mixture from Step 1 should be withdrawn from the vial and injected 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.
• Appropriate administration materials should 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 should consist of non-DEHP, non-PVC tubing with appropriate filter. An in-line filter with a pore size of not greater than 5 microns is recommended for administration.
• 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, including storage time elapsed in a polyvinyl chloride container 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.
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).
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 25 mg/ml concentrate must be diluted with the supplied diluent before administration in sodium chloride infusion.
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 25 MG/ML 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 25 mg/ml concentrate which contains 30 mg of temsirolimus (1.2 ml of 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 1.2 ml of TORISEL 25 mg/ml 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.
• 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.
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