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temsirolimus
temsirolimus
SYNONYM(S): cell cycle inhibitor 779 (CCI-779); rapamycin analog CCI-779
COMMON TRADE NAME(S): Torisel ®
Temsirolimus, an ester analog of sirolimus, is an inhibitor of mammalian target of rapamycin (mTOR). mTOR, a protein kinase, is involved in a variety of cell signalling events in the P13 kinase/AKT pathway that control cell division, and result in G1 growth arrest in treated tumour cells. It has anti-angiogenic effects by regulating hypoxia-inducible factors (HIF) and vascular endothelial growth factor (VEGF).
Following a single 25 mg IV dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus. Following varying IV temsirolimus doses, the AUC (sum of temsirolimus and sirolimus) is dose-related, but non-proportional. Significantly higher exposure was observed in Japanese patients.
Well distributed to tissues
Cross blood brain barrier? | yes |
PPB | Temsirolimus (87%); Sirolimus (92%) |
Temsirolimus is metabolized primarily by CYP3A4 in the liver and is an inhibitor of CYP3A4/5 and CYP2D6. It is also a substrate and potential inhibitor of P-glycoprotein. Additional metabolic pathways include hydroxylation, reduction and demethylation.
Active metabolites |
yes (sirolimus) |
Inactive metabolites | yes |
Feces |
78% |
Urine |
4.6% |
Half-life |
Mean half-life: 17.3 h (temsirolimus); 54.6 h (sirolimus) |
- Renal cell carcinoma
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: None
The following table contains side effects from the pivotal phase III study in metastatic renal cell carcinoma.
ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
---|---|---|---|---|---|
Cardiovascular | Hypertension (7%) | E | |||
Pericardial effusion (1%) | E | ||||
QT interval prolonged (rare) | I E | ||||
Venous thromboembolism (2%) | E | ||||
Dermatological | Hand-foot syndrome (rare) | E | |||
Nail disorder (14%) | E | ||||
Rash (47%) (may be severe) | I E | ||||
Gastrointestinal | Abdominal pain (21%) | E | |||
Anorexia, weight loss (32%) | E | ||||
Constipation (21%) | E | ||||
Diarrhea (27%) | E | ||||
GI perforation (1%) | E | ||||
Mucositis (41%) | E | ||||
Nausea, vomiting (37%) | E | ||||
General | Delayed wound healing (1%) | E | |||
Edema (42%) (may be severe) | E | ||||
Fatigue (51%) | E | ||||
Hematological | Hemorrhage (25%) (3% severe) | E | |||
Myelosuppression (mainly anemia; up to 20% severe) | E | ||||
Hepatobiliary | ↑ LFTs (68%) (3% severe) | E | |||
Hypersensitivity | Hypersensitivity (9%) | I | |||
Infection | Infection (31%) (including opportunistic) | E | |||
Metabolic / Endocrine | Abnormal electrolyte(s) (21-50%; K, Ca, PO4) | E | |||
Hyperglycemia (89%) (16% grade 3-4) | E | ||||
Hyperlipidemia (87%) (2% grade 3-4) | E | ||||
Musculoskeletal | Musculoskeletal pain (20%) | E | |||
↑CPK (rare) | E | ||||
Rhabdomyolysis (rare) | E | ||||
Neoplastic | Secondary malignancy (rare) | D L | |||
Nervous System | Dysgeusia (20%) | E | |||
Insomnia (12%) | E | ||||
Seizure (rare) | E | ||||
Ophthalmic | Conjunctivitis (7%) | E | |||
Renal | Creatinine increased (57%) (3% severe) | E | |||
Respiratory | Cough, dyspnea (30%) | E | |||
Interstitial lung disease (pneumonitis; 2%) | E L | ||||
Pleural effusion (5%) | E |
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common adverse reactions associated with temsirolimus were rash, fatigue, mucositis, nausea, edema, and anorexia, hyperlipidemia, hyperglycemia.
Hypersensitivity reactions (anaphylactic reactions, hypotension, dyspnea, flushing and/or chest pain) have been associated with temsirolimus. These can occur early in the first infusion, as well as in subsequent infusions. Patients should receive prophylactic H1 antihistamine, i.e. diphenhydramine 25 to 50mg, 30 minutes prior to the administration of temsirolimus. Angioneurotic edema has been reported especially in combination with ACEI / calcium channel blockers, and may occur after temsirolimus treatment has been discontinued.
Interstitial lung disease (ILD, pneumonitis) has been associated with temsirolimus and may be life-threatening/fatal. Symptoms include dry cough, fever, eosinophilia, chest pain, and dyspnea on exertion. The risk of ILD is increased with temsirolimus doses greater than 25 mg. Monitor patients for symptoms or radiographic changes of ILD. Advise patients to promptly report any new or worsening respiratory symptoms. (See Section E - Dosing)
Hyperglycemia associated with temsirolimus may require patients with diabetes mellitus (DM) to adjust dosages of their antidiabetic medications, while patients without a history of DM may need the initiation of insulin or oral hypoglycemic agent therapy.
Hyperlipidemia is common and patients who require statins should be carefully monitored, as there may be an increased risk of rhabdomyolysis. (See Interactions section)
Temsirolimus may be immunosuppressive. Patients should be carefully observed for the occurrence of infections, including opportunistic infections. Consider prophylaxis of pneumocystis jiroveci pneumonia (PJP).
Pleural and cardiac effusions and other cardiac events have been reported in patients taking ACE inhibitors (see Drug Interactions).
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Do not administer if bilirubin > 1.5 x ULN.
Pre-medications (prophylaxis for infusion reaction):
- Diphenhydramine 25-50 mg IV (or equivalent) should be given 30 minutes before the start of the infusion.
Toxicity and Grade |
Action |
Dose |
Pneumonitis (grade 1 or 2) |
Hold until ≤ grade 1; may continue if asymptomatic. Consider steroids. |
Consider dose reduction (by 5mg/week)* |
Pneumonitis (grade 3 or 4) |
Discontinue, consider steroids |
Discontinue permanently |
Intolerable grade 2 non-hematological |
May continue AND |
Reduce by 5mg/week* |
Grade 3 or 4 non-hematological |
Hold until recovered to ≤ grade 2 AND |
Reduce by 5mg/week* |
Platelet < 75 x 109/L and/or ANC < 1 x 109/L |
Hold until recovery to ≥ 75 x 109/L and ≥1 x 109/L AND |
Reduce by 5mg/week* |
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
Grade | Action |
1 or 2 |
|
3 or 4 |
|
Hepatic metabolism is significant.
|
AST |
Bilirubin |
Action |
Mild |
> ULN |
≤ ULN |
Caution. Dose at 15mg |
|
|
>1 - 1.5 x ULN |
Caution. Dose at 15mg |
Moderate to severe |
|
>1.5 x ULN |
Do not treat. |
Use with caution. No formal studies have been performed in renally impaired patients. Dose adjustment may not be required since <5% of the dose is excreted in the urine. Temsirolimus use in hemodialysis was described in a case series.
No dose adjustment is required. Elderly patients may be more likely to experience edema, diarrhea and pneumonia. Overall survival was shorter in patients 65 years or older.
Effectiveness in children was not established.
-
Inject supplied diluent (contains polysorbate 80 and PEG 400) into the drug vial and then dilute further in 250mL Normal Saline; infuse over 30 -60 minutes. Avoid excessive shaking as this may cause foaming.
-
To decrease di-(2-ethylhexyl) phthalate (DEHP) leaching or avoid excessive drug loss, materials used in administration must be composed of glass, polyolefin or polyethylene. Use a non-PVC non-DEHP tubing, including an in-line polyethersulfone filter ≤ 5 microns. A polyethersulfone end-filter (0.2 to 5 microns) may be added if the administration set does not have an in-line filter component. The use of both an in-line and end-filter is not recommended.
-
The drug concentrate-diluent mixture is stable for up to 24 hours at room temperature and protected from light. The final diluted drug solution should be completely administered within 6 hours from the time that the concentrate-diluent mixture is added to the Normal Saline bag.
-
Keep unopened drug and diluent vials refrigerated (2-8°C); do not freeze.
-
Protect the drug and diluted solutions from light. Do not use if drug is discoloured or if particulates are present.
- patients with known hypersensitivity to this sirolimus, temsirolimus, or any ingredients in the formulation
- patients with elevated bilirubin (> 1.5 x ULN)
- patients with pre-existing or at risk of prolonged QTc
- patients with brain metastases (increased risk of bleeding)
- patients who have known hypersensitivity to an antihistamine or cannot receive an antihistamine for other medical reasons
- patients on anticoagulants or who have had recent surgery
- avoid use of live vaccines
Other Drug Properties:
-
Carcinogenicity:
Probable
-
Genotoxicity:
No
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Temsirolimus is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 3 months after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended. -
Fertility effects:
Probable
CYP3A4 is the major CYP isozyme responsible for the metabolism of temsirolimus and the active metabolite, sirolimus.
AGENT | EFFECT | MECHANISM | MANAGEMENT |
---|---|---|---|
CYP3A4 inhibitors (e.g. ketoconazole, nefazodone, clarithromycin, itraconazole, ritonavir, verapamil, grapefruit juice, aprepitant, erythromycin, fluconazole) | ↑ sirolimus concentrations (↑ AUC by 3.1-fold with ketoconazole) | ↓ metabolism of CYP3A4 substrates | Avoid concomitant usage with strong CYP3A4 inhibitors |
CYP3A4/5 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort, nevirapine) | ↓ sirolimus concentrations (↓ Cmax by 65% and ↓ AUC by 56% with rifampin) | ↑ metabolism of CYP3A4 substrates | Avoid concomitant usage with strong CYP3A4 inducers |
CYP3A4/5 substrates (e.g. HMG CoA reductase inhibitors, macrolide antibiotics, benzodiazepine, pimozide, quinidine, ergot alkaloids) | ↑ substrate’s concentrations (theoretical) | Temsirolimus inhibits CYP3A4/5 in vitro | Caution. Monitor for signs and symptoms of substrate toxicity. (e.g. rhabdomyolysis with statins). |
CYP2D6 substrates (e.g. desipramine, amitriptyline, paroxetine, fluoxetine, haloperidol, risperidone) | ↑ substrate’s concentrations | Temsirolimus inhibits CYP2D6 in vitro | Caution. Monitor for signs and symptoms of substrate toxicity. |
Gemcitabine, 5FU, Sunitinib | Severe GI, rash, other toxicity | Additive | Avoid or use with extreme caution |
Anticoagulants | ↑ risk of intracerebral bleeding in patients with CNS tumours | Additive | Extreme Caution |
ACE Inhibitors (e.g., enalapril, lisinopril, ramipril) or calcium channel blockers (e.g., amlodipine) | ↑ risk of angioneurotic edema (may be delayed) | Unknown | Caution |
Cannabidiol | ↑ temsirolimus toxicity | ↑ levels of other mTOR inhibitors were observed | Caution; monitor for toxicity |
Pgp substrates | ↓ transport of digoxin in vitro | inhibition of Pgp | Caution |
Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of Torsades de pointes | Additive | Avoid if possible; caution and monitor if used together |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
Monitor Type | Monitor Frequency |
---|---|
CBC | Baseline and weekly |
Fasting glucose |
Baseline and weekly |
Liver function tests |
Baseline and every 2 weeks |
Renal function tests & electrolytes |
Baseline and every 2 weeks |
Lipids |
Baseline and monthly |
Radiologic screening for ILD |
Baseline and periodic |
Routine assessment for signs and symptoms of fatigue, hyperglycemia, bleeding, pneumonitis, fluid retention, skin toxicity, infections, mucositis, delayed wound healing, infusion reactions, rhabdomyolysis (especially with statins). |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Temsirolimus - Metastatic Renal Cell Carcinoma
Bellmunt J, Szczylik C, Feingold J, et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Annals of Oncology 2008; 19: 1387–92.
Duran I, Siu L, Oza A, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer. 2006;42(12):1875-80.
Kuhn JG, Chang SM, Wen PY et al. Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma. Clin Cancer Res 2007; 13: 7401-7406.
Lunardi G, Vanozzi MO, Arminotti A, et al. Temsirolimus in Patients With Renal Cancer on Hemodialysis. JCO 2008; 26(34): 5652-4.
Product Monograph: Torisel® (temsirolimus). Pfizer Canada, July 2022.
June 2024 Modified Interactions and Monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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