Temsirolimus

This medication will be stored at your doctor's office or clinic.

Dosage Forms & Strengths

injectable solution

• 25mg/mL

Advanced Renal Cell Carcinoma

Pretreat with antihistamines (eg, diphenhydramine 25-50 mg IV 30 minutes preinfusion)

25 mg IV infusion qWeek until disease progression or unacceptable toxicity

Interrupt if ANC <1000/mm³ and/or platelets <75000/mm³ and/or Grade 3 or higher AE; restart after toxicity is reduced to at least Grade 2 at 5 mg lower dose but no lower than 15 mg

Dosage modifications

• Avoid strong CYP3A4 inducers if other therapy is availableIf coadministration with strong CYP3A4 inducer required, increase initial dose to 50 mg/week initially; base subsequent doses on serum concentration; reduce dose if strong CYP3A4 inducer is discontinued to that administered prior to initiating CYP3A4 inducer
• Avoid strong CYP3A4 inhibitors; if coadministration with strong CYP3A4 inhibitor required,reduce dose to 12.5 mg/week initially; base subsequent doses on serum concentration; if strong CYP3A4 inhibitor is discontinued; wait 1 week prior to increasing the dose to that administered prior to initiating CYP3A4 inhibitor
• Moderate to severe hepatic impairment (bilirubin >1.5 times ULN): Contraindicated
• Mild hepatic impairment: Reduce dose to 15 mg qweek

Safety and efficacy not established

Contraindications

Bilirubin > 1.5 times the upper limit of normal

Cautions

May increase risks of hypersensitivity reactions; hyperglycemia; hyperlipidemia; intracerebral hemorrhage (CNS tumor and/or on anticoagulants)

To treat hypersensitivity reactions, stop therapy and treat with an antihistamine; therapy may be restarted at physician discretion at a slower rate

Monitor for symptoms or radiographic changes of interstitial lung disease (ILD); if ILD suspected, discontinue therapy, and consider use of corticosteroids and/or antibiotics

Infections may result from immunosuppression

Bowel perforation may occur; evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly

Renal failure, sometimes fatal, has occurred; monitor renal function at baseline and while on therapy

Due to abnormal wound healing, use caution in perioperative period

Elderly patients may be more likely to experience certain adverse reactions, including diarrhea, edema and pneumonia

Monitor throughout the infusion and appropriate supportive care should be available; interrupt infusion in all patients with severe infusion reactions and administer medical therapy

Interstitial lung disease reported, some resulting in death; prescribing information recommends baseline radiographic assessment by lung CT or chest radiograph prior to initiation

Avoid pregnancy during and for 3 months post-treatment

Consider dose modification if used concurrently with CYP3A4 inhibitors or inducers

Avoid grapefruit juice

May decrease effects of live vaccinations

Angioedema reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with ramipril and/or amlodipine; monitor patients for signs and symptoms of angioedema when temsirolimus is given concomitantly with an angiotensin converting enzyme (ACE) inhibitors (eg, ramipril) or calcium channel blockers (CCB; eg, amlodipine)

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if temsirolimus crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using this medication.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to temsirolimus.

You should not use temsirolimus if you have severe liver disease.

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma1 2 12 (designated an orphan drug by FDA for this use);17 considered to be a first-line therapy in poor-risk patients.2 10 13 14 20

Also has been studied in combination with interferon alfa to treat advanced renal cell carcinoma†.1 2 19 Results from a randomized study indicate overall survival benefit with temsirolimus alone compared with interferon alfa alone.1 2 Combination therapy with interferon alfa and temsirolimus also did not result in improved overall survival compared with interferon alfa alone.1 2

• Inhibits mammalian target of rapamycin (mTOR) kinase.1 2 3 4 5 6 7 8 9 10 11 12

• Although the mechanism of action has not been fully elucidated, temsirolimus binds to the intracellular protein FK506 binding protein-12, forming a drug-protein complex that inhibits activation of mTOR signaling (which regulates cell division).1 2 3 6 12 Proteins that regulate cell-cycle progression are suppressed, and G1phase of the cell cycle is blocked.1 2 3 8 11

• Temsirolimus also reduces expression of hypoxia inducible factor 1α and 2α (HIF-1α and HIF-1β) in vitro, resulting in reduced expression of vascular endothelial growth factor (VEGF) and a potential antiangiogenic effect .1 3 6 7 10

• Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.15

• Temsirolimus inhibited T lymphocyte activity in mice, but effects were reversible and T lymphocyte activity returned to normal within 24 hours of discontinuance.6 No consistent effect demonstrated on lymphocyte population or activation in humans.6 However, infections may result from immunosuppression.1

• It is used to treat kidney cancer.

• If you have an allergy to temsirolimus, sirolimus, or any other part of this medicine (temsirolimus).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a high bilirubin level.
• If you are taking St. John's wort. Do not take St. John's wort with this medicine. This medicine may not work as well.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine (temsirolimus).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Pimples (acne).
• Upset stomach or throwing up.
• Mouth irritation or mouth sores.
• Hard stools (constipation).
• Headache.
• Back pain.
• Muscle or joint pain.
• Not able to sleep.
• Dry skin.
• Change in nails.
• Nosebleed.
• Runny nose.
• Throat irritation.
• Not hungry.
• Change in taste.
• Weight loss.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If you need to store this medicine (temsirolimus) at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Review Date: October 4, 2017

(tem sir OH li mus)

• CCI-779

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Torisel: 25 mg/mL (1 mL) [contains alcohol, usp, polyethylene glycol, polysorbate 80, propylene glycol]

Note: For infusion reaction prophylaxis, premedicate with an H1 antagonist (eg, diphenhydramine 25 to 50 mg IV) ~30 minutes prior to infusion.

Renal cell cancer (RCC), advanced: IV: 25 mg once weekly; continue until disease progression or unacceptable toxicity

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, telithromycin, voriconazole); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction to 12.5 mg once weekly. When a strong CYP3A4 inhibitor is discontinued; allow ~1 week to elapse prior to adjusting the temsirolimus upward to the dose used prior to initiation of the CYP3A4 inhibitor.

CYP3A4 inducers: Avoid concomitant administration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St John’s wort); if concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider adjusting temsirolimus dose up to 50 mg once weekly. If the strong CYP3A4 enzyme inducer is discontinued, reduce the temsirolimus to the dose used prior to initiation of the CYP3A4 inducer.

Endometrial cancer (locally advanced, recurrent, and/or metastatic) (off-label use): IV: 25 mg once weekly; continue until disease progression or unacceptable toxicity (Oza 2011). Additional trials may be necessary to further define the role of temsirolimus in this condition.

Hematologic toxicity: ANC <1000/mm3 or platelets <75,000/mm3: Withhold treatment until resolves and reinitiate treatment with the dose reduced by 5 mg weekly; minimum dose: 15 mg weekly if adjustment for toxicity is needed.

Nonhematologic toxicity: Any toxicity ≥grade 3: Withhold treatment until resolves to ≤grade 2; reinitiate treatment with the dose reduced by 5 mg weekly; minimum dose: 15 mg weekly if adjustment for toxicity is needed.

Infusion/hypersensitivity reaction: Interrupt infusion and observe for 30 to 60 minutes; treatment may be resumed with discretion at a slower infusion rate (up to 60 minutes); administer an H1 antagonist (if not given as premedication) and/or an IV H2 antagonist 30 minutes prior to resuming infusion.

Interstitial lung disease: Consider withholding treatment for clinically significant respiratory symptoms until after recovery of symptoms or radiographic improvement.

Infuse over 30 to 60 minutes via an infusion pump (preferred). Use polyethylene-lined non-DEHP administration tubing. Administer through an inline polyethersulfone filter ≤5 micron; if set does not contain an inline filter, a polyethersulfone end filter (0.2 to 5 micron) should be added (do not use both an inline and an end filter). Premedicate with an H1 antagonist (eg, diphenhydramine 25 to 50 mg IV) ~30 minutes prior to infusion. Monitor during infusion; interrupt infusion for hypersensitivity/infusion reaction; monitor for 30 to 60 minutes; may reinitiate at a reduced infusion rate (over 60 minutes) with discretion, 30 minutes after administration of a histamine H1 antagonist and/or a histamine H2 antagonist (eg, famotidine or ranitidine). Administration should be completed within 6 hours of admixture.

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Diluted solution in the vial (10 mg/mL) is stable for 24 hours at room temperature (below 25°C [77°F]). Solutions diluted for infusion (in NS) must be infused within 6 hours of preparation. Protect from light during storage, preparation, and handling.

CBC with differential and platelets (weekly), serum chemistries including glucose (baseline and every other week), serum cholesterol and triglycerides (baseline and periodic), liver function (baseline and periodic), renal function tests (baseline and periodic)

Monitor for infusion reactions; infection; symptoms of ILD (or radiographic changes), symptoms of hyperglycemia (excessive thirst, polyuria); symptoms of bowel perforation