temsirolimus

Absorption: IV administration results in complete bioavailability.

Distribution: Temsirolimus and sirolimus partition extensively in formed blood elements.

Metabolism/Excretion: Mostly metabolized by the liver to sirolimus, an active metabolite. Primarily eliminated in feces.

Half-Life: Temsirolimus: 17.3 hr; sirolimus: 54.6 hr.

Time/Action Profile ⬆ ⬇

ROUTE	ONSET	PEAK	DURATION
IV	unknown	end of infusion	1 wk

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Bilirubin >1.5 times upper limit of normal (ULN);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Hypersensitivity to temsirolimus, sirolimus, or polysorbate 80;
Perioperative patients (may impair wound healing);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: risk for adverse reactions in older adults (especially diarrhea, edema, and pneumonia).

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, DEEP VEIN THROMBOSIS, hypertension

Derm: rash, abnormal wound healing

EENT: conjunctivitis

Endo: hyperglycemia

F and E: hypophosphatemia

GI: ↑liver enzymes, anorexia, diarrhea, mucositis, nausea, BOWEL PERFORATION

GU: nephrotic syndrome, proteinuria, RENAL FAILURE

Hemat: anemia, leukopenia, lymphopenia, thrombocytopenia

Metab: hyperlipidemia, hypertriglyceridemia

Neuro: weakness

Resp: INTERSTITIAL LUNG DISEASE (ILD), PULMONARY EMBOLISM

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), INFECTION

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including ketoconazole, itraconazole, voriconazole, clarithromycin, atazanavir, nelfinavir, and ritonavir, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use unavoidable, consider ↓ temsirolimus dose.
Strong CYP3A4 inducers, including dexamethasone, phenytoin, phenobarbital, carbamazepine, rifampin, and rifabutin, may ↓ levels and effectiveness; avoid concurrent use; if concurrent use unavoidable, consider ↑ temsirolimus dose.
Sunitinib may ↑ risk of toxicity (rash, gout, cellulitis).
May ↓ antibody response to and ↑ risk of adverse reactions from live-virus vaccines; avoid current use.
↑risk of angioedema when used with ACE inhibitors or calcium channel blockers.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Grapefruit juice may ↑ levels and ↑ risk of toxicity.

Route/Dosage ⬆ ⬇

IV (Adults ): 25 mg once weekly. Concurrent use of strong CYP3A4 inhibitor: 12.5 mg once weekly. Concurrent use of strong CYP3A4 inducer: 50 mg once weekly.

Hepatic Impairment

IV (Adults ): Mild hepatic impairment (bilirubin >1–1.5 times ULN or AST >ULN with bilirubin <ULN): 15 mg once weekly.

Availability ⬆ ⬇

(Generic available)

Solution for injection: 25 mg/mL (comes with a diluent containing polysorbate 80, polyethylene glycol 400, and dehydrated alcohol)

Assessment ⬆ ⬇

Assess for signs of hypersensitivity reactions (anaphylaxis, dyspnea, flushing, chest pain) during administration. If reaction occurs, stop infusion and observe patient for ≥30–60 min. May resume treatment with administration of an antihistamine (if not previously administered) and/or an H₂ antagonist (such as IV famotidine 20 mg) 30 min before restarting temsirolimus. Infuse temsirolimus at a slower rate over 60 min.
Monitor for signs of infection, including opportunistic infection (sore throat; appearance of sputum, urine, stool; vital signs) during therapy. Monitor for signs and symptoms of
Pneumocystis jirovecii
pneumonia (cough, fever, chills, dyspnea, tachypnea, night sweats, weight loss); ↑ risk in patients receiving corticosteroids or longer dosing regimens. Consider use of prophylaxis.
Monitor for signs of ILD (dyspnea, cough, hypoxia, fever). CT scan or chest x-ray should be done prior to and periodically during therapy to monitor lung status. If clinically significant symptoms occur, discontinuation of temsirolimus and/or treatment with corticosteroids and/or antibiotics may be required.

Lab Test Considerations:

Monitor CBC prior to and during therapy. May cause ↓ ANC and platelets. If ANC <1000/mm³, platelet count <75,000/mm³, or adverse reactions ≥Grade 3, hold dose. Once toxicities have resolved to ≤Grade 2, may restart temsirolimus at a dose ↓ by 5 mg/wk to a dose no lower than 15 mg/wk. May ↓ hemoglobin, lymphocytes, and leukocytes.
- Monitor serum glucose prior to and periodically during therapy. May ↑ serum glucose, requiring ↑ in dose of or initiation of insulin or oral hypoglycemia agent therapy.
- Monitor serum cholesterol and triglycerides prior to and during therapy. May ↑ lipids, requiring initiation or ↑ in dose of lipid-lowering agents.
- Monitor liver enzymes and renal function prior to and during therapy. May ↑ AST, alkaline phosphatase, serum creatinine, and total bilirubin. May ↓ serum phosphorous and potassium.
- Monitor urine protein before starting and periodically during therapy. If nephrotic syndrome occurs, discontinue temsirolimus.

Implementation ⬆ ⬇

Premedicate with IV diphenhydramine 25–50 mg (or similar antihistamine) 30 min before start of each dose of temsirolimus.

IV Administration:

Diluent: Inject 1.8 mL of diluent for Torisel into temsirolimus vial for a concentration of 10 mg/mL.Concentration: Vial contains an overfill and total volume will be 3 mL of 10 mg/mL solution. Mix well by inversion of vial. Allow sufficient time for air bubbles to subside. Solution should be clear to slightly turbid, colorless to yellow, and free from visual particles. Store undiluted solution in refrigerator and protect from light during storage and preparation. Diluted solution is stable for 24 hr at room temperature. Withdraw required amount of temsirolimus solution and inject rapidly into 250 mL container (glass, polyolefin, or polyethylene) of 0.9% NaCl. Mix by inversion; avoid excessive shaking to prevent foaming. Administer with non-DEHP (di-2-ethylhexyl) phthalate tubing and an in-line polyethersulfone filter with pore size of not >5 microns or add an end-filter with filter pore size 0.2 microns up to 5 microns; use of both an in-line and end-filter is not recommended.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of temsirolimus to patient. Do not stop receiving drug without consulting health care professional. If an appointment is missed, contact health care professional as soon as possible to reschedule. Advise patient to read Medication Guide before starting and periodically during therapy in case of changes. .
Emphasize the importance of follow-up examination to monitor progress and side effects.
Instruct patient to immediately report signs and symptoms of a hypersensitivity or infusion reaction, including swelling of face, lips, tongue, or throat; wheezing; difficulty breathing; flushing; and chest pain.
Advise patient to notify health care professional immediately if any new or worsening abdominal pain or blood in stools occur or if signs of bowel perforation (fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea) occur.
Advise patient to notify health care professional immediately of symptoms of lung problems such as difficulty breathing, cough, fever.
Advise patient to avoid drinking grapefruit juice while taking temsirolimus.
Advise patients to notify health care professional if excessive thirst or volume or frequency of urination. Advise patients with diabetes to closely monitor glucose.
Inform patient of the ↑ risk for intracerebral bleeding with temsirolimus.
Advise patient to consult health care professional prior to taking any Rx, OTC, or herbal products, especially St. John's wort.
Instruct patient not to receive any vaccinations without advice of health care professional and to avoid contact with persons who have received live vaccines during therapy.
Rep: May cause fetal harm. Advise women of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 mo after last dose of therapy. Advise women to avoid breastfeeding during therapy and for 3 wk after last dose. May cause male and female infertility.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇