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  • CLASSES

    Small Molecule Antineoplastic Mammallian Target of Rapamycin (mTOR) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Inhibitor of mammalian target of rapamycin (mTOR)
    Used for advanced renal cell cancer
    Premedication with antihistamine is recommended due to risk of hypersensitivity / infusion reaction

    COMMON BRAND NAMES

    Torisel

    HOW SUPPLIED

    Temsirolimus/Torisel Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of advanced renal cell cancer.
    Intravenous dosage
    Adults

    25 mg IV over 30 to 60 minutes once weekly until disease progression or unacceptable toxicity. Premedicate patients with diphenhydramine 25 mg to 50 mg IV (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a phase 3 randomized, open-label study, treatment with temsirolimus significantly improved median overall survival (10.9 months vs. 7.3 months) and median progression-free survival (5.5 months vs. 3.1 months) compared with interferon-alpha therapy. The overall response rate was 8.6% versus 4.8%, respectively.

    For the treatment of heavily pretreated, relapsed or refractory mantle cell lymphoma (MCL)†.
    Intravenous dosage
    Adults

    175 mg IV over 30 to 60 minutes once weekly for 3 weeks followed by 75 mg IV weekly until unacceptable toxicity or disease progression. Temsirolimus was studied in a randomized, phase 3 study in 162 patients with relapsed or refractory mantle cell lymphoma. In this study, the median progression-free survival time was significantly improved with temsirolimus 175 mg IV once weekly for 3 weeks followed by 75 mg IV once weekly (175/75 arm) (4.8 months) but not 175 mg IV once weekly for 3 weeks followed by 25 mg IV once weekly (175/25 arm) (3.4 months) as compared to the single-agent investigator’s choice arm (1.9 months). All patients had received between 2 and 7 prior therapies including combination therapy and regimens that included an alkylating agent, an anthracycline, and rituximab; additionally, 32% of patients had received hematopoietic stem-cell transplantation. Grade 3 or 4 thrombocytopenia occurred significantly more often with temsirolimus therapy and grade 3 or 4 leukopenia occurred significantly more often in the investigator’s choice arm.

    For the treatment of relapsed or refractory high-grade malignant glioma†.
    Intravenous dosage
    Children, Adolescents, and Adults

    The efficacy of temsirolimus in pediatric patients with advanced recurrent or refractory solid tumors has not been established. Treatment with temsirolimus 75 mg/m2 IV over 60 minutes once weekly until disease progression or unacceptable toxicity resulted in no complete or partial responses in a subpopulation of 17 pediatric patients (median age, 12 years; range, 1 to 21 years) with high-grade glioma in a phase 2 study.

    For the treatment of relapsed or refractory neuroblastoma† in pediatric patients.
    Intravenous dosage
    Children, Adolescents, and Adults younger than 22 years

    The efficacy of temsirolimus in pediatric patients with advanced recurrent or refractory solid tumors has not been established. Treatment with temsirolimus 75 mg/m2 IV over 60 minutes once weekly until disease progression or unacceptable toxicity resulted in 1 partial response in a subpopulation of 19 pediatric patients (median age, 7 years; range, 3 to 14 years) with neuroblastoma in a phase 2 study.

    For the treatment of relapsed or refractory rhabdomyosarcoma†.
    Intravenous dosage
    Children, Adolescents, and Adults younger than 22 years

    The efficacy of temsirolimus in pediatric patients with advanced recurrent or refractory solid tumors has not been established. Treatment with temsirolimus 75 mg/m2 IV over 60 minutes once weekly until disease progression or unacceptable toxicity resulted in 1 partial response in a subpopulation of 16 pediatric patients (median age, 11 years; range, 1 to 21 years) with rhabdomyosarcoma in a phase 2 study.

    For the treatment of recurrent glioblastoma multiforme†.
    Intravenous dosage
    Adults

    Dosage not defined. In a phase 2 study of 65 patients, treatment with temsirolimus 250 mg IV over 30 minutes once weekly resulted in a 6-month progression-free survival (PFS) rate of 7.8%, which was less than the prespecified efficacy criteria of 30% or higher. In addition, no patient had an objective response. Two deaths, attributed to pneumonia and pneumonitis, were possibly related to treatment. In another phase 2 study in 41 evaluable patients, one patient who received temsirolimus therapy had no disease progression at 6 months resulting in a 6-month PFS rate of 2.4%; the prespecified criteria for rejecting therapy was a 6-month PFS rate of less than 15%. Two patients in this study experienced a partial response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    25 mg IV once weekly.

    Geriatric

    25 mg IV once weekly.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild impairment (bilirubin greater than 1 to 1.5 times the upper limit of normal (ULN) or AST greater than ULN but bilirubin less than or equal to the upper limit of normal): Reduce the dose to 15 mg per week.
     
    Bilirubin greater than 1.5 times ULN: Temsirolimus is contraindicated for use.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    Extravasation Risk
    Nonvesicant

    Injectable Administration

    Premedicate patients with diphenhydramine (or similar antihistamine) 25 mg to 50 mg IV approximately 30 minutes before the start of each dose of temsirolimus.
    Do not add other drugs or nutritional agents to the admixture.
    Temsirolimus is degraded by both acids and bases; do not add agents that are capable of modifying pH.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    Initial dilution of temsirolimus with the supplied diluent solution:
    NOTE: Two dilutions are required before intravenous infusion; the addition of undiluted drug solution directly to normal saline will cause drug precipitation. Only use the supplied diluent for the initial dilution.
    Using aseptic technique, dilute temsirolimus vial contents with 1.8 mL of the provided diluent; the resulting 3 mL of solution will have a drug concentration of 10 mg/mL, which is stable below 25 degrees C for up to 24 hours.
    Invert the vial to mix well and allow sufficient time for air bubbles to subside. Inspect the solution for particulate matter and discoloration; the solution should be clear to slightly turbid, colorless to light-yellow, and essentially free from visual particulates.
    Protect from excessive room light and sunlight.
     
    Further dilution of concentrated temsirolimus-diluent mixture:
    Withdraw the required amount from the 10 mg/mL concentrated temsirolimus-diluent solution.
    Use bottles (e.g., glass, polypropylene) or plastic bags that do not contain PVC (e.g., polypropylene, polyolefin) for the final temsirolimus dilution. Do not use PVC infusion bags or sets, as the plasticizer DEHP (di-2-ethylhexyl phthalate) may be leached from PVC. Temsirolimus contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC.
    Inject into an infusion bag or bottle containing 250 mL of 0.9% Sodium Chloride Injection. The stability of temsirolimus in other infusion solutions has not been evaluated.
    Mix the admixture by inversion of the bag or bottle; avoid excessive shaking, as this may cause foaming. Protect from excessive room light and sunlight.
    Administer the temsirolimus final dilution through polyethylene-lined administration sets within 6 hours from the time temsirolimus is first added to 0.9% Sodium Chloride Injection.

    Intravenous Administration

    Intravenous infusion:
    Administer intravenously over 30 to 60 minutes. The use of an infusion pump is preferred to ensure accurate delivery.
    Use non-DEHP, non-PVC tubing (e.g., glass, polyolefin, or polyethylene) to avoid excessive loss of product and DEHP extraction. If a PVC administration set must be used, it should not contain DEHP.
    Use an in-line polyethersulfone filter with a pore size of not greater than 5 microns for administration. If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter (0.2 microns to 5 microns) should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. The use of both an in-line and end-filter is not recommended.

    STORAGE

    Torisel:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Keep away from heat and flame
    - Protect from direct sunlight
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store diluted product in accordance with package insert instructions

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during temsirolimus treatment and for 3 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, temsirolimus can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving temsirolimus should be apprised of the potential hazard to the fetus. In animal reproduction studies, daily oral administration of temsirolimus during organogenesis caused adverse embryo-fetal effects in rats (e.g., reduced fetal weight, reduced ossifications) and rabbits (e.g., reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications) at approximately 0.04 and 0.12 times the AUC at the recommended dose in human, respectively.

    Children, infants, neonates

    There is limited data for the use of temsirolimus in adolescents, children, infants, and neonates. The effectiveness of temsirolimus has not been established for the treatment of pediatric patients with advanced recurrent/refractory solid tumors.

    Adverse effects in pediatric patients who received temsirolimus in small studies were similar to those observed in adult patients.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from temsirolimus, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether temsirolimus is present in human milk, although many drugs are excreted in human milk.

    Hepatic disease

    Temsirolimus is contraindicated for use by patients with a bilirubin greater than 1.5 times the upper limit of normal (ULN). Use temsirolimus with caution in patients with mild hepatic disease (bilirubin 1 to 1.5 times ULN; or AST greater than ULN but bilirubin less than or equal to ULN); concentrations of temsirolimus and its metabolite, sirolimus, were increased in patients with elevated AST or bilirubin levels. If temsirolimus therapy is necessary in patients with mild hepatic impairment, reduce the dose to 15 mg per week. Monitor AST and bilirubin before initiation of temsirolimus therapy and periodically thereafter. In a phase 1 dose escalation trial, patients with a baseline bilirubin greater than 1.5 times ULN experienced greater toxicity compared to patients with a baseline bilirubin less than or equal to 1.5 times ULN. These patients also had an increased risk of death, including deaths due to progressive disease, and an increased overall frequency of grade 3 or higher adverse reactions.

    Polysorbate 80 hypersensitivity

    Administer temsirolimus with caution to patients with known hypersensitivity to temsirolimus, sirolimus, or any other component, including patients with polysorbate 80 hypersensitivity. Hypersensitivity/infusion reactions (e.g., flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, and anaphylaxis) have occurred with administration of temsirolimus. These reactions can occur very early in the first infusion, but can also occur with subsequent infusions. Administer an H1 antihistamine (e.g., diphenhydramine) prior to starting the intravenous infusion of temsirolimus; administer with caution in patients who are unable to receive an antihistamine. Monitor patients throughout the infusion and have appropriate supportive care available. Interrupt the infusion of temsirolimus in all patients with severe infusion reactions and administer appropriate medical therapy. Observe the patient for at least 30 to 60 minutes, depending on the severity of the reaction. Treatment may be resumed at a slower rate (up to 60 minutes) at the physician's discretion approximately 30 minutes after administration of an H1-receptor antagonist (if not previously given) and/or an H2-receptor antagonist (e.g., famotidine 20 mg IV). Assess the risks and benefits before continuing temsirolimus therapy in patients with severe or life-threatening reactions.

    Diabetes mellitus

    Use temsirolimus with caution in patients with diabetes mellitus, as treatment is likely to increase serum glucose. An increase in the dose of antidiabetic medication may be necessary. Measure the serum glucose concentration before and during temsirolimus therapy. Instruct patients to report excessive thirst or any increase in the volume or frequency of urination.

    Corticosteroid therapy, immunosuppression, infection, vaccination

    Temsirolimus may cause immunosuppression, increasing susceptibility to infection. Carefully monitor patients for the occurrence of infections, including opportunistic infections. Cases of Pneumocystis jiroveci pneumonia (PJP), some fatal, have been reported and may be associated with the coadministration of corticosteroid therapy or other immunosuppressive agents. Consider PJP prophylaxis when temsirolimus and corticosteroids or other immunosuppressives are used in combination. Avoid vaccination with live vaccines and close contact with those who have received live vaccines during treatment with temsirolimus.

    Pneumonitis, pulmonary disease

    Use temsirolimus with caution in patients with pre-existing pulmonary disease. Temsirolimus has been associated with sometimes fatal cases of interstitial lung disease (ILD) and pneumonitis. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography (CT) scan or chest radiograph (X-ray). Symptoms may include dyspnea, cough, hypoxia, and fever. Patients should undergo a radiographic assessment by lung CT scan or chest X-ray prior to the initiation of therapy; follow such assessments periodically, even in the absence 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. Empiric treatment with corticosteroids and/or antibiotics may be considered. Consider opportunistic infections in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of Pneumocystis jiroveci pneumonia (PJP), may be considered. Advise patients to promptly report any new or worsening respiratory symptoms.

    Coronary artery disease, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Use temsirolimus with caution in patients with a history of coronary artery disease or hyperlipidemia. Temsirolimus has been associated with hypercholesterolemia and hypertriglyceridemia in clinical trials, which may require initiation or dose adjustment of lipid-lowering therapy. Monitor serum cholesterol and triglycerides before and during treatment with temsirolimus.

    Surgery

    Use temsirolimus with caution in patients undergoing surgery during the perioperative period. Temsirolimus has been associated with impaired wound healing.

    Anticoagulant therapy, brain tumor

    Use temsirolimus with caution in patients who have a brain tumor (primary CNS tumor or metastases) or who are taking anticoagulant therapy. These patients may be at increased risk of potentially fatal intracerebral or intracranial bleeding.

    Geriatric

    Use temsirolimus with caution in geriatric patients, as they may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.

    GI perforation

    Cases of fatal GI perforation have occurred in patients treated with temsirolimus. Advise patients to report any new or worsening abdominal pain or blood in their stools.

    Proteinuria

    Monitor the urine protein of patients receiving treatment with temsirolimus prior to the start of therapy and periodically thereafter. Proteinuria, including cases of nephrotic syndrome, has occurred in patients treated with temsirolimus; discontinue temsirolimus if nephrotic syndrome occurs.

    Contraception requirements, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during temsirolimus treatment. Temsirolimus can be teratogenic if taken by the mother during pregnancy. Females and should avoid pregnancy and use effective contraception during and for 3 months after treatment with temsirolimus. Women who become pregnant while receiving temsirolimus should be apprised of the potential hazard to the fetus. Additionally, due to male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose. Although there are no data regarding the effect of temsirolimus on human fertility, male and female infertility has been observed in animal studies; it is not known if these effects were reversible.

    ADVERSE REACTIONS

    Severe

    hypertriglyceridemia / Delayed / 44.0-44.0
    anemia / Delayed / 20.0-20.0
    hypophosphatemia / Delayed / 18.0-18.0
    hyperglycemia / Delayed / 16.0-16.0
    lymphopenia / Delayed / 16.0-16.0
    asthenia / Delayed / 11.0-11.0
    dyspnea / Early / 9.0-9.0
    hypokalemia / Delayed / 5.0-5.0
    rash / Early / 5.0-5.0
    neutropenia / Delayed / 5.0-5.0
    abdominal pain / Early / 4.0-4.0
    pleural effusion / Delayed / 4.0-4.0
    infection / Delayed / 3.0-3.0
    anorexia / Delayed / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    stomatitis / Delayed / 0-3.0
    peripheral edema / Delayed / 0-3.0
    elevated hepatic enzymes / Delayed / 2.0-3.0
    hypercholesterolemia / Delayed / 2.0-2.0
    vomiting / Early / 2.0-2.0
    nausea / Early / 2.0-2.0
    thrombosis / Delayed / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    thromboembolism / Delayed / 2.0-2.0
    fever / Early / 1.0-1.0
    cough / Delayed / 1.0-1.0
    GI bleeding / Delayed / 1.0-1.0
    diarrhea / Early / 1.0-1.0
    cholecystitis / Delayed / 0-1.0
    GI perforation / Delayed / 0-1.0
    weight loss / Delayed / 1.0-1.0
    pancreatitis / Delayed / 0-1.0
    insomnia / Early / 1.0-1.0
    chills / Rapid / 1.0-1.0
    myalgia / Early / 1.0-1.0
    headache / Early / 1.0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    arthralgia / Delayed / 1.0-1.0
    seizures / Delayed / 1.0-1.0
    pericardial effusion / Delayed / 1.0-1.0
    hyperbilirubinemia / Delayed / 1.0-1.0
    leukopenia / Delayed / 1.0-1.0
    thrombocytopenia / Delayed / 1.0-1.0
    angioedema / Rapid / 0-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known

    Moderate

    edema / Delayed / 32.0-32.0
    constipation / Delayed / 20.0-20.0
    conjunctivitis / Delayed / 8.0-8.0
    hypertension / Early / 7.0-7.0
    diabetes mellitus / Delayed / 5.0-5.0
    depression / Delayed / 4.0-4.0
    cholelithiasis / Delayed / 0-1.0
    phlebitis / Rapid / 1.0-1.0
    hyperlipidemia / Delayed / 10.0
    infusion-related reactions / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    immunosuppression / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    proteinuria / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 20.0-20.0
    pruritus / Rapid / 19.0-19.0
    pharyngitis / Delayed / 12.0-12.0
    epistaxis / Delayed / 12.0-12.0
    xerosis / Delayed / 11.0-11.0
    rhinitis / Early / 10.0-10.0
    acne vulgaris / Delayed / 10.0-10.0
    flushing / Rapid / Incidence not known
    increased urinary frequency / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
    Abrocitinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with abrocitinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and abrocitinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Afatinib: (Moderate) If the concomitant use of temsirolimus and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of temsirolimus. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Aliskiren; Amlodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amiodarone: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with amiodarone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Concomitant use may lead to increased concentrations of temsirolimus.
    Amlodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions if coadministration with temsirolimus is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of atorvastatin. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amlodipine; Benazepril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with benazepril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Amlodipine; Celecoxib: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amlodipine; Olmesartan: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amlodipine; Valsartan: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of clarithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Apalutamide: (Major) Avoid coadministration of temsirolimus with apalutamide due to the risk of decreased plasma concentrations of temsirolimus. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If apalutamide is discontinued, decrease the dose of temsirolimus to the dose used before initiation of apalutamide. Temsirolimus is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Atazanavir: (Major) Avoid coadministration of atazanavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of atazanavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of atazanavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of atazanavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions if coadministration with temsirolimus is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of atorvastatin.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions if coadministration with temsirolimus is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of atorvastatin.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of temsirolimus and phenobarbital due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If phenobarbital is discontinued, decrease the dose of temsirolimus to the dose used before initiation of phenobarbital. Temsirolimus is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer had no significant effect on the AUC or Cmax of temsirolimus but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Benazepril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with benazepril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with benazepril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking temsirolimus. Additionally, monitor for an increase in temsirolimus-related adverse reactions. Concurrent use may increase the exposure and risk of adverse effects of both drugs. Both drugs are P-gp substrates and inhibitors. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving temsirolimus. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving temsirolimus. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of betrixaban.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Brigatinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with brigatinib is necessary. Temsirolimus is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Budesonide: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with temsirolimus is necessary. Budesonide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of budesonide.
    Budesonide; Formoterol: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with temsirolimus is necessary. Budesonide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of budesonide.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for an increase in budesonide-related adverse reactions if coadministration with temsirolimus is necessary. Budesonide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of budesonide.
    Cabozantinib: (Minor) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with cabozantinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Cannabidiol: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with cannabidiol is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and cannabidiol is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Capmatinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with capmatinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Captopril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with captopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with captopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Carbamazepine: (Major) Avoid coadministration of temsirolimus with carbamazepine due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If carbamazepine is discontinued, decrease the dose of temsirolimus to the dose used before initiation of carbamazepine. Temsirolimus is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Carvedilol: (Moderate) Monitor for an increase in temsirolimus- and carvedilol-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of carvedilol; exposure to temsirolimus may also increase.
    Ceritinib: (Major) Avoid coadministration of ceritinib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week and monitor for temsirolimus-related adverse reactions. Allow a washout period of approximately 1 week after discontinuation of ceritinib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Chloramphenicol: (Major) Avoid coadministration of chloramphenicol with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of chloramphenicol before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of clarithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Clevidipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with clevidipine Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Cobicistat: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with temsirolimus is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and temsirolimus in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Temsirolimus can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken temsirolimus in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with conivaptan is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Cyclosporine: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of temsirolimus with cyclosporine is necessary; monitor cyclosporine levels. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use may lead to increased concentrations of both cyclosporine and temsirolimus.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with temsirolimus is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Dabigatran is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dabigatran; serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function.
    Daclatasvir: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with daclatasvir is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and daclatasvir is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Darunavir: (Major) Avoid coadministration of darunavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to darunavir may also be increased. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of darunavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Darunavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of darunavir.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Major) Avoid coadministration of darunavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to darunavir may also be increased. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of darunavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Darunavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of darunavir.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Major) Avoid coadministration of darunavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to darunavir may also be increased. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of darunavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Darunavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of darunavir. (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with temsirolimus is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dasabuvir. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with temsirolimus is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of ombitasvir. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with temsirolimus is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of paritaprevir.
    Delavirdine: (Major) Avoid coadministration of delavirdine with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of delavirdine before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Dexamethasone: (Major) Avoid coadministration of temsirolimus with dexamethasone due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If dexamethasone is discontinued, decrease the dose of temsirolimus to the dose used before initiation of dexamethasone. Temsirolimus is a CYP3A4 substrate and dexamethasone is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in temsirolimus- and quinidine-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and quinidine.
    Digoxin: (Moderate) Monitor digoxin levels and watch for an increase in digoxin -related adverse reactions if coadministration with temsirolimus is necessary. Digoxin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of digoxin.
    Diltiazem: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with diltiazem; an increase in diltiazem-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
    Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with temsirolimus due to the potential for increased doxorubicin exposure. Doxorubicin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Clinically significant interactions have been reported with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin with temsirolimus due to the potential for increased doxorubicin exposure. Doxorubicin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Clinically significant interactions have been reported with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin.
    Dronedarone: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with dronedarone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Edoxaban: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with temsirolimus is necessary. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. Edoxaban is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of edoxaban.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Both ivacaftor and its M1 metabolite have the potential to inhibit P-gp. Concomitant use is likely to lead to increased concentrations of temsirolimus. (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with tezacaftor; ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and tezacaftor is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Eliglustat: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with eliglustat is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and eliglustat is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Enalapril, Enalaprilat: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with enalapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Enalapril; Felodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with enalapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with felodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with enalapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Enasidenib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with enasidenib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Enzalutamide: (Major) Avoid coadministration of temsirolimus with enzalutamide due to the risk of decreased plasma concentrations of temsirolimus. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If enzalutamide is discontinued, decrease the dose of temsirolimus to the dose used before initiation of enzalutamide. Temsirolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Erythromycin: (Moderate) Monitor for an increase in adverse reactions of both temsirolimus and erythromycin if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use may lead to increased concentrations of both drugs.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for an increase in adverse reactions of both temsirolimus and erythromycin if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use may lead to increased concentrations of both drugs.
    Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Etravirine: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with etravirine is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and etravirine is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with temsirolimus is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Felodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with felodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Flibanserin: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with flibanserin is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and flibanserin is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with temsirolimus is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of umeclidinium.
    Fosamprenavir: (Major) Avoid coadministration of fosamprenavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to fosamprenavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of fosamprenavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Fosamprenavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of fosamprenavir.
    Fosinopril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with fosinopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with fosinopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Fosphenytoin: (Major) Avoid coadministration of temsirolimus with fosphenytoin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If fosphenytoin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of fosphenytoin. Temsirolimus is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Fostamatinib: (Moderate) Monitor for temsirolimus toxicities that may require temsirolimus dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; temsirolimus is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
    Gilteritinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with gilteritinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of pibrentasvir and temsirolimus as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and temsirolimus are substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Monitor for an increase in adverse reactions of both glecaprevir and temsirolimus if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use may lead to increased concentrations of both glecaprevir and temsirolimus.
    Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions if coadministration with temsirolimus is necessary. Glyburide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of glyburide.
    Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions if coadministration with temsirolimus is necessary. Glyburide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of glyburide.
    Grapefruit juice: (Major) Avoid consumption of grapefruit or grapefruit juice with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). Temsirolimus is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with moexipril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Ibrutinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ibrutinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and ibrutinib is a P-gp inhibitor. Concomitant use may lead to increased concentrations of temsirolimus.
    Idelalisib: (Major) Avoid coadministration of idelalisib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of idelalisib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Indinavir: (Major) Avoid coadministration of indinavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to indinavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of indinavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Indinavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of indinavir.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with temsirolimus is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of irinotecan.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with temsirolimus is necessary. Irinotecan is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of irinotecan.
    Isavuconazonium: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with isavuconazonium is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and isavuconazonium is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of temsirolimus with rifampin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifampin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifampin. Temsirolimus is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 56% and 65%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of temsirolimus with rifampin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifampin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifampin. Temsirolimus is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 56% and 65%, respectively.
    Isradipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with isradipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Istradefylline: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase temsirolimus exposure. Temsirolimus is a P-gp substrate and istradefylline is a P-gp inhibitor.
    Itraconazole: (Major) Avoid use of temsirolimus during and for 2 weeks after discontinuation of itraconazole treatment. If coadministration cannot be avoided, consider a dose reduction of temsirolimus to 12.5 mg per week. If itraconazole is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus dose is adjusted back to the dose used prior to initiation of itraconazole. Concomitant use of temsirolimus with strong CYP3A4 inhibitors such as itraconazole may increase blood concentrations of the temsirolimus active metabolite, sirolimus. Although coadministration of another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus Cmax and AUC, the Cmax and AUC of sirolimus increased by 2.2-fold and 3.1-fold, respectively.
    Ivacaftor: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Both ivacaftor and its M1 metabolite have the potential to inhibit P-gp. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ketoconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of clarithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Lapatinib: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of lapatinib with temsirolimus is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of temsirolimus and lapatinib.
    Ledipasvir; Sofosbuvir: (Moderate) Monitor for an increase in temsirolimus- and ledipasvir-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and ledipasvir.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with temsirolimus as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and temsirolimus is a P-gp inhibitor.
    Letermovir: (Moderate) Concurrent administration of temsirolimus with letermovir may result in a clinically relevant increase in sirolimus plasma concentration, the active metabolite of temsirolimus. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. If temsirolimus must be coadministered with both letermovir and cyclosporine, a temsirolimus dose reduction to 12.5 mg per week should be considered. If letermovir or cyclosporine is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus dose is adjusted back to the dose used prior to initiation of concurrent treatment. Temsirolimus is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor had no significant effect on temsirolimus maximum plasma concentration (Cmax) or exposure (AUC); however, sirolimus AUC increased 3.1-fold and Cmax increased 2.2-fold.
    Levamlodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Levoketoconazole: (Major) Avoid coadministration of ketoconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ketoconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Lisinopril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with lisinopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with lisinopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Live Vaccines: (Contraindicated) The use of live vaccines should be avoided during treatment with temsirolimus. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lomitapide: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with lomitapide is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and lomitapide is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Lonafarnib: (Major) Avoid coadministration of temsirolimus and lonafarnib due to the risk of increased temsirolimus exposure resulting in an increased risk of adverse reactions. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. If lonafarnib is discontinued, resume the original temsirolimus dose after a washout period of approximately 1 week. Temsirolimus is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus exposure but increased the exposure of sirolimus (the primary and active metabolite) by 3.1-fold.
    Loperamide: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS and cardiac effects, if coadministration with temsirolimus is necessary. Loperamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased loperamide exposure by 2-fold to 3-fold. Concomitant use is likely to lead to increased concentrations of loperamide.
    Loperamide; Simethicone: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS and cardiac effects, if coadministration with temsirolimus is necessary. Loperamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased loperamide exposure by 2-fold to 3-fold. Concomitant use is likely to lead to increased concentrations of loperamide.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of temsirolimus with lumacaftor; ivacaftor due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If lumacaftor; ivacaftor is discontinued, decrease the dose of temsirolimus to the dose used before initiation of lumacaftor. Temsirolimus is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively. (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Both ivacaftor and its M1 metabolite have the potential to inhibit P-gp. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of temsirolimus with lumacaftor; ivacaftor due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If lumacaftor; ivacaftor is discontinued, decrease the dose of temsirolimus to the dose used before initiation of lumacaftor. Temsirolimus is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with temsirolimus is necessary; a dose adjustment of maraviroc may be necessary. Maraviroc is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of maraviroc.
    Maribavir: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with maribavir is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and maribavir is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Mefloquine: (Moderate) Monitor for an increase in temsirolimus- and mefloquine-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates inhibitors. Concomitant use is likely to lead to increased concentrations of temsirolimus and mefloquine.
    Mephobarbital: (Major) Avoid coadministration of temsirolimus with mephobarbital due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If mephobarbital is discontinued, decrease the dose of temsirolimus to the dose used before initiation of mephobarbital. Temsirolimus is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Mifepristone: (Major) Avoid chronic coadministration of mifepristone with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of mifepristone before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitapivat: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with mitapivat is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and mitapivat is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Mitotane: (Major) Avoid coadministration of temsirolimus with mitotane due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If mitotane is discontinued, decrease the dose of temsirolimus to the dose used before initiation of mitotane. Temsirolimus is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Modafinil: (Moderate) Use caution if coadministration of temsirolimus with modafinil is necessary, and monitor for decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate, and modafinil is a moderate inducer of CYP3A4. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Co-administration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased sirolimus AUC by 56% and Cmax by 65%.
    Moexipril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with moexipril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including sedation and respiratory depression, if coadministration with temsirolimus is necessary; a morphine dose adjustment may be necessary. Morphine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including sedation and respiratory depression, if coadministration with temsirolimus is necessary; a morphine dose adjustment may be necessary. Morphine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Naldemedine: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with temsirolimus is necessary. Naldemedine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of naldemedine.
    Nanoparticle Albumin-Bound Sirolimus: (Contraindicated) Do not use sirolimus concomitantly with temsirolimus. Temsirolimus is extensively metabolized in the liver primarily by cytochrome P450 3A4, but also by P-glycoprotein (P-gp). Five metabolites are formed, but sirolimus is the principal and active metabolite; the remainder of the metabolites account for less than 10% of radioactivity in plasma. Residual sirolimus concentrations are present up to a week after temsirolimus administration.
    Nefazodone: (Major) Avoid coadministration of nefazodone with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of nefazodone before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to nelfinavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of nelfinavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and a P-glycoprotien (P-gp) inhibitor. Nelfinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Concomitant use may lead to increased concentrations of nelfinavir via P-gp inhibition.
    Neratinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with neratinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Nicardipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with nicardipine; an increase in temsirolimus-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Nifedipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with nifedipine; an increase in temsirolimus-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Nimodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with nimodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir.
    Nisoldipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with nisoldipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with temsirolimus is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of ombitasvir. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with temsirolimus is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of paritaprevir.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of temsirolimus with rifabutin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifabutin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifabutin. Temsirolimus is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Osimertinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with osimertinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Pacritinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with pacritinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and pacritinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perindopril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with perindopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Perindopril; Amlodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with perindopril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Phenobarbital: (Major) Avoid coadministration of temsirolimus and phenobarbital due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If phenobarbital is discontinued, decrease the dose of temsirolimus to the dose used before initiation of phenobarbital. Temsirolimus is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer had no significant effect on the AUC or Cmax of temsirolimus but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of temsirolimus and phenobarbital due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If phenobarbital is discontinued, decrease the dose of temsirolimus to the dose used before initiation of phenobarbital. Temsirolimus is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer had no significant effect on the AUC or Cmax of temsirolimus but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Phenytoin: (Major) Avoid coadministration of temsirolimus and phenytoin/fosphenytoin due to the risk of decreased temsirolimus exposure which may reduce its efficacy. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If phenytoin/fosphenytoin is discontinued, resume the original temsirolimus dose. Temsirolimus is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer did not have a significant effect on temsirolimus exposure but decreased the exposure of sirolimus (the primary and active metabolite) by 56%.
    Posaconazole: (Major) Avoid coadministration of posaconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to posaconazole may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of posaconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Posaconazole is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Concomitant use may lead to increased concentrations of posaconazole.
    Primidone: (Major) Avoid coadministration of temsirolimus with primidone due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If primidone is discontinued, decrease the dose of temsirolimus to the dose used before initiation of primidone. Temsirolimus is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and temsirolimus in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Temsirolimus can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken temsirolimus in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Propafenone: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with propafenone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Quinapril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with quinapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with quinapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Quinidine: (Moderate) Monitor for an increase in temsirolimus- and quinidine-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and quinidine.
    Quinine: (Major) Monitor for an increase in temsirolimus- and quinine-related adverse reactions if coadministration is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and inhibitor. Quinine is also a P-gp substrate, as well as a weak P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of quinine; exposure to temsirolimus may also increase.
    Ramipril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with ramipril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with ramipril.
    Ranolazine: (Moderate) Monitor for an increase in temsirolimus- and ranolazine-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and ranolazine.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral temsirolimus. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer temsirolimus at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral temsirolimus. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer temsirolimus at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of ribociclib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ribociclib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ribociclib before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Rifabutin: (Major) Avoid coadministration of temsirolimus with rifabutin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifabutin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifabutin. Temsirolimus is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Rifampin: (Major) Avoid coadministration of temsirolimus with rifampin due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifampin is discontinued, decrease the dose of temsirolimus to the dose used before initiation of rifampin. Temsirolimus is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 56% and 65%, respectively.
    Rifapentine: (Major) Avoid coadministration of temsirolimus and rifapentine due to the risk of decreased temsirolimus exposure which may reduce its efficacy. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If rifapentine is discontinued, resume the original temsirolimus dose. Temsirolimus is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer did not have a significant effect on temsirolimus exposure but decreased the exposure of sirolimus (the primary and active metabolite) by 56%.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with temsirolimus is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased the mean rifaximin Cmax by 83-fold and the mean AUC by 124-fold. The effect may be greater in patients with hepatic impairment.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with temsirolimus; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and temsirolimus is a P-gp inhibitor.
    Riociguat: (Moderate) Use caution if coadministration of temsirolimus with riociguat is necessary, and monitor for an increase in riociguat-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and riociguat is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to riociguat is likely to increase.
    Ritonavir: (Major) Avoid coadministration of ritonavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to ritonavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ritonavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Ritonavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of ritonavir.
    Rolapitant: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with rolapitant is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Romidepsin: (Moderate) Monitor for an increase in romidepsin-related adverse reactions if coadministration with temsirolimus is necessary. Romidepsin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of romidepsin.
    Saquinavir: (Major) Avoid coadministration of saquinavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to saquinavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of saquinavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Saquinavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of saquinavir.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in ethinyl estradiol-related adverse reactions if coadministration with temsirolimus is necessary. Ethinyl estradiol is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may to lead to increased concentrations of ethinyl estradiol.
    Silodosin: (Moderate) Monitor for an increase in silodosin-related adverse reactions if coadministration with temsirolimus is necessary. Silodosin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of silodosin.
    Simeprevir: (Moderate) Monitor for an increase in temsirolimus- and simeprevir-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and simeprevir.
    Sirolimus: (Contraindicated) Do not use sirolimus concomitantly with temsirolimus. Temsirolimus is extensively metabolized in the liver primarily by cytochrome P450 3A4, but also by P-glycoprotein (P-gp). Five metabolites are formed, but sirolimus is the principal and active metabolite; the remainder of the metabolites account for less than 10% of radioactivity in plasma. Residual sirolimus concentrations are present up to a week after temsirolimus administration.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with velpatasvir is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with velpatasvir is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus. (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with voxilaprevir is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and voxilaprevir is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Sorafenib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with sorafenib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Sotorasib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with sotorasib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of temsirolimus with St. Johns Wort due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). Temsirolimus is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer; however, the amount of individual constituents in various products may alter the inducing effects of St. Johns Wort, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Sunitinib: (Major) Avoid the use of temsirolimus with sunitinib if possible, due to the combination resulting in dose-limiting toxicity. In the first cohort of a phase 1 study with temsirolimus (15 mg/kg IV per week) and sunitinib (25 mg by mouth daily on days 1 through 28, followed by a 2-week rest), dose-limiting toxicities such as grade 3 or 4 erythematous maculopapular rash and gout/cellulitis requiring hospitalization were observed in 2 of 3 patients treated.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with temsirolimus is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telithromycin: (Major) Avoid coadministration of telithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of telithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Telmisartan; Amlodipine: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tenofovir alafenamide.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
    Tepotinib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with tepotinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and tepotinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Tezacaftor; Ivacaftor: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Both ivacaftor and its M1 metabolite have the potential to inhibit P-gp. Concomitant use is likely to lead to increased concentrations of temsirolimus. (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with tezacaftor; ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and tezacaftor is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Ticagrelor: (Moderate) Monitor for an increase in temsirolimus- and ticagrelor-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of temsirolimus and ticagrelor.
    Tipranavir: (Major) Avoid coadministration of tipranavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); tipranavir exposure may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of tipranavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Tipranavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tipranavir.
    Topotecan: (Major) Avoid coadministration of temsirolimus with oral topotecan due to increased topotecan exposure; temsirolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and temsirolimus is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Trandolapril: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with trandolapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor.
    Trandolapril; Verapamil: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with trandolapril. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another ACE inhibitor. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with verapamil; an increase in treatment-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker. Both drugs are also P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and diltiazem.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Tucatinib: (Major) Avoid coadministration of temsirolimus and tucatinib due to the risk of increased temsirolimus exposure resulting in an increased risk of adverse reactions. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. If tucatinib is discontinued, resume the original temsirolimus dose after a washout period of approximately 1 week. Temsirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus exposure, but increased the exposure of sirolimus (the primary and active metabolite) by 3.1-fold.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with temsirolimus. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; temsirolimus is a P-gp inhibitor.
    Umeclidinium: (Minor) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with temsirolimus is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of umeclidinium.
    Umeclidinium; Vilanterol: (Minor) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with temsirolimus is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of umeclidinium.
    Vemurafenib: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with vemurafenib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and vemurafenib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with temsirolimus due to the potential for increased venetoclax exposure. Additionally, temsirolimus exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of temsirolimus. Both venetoclax and temsirolimus are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with verapamil; an increase in treatment-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker. Both drugs are also P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and diltiazem.
    Vincristine Liposomal: (Major) Avoid coadministration of temsirolimus with vincristine due to increased plasma concentrations of vincristine. Vincristine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. The effect of concomitant use of P-gp inhibitors has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Vincristine: (Major) Avoid coadministration of temsirolimus with vincristine due to increased plasma concentrations of vincristine. Vincristine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. The effect of concomitant use of P-gp inhibitors has not been investigated, but it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of vincristine.
    Voclosporin: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with voclosporin is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and voclosporin is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Voriconazole: (Major) Avoid coadministration of voriconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of voriconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Zonisamide: (Minor) Monitor for an increase in temsirolimus-related adverse reactions when starting or stopping therapy with zonisamide, or when changing the dose of zonisamide. Temsirolimus is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. There is a theoretical potential for zonisamide to affect the pharmacokinetics of drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during temsirolimus treatment and for 3 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, temsirolimus can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving temsirolimus should be apprised of the potential hazard to the fetus. In animal reproduction studies, daily oral administration of temsirolimus during organogenesis caused adverse embryo-fetal effects in rats (e.g., reduced fetal weight, reduced ossifications) and rabbits (e.g., reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications) at approximately 0.04 and 0.12 times the AUC at the recommended dose in human, respectively.

    Due to the potential for serious adverse reactions in nursing infants from temsirolimus, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether temsirolimus is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR), which is a protein kinase. Sirolimus, the active metabolite of temsirolimus, also inhibits mTOR. Both temsirolimus and sirolimus bind to an intracellular protein called FKBP-12, and this protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity results in a G1 growth arrest in tumor cells. When mTOR is inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase / AKT pathway, is blocked. In vitro, using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced concentrations of vascular endothelial growth factor (VEGF) and the hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha.

    PHARMACOKINETICS

    Temsirolimus is administered by intravenous infusion. The mean steady-state volume of distribution (Vd) of temsirolimus in whole blood was 172 liters in cancer patients after a single 25 mg IV dose; both temsirolimus and sirolimus are extensively partitioned into formed blood elements. Temsirolimus is extensively metabolized in the liver primarily by CYP3A4. Five metabolites are formed, with sirolimus as the principal and active metabolite; the remainder of the metabolites account for less than 10% of radioactivity in plasma. Temsirolimus is primarily eliminated via the feces. After a single radiolabeled IV dose, 4.6% was recovered in the urine, and 78% was recovered in the feces, and approximately 82% of total radioactivity was eliminated within 14 days. After a single 25 mg dose of temsirolimus in cancer patients, the mean systemic clearance was 16.2 L/hour (CV, 22%). Temsirolimus exhibits a bi-exponential decline in whole blood concentrations. The mean half-life of temsirolimus was 17.3 hours, and the mean half-life of sirolimus was 54.6 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, P-glycoprotein (P-gp)
    Temsirolimus is extensively metabolized in the liver primarily by CYP3A4. Temsirolimus is also a substrate and inhibitor of the efflux transporter P-gp. Increased plasma concentrations of temsirolimus are likely when administered with P-gp inhibitors; increased concentrations of P-gp substrates are likely when administered with temsirolimus. In human liver microsomes, temsirolimus was an inhibitor of CYP2D6 and CYP3A4. However, no clinically significant effect is anticipated when temsirolimus is coadministered with agents that are metabolized by CYP2D6 or CYP3A4.

    Intravenous Route

    In patients with cancer, the mean maximum serum concentration (Cmax) of temsirolimus in whole blood after a single 25 mg IV dose was 585 ng/mL, typically occurring at the end of the infusion; the mean AUC was 1,627 ng x hr/mL. Temsirolimus exposure increased in a less than dose-proportional manner over the dose range of 1 to 25 mg. In contrast, exposure of the active metabolite, sirolimus, increased proportionally with dose. The sirolimus AUC was 2.7-fold that of the temsirolimus AUC after a single 25 mg intravenous dose of temsirolimus in patients with cancer, primarily due to the longer half-life of sirolimus.