Temsirolimus

Temsirolimus is indicated for the treatment of advanced renal cell carcinoma.

Advanced Renal Cell Carcinoma

The recommended dose of Temsirolimus for advanced renal cell carcinoma is 25 mg infused over a 30 – 60 minute period once a week.

Treatment should continue until disease progression or unacceptable toxicity occurs.

Premedication

Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of Temsirolimus.

Dosage Interruption/Adjustment

Temsirolimus should be held for absolute neutrophil count (ANC) <1,000/mm³, platelet count <75,000/mm³, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, Temsirolimus may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.

Dose Modification Guidelines

Hepatic Impairment

Use caution when treating patients with hepatic impairment. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week. Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN.

Concomitant Strong CYP3A4 Inhibitors

The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a Temsirolimus dose reduction to 12.5 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor 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 the strong CYP3A4 inhibitor.

Concomitant Strong CYP3A4 Inducers

The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a Temsirolimus dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of Temsirolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Instructions For Preparation

Temsirolimus must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, Temsirolimus should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final Temsirolimus dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Temsirolimus 25 mg/mL injection must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP.

Please note that both the Temsirolimus injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn.

Follow this two-step dilution process in an aseptic manner.

Step 1:

DILUTION OF Temsirolimus INJECTION 25 MG/ML WITH SUPPLIED DILUENT

• Each Vial of Temsirolimus (temsirolimus) must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL).
• Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates.

The concentrate-diluent mixture is stable below 25ºC for up to 24 hours.

Step 2:

DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP

• Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
• Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.

The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of Temsirolimus in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight.

Administration

• Administration of the final diluted solution should be completed within six hours from the time that Temsirolimus is first added to 0.9% Solution Chloride Injection, USP.
• Temsirolimus is infused over a 30-to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product.
• Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended.
• Temsirolimus, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of Temsirolimus, including storage time elapsed when in direct contact with PVC following constitution.

Compatibilities And Incompatibilities

Undiluted Temsirolimus injection should not be added directly to aqueous infusion solutions. Direct addition of Temsirolimus injection to aqueous solutions will result in precipitation of drug. Always combine Temsirolimus injection with DILUENT for Temsirolimus before adding to infusion solutions. It is recommended that Temsirolimus be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of Temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of Temsirolimus in 0.9% Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.

Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypersensitivity/Infusion Reactions

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.

Temsirolimus should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of Temsirolimus.

An H₁ antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. Temsirolimus should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons.

If a patient develops a hypersensitivity reaction during the Temsirolimus infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H₁-receptor antagonist (such as diphenhydramine), if not previously administered , and/or an H₂-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the Temsirolimus infusion. The infusion may then be resumed at a slower rate (up to 60 minutes).

A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.

Hepatic Impairment

The safety and pharmacokinetics of Temsirolimus were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5×ULN when treated with Temsirolimus. The overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5×ULN due to increased risk of death.

Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week.

Hyperglycemia/Glucose Intolerance

The use of Temsirolimus is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving Temsirolimus had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with Temsirolimus. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Infections

The use of Temsirolimus may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis of PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

Interstitial Lung Disease

Cases of interstitial lung disease, some resulting in death, occurred in patients who received Temsirolimus. Some patients were asymptomatic, or had minimal symptoms, with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of Temsirolimus and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms.

It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of Temsirolimus therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.

It is recommended that patients be followed closely for occurrence 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. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.

Hyperlipemia

The use of Temsirolimus is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving Temsirolimus had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with Temsirolimus.

Bowel Perforation

Cases of fatal bowel perforation occurred in patients who received Temsirolimus. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools.

Renal Failure

Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received Temsirolimus. Some of these cases were not responsive to dialysis.

Wound Healing Complications

Use of Temsirolimus has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of Temsirolimus in the perioperative period.

Intracerebral Hemorrhage

Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving Temsirolimus.

Co-Administration With Inducers Or Inhibitors Of CYP3A Metabolism

Agents Inducing CYP3A Metabolism:

Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John’s Wort may decrease Temsirolimus plasma concentrations unpredictably. Patients receiving Temsirolimus should not take St. John’s Wort concomitantly.

Agents Inhibiting CYP3A Metabolism:

Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.

Concomitant Use Of Temsirolimus With Sunitinib

The combination of Temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of Temsirolimus 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest).

Vaccinations

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Temsirolimus. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Use In Pregnancy

There are no adequate and well-controlled studies of Temsirolimus in pregnant women. However, based on its mechanism of action, Temsirolimus may cause fetal harm when administered to a pregnant woman. Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped.

Men should be counseled regarding the effects of Temsirolimus on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of Temsirolimus.

Elderly Patients

Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.

Monitoring Laboratory Tests

In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving Temsirolimus may need to be performed more or less frequently at the physician’s discretion.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with temsirolimus. However, sirolimus, the major metabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects were reported in mice and/or rats in the carcinogenicity studies conducted with sirolimus: lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma.

Temsirolimus was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonella typhimurium and Escherichia coli, forward mutation in mouse lymphoma cells, and chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.

In male rats, the following fertility effects were observed: decreased number of pregnancies, decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration. These effects were observed at oral temsirolimus doses ≥3 mg/m²/day (approximately 0.2-fold the human recommended intravenous dose). Fertility was absent at 30 mg/m²/day.

In female rats, an increased incidence of pre-and post-implantation losses occurred at oral doses ≥4.2 mg/m²/day (approximately 0.3-fold the human recommended intravenous dose), resulting in decreased numbers of live fetuses.

Use In Specific Populations

Pregnancy

Pregnancy Category D.

Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after Temsirolimus therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.

In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m²/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m²/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose).

Nursing Mothers

It is not known whether Temsirolimus is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of Temsirolimus) in animal studies, a decision should be made whether to discontinue nursing or discontinue Temsirolimus, taking into account the importance of the drug to the mother.

Pediatric Use

Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established.

Temsirolimus was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1-2 safety and exploratory pharmacodynamic study.

In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received Temsirolimus at doses ranging from 10 mg/m² to 150 mg/m² as a 60-minute intravenous infusion once weekly in three-week cycles.

In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received Temsirolimus at a weekly dose of 75 mg/m². One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma.

Adverse reactions associated with Temsirolimus were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m² dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.

Pharmacokinetics

In phase 1 of the above mentioned pediatric trial, the single dose and multiple dose total systemic exposure (AUC) of temsirolimus and sirolimus were less than dose-proportional over the dose range of 10 to 150 mg/m².

In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of Temsirolimus 75 mg/m² were characterized in an additional 35 patients ages 28 days to 21 years (median age of 8 years). The geometric mean body surface adjusted clearance of temsirolimus and sirolimus was 9.45 L/h/m² and 9.26 L/h/m², respectively. The mean elimination half-life of temsirolimus and sirolimus was 31 hours and 44 hours, respectively.

The exposure (AUCss) to temsirolimus and sirolimus was approximately 6-fold and 2-fold higher, respectively than the exposure in adult patients receiving a 25 mg intravenous infusion.

Geriatric Use

Clinical studies of Temsirolimus did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia.

Renal Impairment

No clinical studies were conducted with Temsirolimus in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]-labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of Temsirolimus is recommended in patients with renal impairment.

Temsirolimus has not been studied in patients undergoing hemodialysis.

Hepatic Impairment

Temsirolimus was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths, including deaths due to progressive disease, during the study (Table 3).

Table 3 – Adverse Reactions in Patients with Advanced Malignancies Plus Normal or Impaired Hepatic Function

Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN. Use caution when treating patients with mild hepatic impairment. If Temsirolimus must be given in patients with mild hepatic impairment (bilirubin >1-1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of Temsirolimus to 15 mg/week. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of Temsirolimus and periodically thereafter.

The following serious adverse reactions have been associated with Temsirolimus in clinical trials and are discussed in greater detail in other sections of the label.

• Hypersensitivity/Infusion Reactions
• Hepatic Impairment
• Hyperglycemia/Glucose Intolerance
• Infections
• Interstitial Lung Disease
• Hyperlipemia
• Bowel Perforation
• Renal Failure
• Wound Healing Complications
• Intracerebral Hemorrhage

The most common (≥30%) adverse reactions observed with Temsirolimus are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with Temsirolimus are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Temsirolimus alone, and Temsirolimus and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Temsirolimus 25 mg weekly, and 208 patients received a combination of Temsirolimus and IFN-α weekly.

Treatment with the combination of Temsirolimus 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.

Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Temsirolimus 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:

Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV Temsirolimus or IFN-α in the Randomized Trial

The following selected adverse reactions were reported less frequently (<10%).

Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).

Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).

Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received Temsirolimus and ACE inhibitors concomitantly.

Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/postoperative wound infection (1%), sepsis (1%).

General Disorders and Administration Site Conditions -Diabetes mellitus (5%).

Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).

Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).

Nervous System Disorders – Convulsion (1%).

Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV Temsirolimus or IFN-α in the Randomized Trial

Post-Marketing And Other Clinical Experience

The following adverse reactions have been identified during post approval use of Temsirolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.

There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

There is no specific treatment for Temsirolimus intravenous overdose. Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m². The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of Temsirolimus greater than 25 mg.

Effects On Electrocardiogram

There were no clinically relevant QT changes observed at the recommended dose for Temsirolimus. In a randomized, single-blinded, crossover study, 58 healthy subjects received Temsirolimus 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg. A supratherapeutic Temsirolimus dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between Temsirolimus and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, Temsirolimus doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF >60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.

Absorption

Following administration of a single 25 mg dose of Temsirolimus in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV = 14%), and mean AUC in blood was 1627 ng•h/mL (CV = 26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

Distribution

Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.

Metabolism

Cytochrome P450 3A4 is the major isozyme responsible for the formation of five temsirolimus metabolites. Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma. In human liver microsomes temsirolimus was an inhibitor of CYP2D6 and 3A4. However, there was no effect observed in vivo when temsirolimus was administered with desipramine (a CYP2D6 substrate), and no effect is anticipated with substrates of CYP3A4 metabolism.

Elimination

Elimination is primarily via the feces. After a single IV dose of [14C]-temsirolimus approximately 82% of total radioactivity was eliminated within 14 days, with 4.6% and 78% of the administered radioactivity recovered in the urine and feces, respectively. Following a single 25 mg dose of Temsirolimus in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hours and 54.6 hours, respectively.

Drug-Transport Systems -P-Glycoprotein

Temsirolimus is a substrate of the efflux transporter P-glycoprotein (Pgp) in vitro. If Temsirolimus is administered with drugs that inhibit Pgp, increased concentrations of temsirolimus are likely and caution should be exercised.

In vitro, temsirolimus inhibited human Pgp (IC₅₀ value of 2 μM). If Temsirolimus is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely and caution should be exercised.

Effects Of Age And Gender

In population pharmacokinetic-based data analyses, no relationship was apparent between drug exposure and patient age or gender.