Pharmaceutical Approval Update

Posted by James

Temsirolimus (Torisel)

Manufacturer: Wyeth Pharmaceuticals, Philadelphia, PA

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

Drug Class: As an inhibitor of the mammalian target of rapamycin kinase (mTOR), temsirolimus is considered to be an antineoplastic agent.

Uniqueness of Drug: Temsirolimus is the only marketed cancer therapy that specifically inhibits mTOR kinase, a key protein in cells that regulates cell proliferation, cell growth, and cell survival. Temsirolimus binds to an intracellular protein, and the protein-drug complex inhibits the mTOR activity that controls cell division. Inhibition of mTOR activity resulted in arrested growth of treated tumor cells in phase G1. Clinically, temsirolimus resulted in prolonged overall survival in patients with renal cell carcinoma.

Warnings and Precautions:

Hypersensitivity Reactions. Hypersensitivity reactions may include anaphylaxis, dyspnea, flushing, and chest pain. Tem-sirolimus should be used with caution in persons with known hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or any of its other components. An H₁ antihistamine agent should be administered to patients before the start of the intravenous (IV) temsirolimus infusion. Temsirolimus should be used with caution in patients with known hypersensitivity to antihistamines or in patients who cannot receive antihistamines for other reasons.

If a hypersensitivity reaction occurs during the infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes. At the discretion of the physician, treatment may be resumed with the administration of an H₁-receptor antagonist such as diphenhydramine (Benadryl, McNeil/Johnson & Johnson), if not previously administered, or with an H₂-receptor antagonist such as IV famotidine 20 mg (Pepcid generic, Merck) or IV ranitidine 50 mg (Zantac drug, Glaxo-SmithKline) approximately 30 minutes before the infusion is restarted. The infusion may then be resumed at a slower rate (up to 60 minutes).

Hyperglycemia/Glucose Intolerance. Temsirolimus is likely to result in increased serum glucose levels. In the phase 3 trial, 89% of patients had at least one elevated serum glucose value during treatment, and 26% of patients reported hyperglycemia as an adverse event. This effect may signal the need for an increased or initial dose of insulin or oral hypoglycemic agent therapy. Glucose levels should be tested before and during treatment. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination.

Infections. Temsirolimus may result in immunosuppres-sion. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

Interstitial Lung Disease. Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus. Some patients were asymptomatic, and infiltrates were detected on computed tomography (CT) scans or chest radiographs. Others presented with dyspnea, cough, hy-poxia, and fever. Some patients need to discontinue temsirolimus or treatment with corticosteroids or antibiotics, and some patients continued treatment without additional intervention. Patients should be advised to promptly report any new or worsening respiratory symptoms.

Hyperlipemia. The use of temsirolimus is likely to result in elevated serum triglyceride and cholesterol levels. In the phase 3 trial, 87% of patients had at least one elevated cholesterol value and 83% had at least one elevated triglyceride value. In this case, an increased or initial dose of lipid-lowering agents might be required. Serum cholesterol and triglyceride levels should be tested before and during treatment with tem-sirolimus.

Bowel Perforation. Cases of fatal bowel perforation have occurred. Patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, or acute abdomen. Patients should be advised to report any new or worsening abdominal pain or blood in the stool.

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 patients were not responsive to dialysis.

Wound Healing Complications. Temsirolimus has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of this product in the peri-operative period.

Intracerebral Hemorrhage. Patients with central nervous system (CNS) tumors or patients who are receiving anti-coagulation therapy may be at an increased risk for intra-cerebral bleeding while receiving temsirolimus.

Coadministration with Inducers or Inhibitors of Cyto-chrome (CYP 3A) Metabolism:

Agents inducing CYP 3A metabolism. Strong inducers of CYP 3A4 and CYP 3A5 such as medication dexamethasone (Decadron tablet, Merck), generic carbamazepine (Tegretol medication, Novartis), phenytoin tablet (Dilantin canadian, Pfizer), phenobarbital, rifampin, rifabutin (Mycobutin, Pfizer), and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be given, a dose adjustment should be considered. St. John’s Wort may unpredictably decrease temsirolimus plasma concentrations; therefore, patients receiving temsirolimus should not take St. John’s Wort concomitantly.

Agents inhibiting CYP3A metabolism. Strong CYP3A4 inhibitors such as atazanavir (Reyataz, Bristol-Myers Squibb), generic clarithromycin (Biaxin 500 mg, Abbott), indinavir drug (Generic Crixivan, Merck), itraconazole tablet (Sporanox medication, PriCara), ketoconazole drug (Nizoral canadian, PriCara), nefazodone (Serzone, Bristol-Myers Squibb), generic nelfi­navir (Medication Viracept, Agouron), ritonavir drug (Norvir 100 mg, Abbott), saquinavir (Fortovase, Roche), and telithromycin (Ketek, Sanofi-Aventis) may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be given, a dose adjustment should be considered.

Concomitant Use with Sunitinib. The combination of tem-sirolimus and sunitinib (Sutent, Pfizer) resulted in dose-limiting toxicities (e.g., grade 3/4 erythematous maculopapular rash; gout or cellulitis requiring hospitalization); these effects were observed in two-thirds of patients treated in the first cohort of a phase 1 study with IV temsirolimus 15 mg/week and oral sunitinib 25 mg/day on days 1 to 28, followed by a two-week rest.

Vaccinations. During temsirolimus treatment, the use of live vaccines and close contact with those who have received live vaccines should be avoided. Examples include intranasal influenza, measles-mumps-rubella, oral polio, bacille Cal-mette-Guerin, yellow fever, varicella, and TY21a typhoid vaccines.

Pregnancy. Temsirolimus (Pregnancy Category D), administered daily as an oral formulation, caused embryofetal and intrauterine toxicities in rats and rabbits at human subthera-peutic exposures. Embryofetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications. In rabbits, adverse effects included reduced fetal weight, omphalocele, bifurcated sternebrae, notched ribs, and incomplete ossifications.

In rats, intrauterine and embryofetal effects were observed with a dose of 2.7 mg/m² per day. In rabbits, the intrauterine and embryofetal adverse effects were observed at the oral dose of 7.2 mg/m² or more per day.

Women of childbearing age should avoid becoming pregnant throughout temsirolimus treatment and for three months after therapy ends. Temsirolimus can cause fetal harm when administered to pregnant women. If it is used during pregnancy or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

Men should be counseled about the effects of temsirolimus on the fetus and sperm before starting treatment. Men with partners of childbearing age should use reliable contraception throughout treatment. It is recommended that the couple continue contraception for three months after the last dose of temsirolimus.

Dosage and Administration:

Advanced Renal Cell Carcinoma. The recommended tem-sirolimus dose is 25 mg infused over 30 to 60 minutes once a week. Treatment should continue until disease progression or unacceptable toxicity occurs.

Premedication. Patients should receive prophylactic IV diphenhydramine 25 to 50 mg or a similar antihistamine approximately 30 minutes before the start of each dose of tem-sirolimus.

Dosage Interruption or Adjustment. Temsirolimus should be delayed if the absolute neutrophil count is below 1,000/mm³; if the platelet count is below 75,000/mm³; or if grade 3 or greater adverse reactions occur. After 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:

Concomitant strong CYP 3A4 inhibitors. The concomitant use of strong CYP 3A4 inhibitors should be avoided (e.g. keto-conazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole [Vfend, Pfizer]). Grapefruit juice may also increase plasma concentrations of sirolimus and should be avoided. If patients must take a strong CYP 3A4 inhibitor, a temsirolimus dose reduction to 12.5 mg/week should be considered. It is predicted that this dose of temsirolimus will adjust the area under-the-curve (AUC) concentration to the range observed without inhibitors; however, there are no clinical data with this dose adjustment in patients receiving strong CYP 3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately one week should be allowed before the temsirolimus dose is adjusted back to the dose that was used before initiation of the strong CYP 3A4 inhibitor.

Concomitant strong CYP 3A4 inducers. The use of concomitant strong CYP 3A4 inducers should be avoided (e.g. dexa-methasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital). If patients must take a strong CYP3A4 inducer, 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 CYP 3A4 inducers. If the strong inducer is discontinued, the tem-sirolimus dose that was used before the strong CYP 3A4 inducer was initiated should be resumed.

Commentary: Renal cell carcinoma accounts for approximately 85% of kidney cancers. The American Cancer Society estimated that 51,190 new cases of kidney cancer would be diagnosed in 2007. More than 40% of these patients have advanced disease when they are initially seen. Temsirolimus is the only cancer therapy that specifically inhibits mTOR kinase, a cellular protein that regulates cell proliferation, cell growth, and cell survival.

Advanced renal cell carcinoma is very difficult to treat. Developing effective treatments for this stage of disease is a major challenge. Temsirolimus is the first drug to demonstrate a significant increase in overall survival for patients with the most aggressive form of kidney cancer, and it is considered a needed option for treatment. The approval of temsirolimus reinforces the potential of mTOR inhibition as a new approach in oncology.

The product’s safety information indicates the possibility of hypersensitivity reactions, elevated blood glucose levels, immunosuppression, interstitial lung disease, and bowel perforation. One caveat of the FDA approval is a postmarketing commitment whereby the company has agreed to submit two completed study reports and data sets: one for QT prolongation and an ongoing report on hepatic impairment.