Adverse Events Profile
In the phase 3 randomized, open-label study of interferon-alpha (IFN
)
alone, TORISEL alone,and TORISEL and IFN, a
total of 616 patients were treated. Two hundred patients received IFN,
208 received TORISEL 25 mg weekly, and 208 patients received a combination
of TORISEL and IFN weekly.1
The most common (incidence ≥ 30%) adverse reactions observed with TORISEL were1
- Rash (47%)
- Asthenia (51%)
- Mucositis (41%)
- Nausea (37%)
- Edema (35%)
- Anorexia (32%)
The most common laboratory abnormalities (incidence ≥ 30%) were1
- Anemia (94%)
- Hyperglycemia (89%)
- Hyperlipemia (87%)
- Hypertriglyceridemia (83%)
- Elevated alkaline phosphatase (68%)
- Elevated serum creatinine (57%)
- Lymphopenia (53%)
- Hypophosphatemia (49%)
- Thrombocytopenia (40%)
- Elevated AST (38%)
- Leukopenia (32%)
- Treatment with the combination of TORISEL 15 mg and IFN was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN1
- Fewer patients experienced Grade 3 or 4 adverse events (AEs) with TORISEL compared with IFN (67% vs 78%, respectively)1
- The incidence of certain metabolic abnormalities was higher with TORISEL compared with IFN, including hyperglycemia, hypophosphatemia, hypokalemia, hyperlipemia, increased creatinine, and elevated alkaline phosphatase1
Adverse reactions reported in at least 10% of patients who received TORISEL or IFN
1
| Adverse Reaction | All Grades* | Grades 3 & 4* | ||
|---|---|---|---|---|
| TORISEL 25 mg IV once weekly (n=208) |
IFN up to 18 MU 3x weekly(n=200) |
TORISEL 25 mg IV once weekly (n=208) |
IFN up to 18 MU 3x weekly(n=200) |
|
| Any | 100 | 100 | 67 | 78 |
| General disorders | ||||
| Asthenia | 51% | 64% | 11% | 26% |
| Edema† | 35% | 11% | 3% | 1% |
| Pain | 28% | 16% | 5% | 2% |
| Pyrexia | 24% | 50% | 1% | 4% |
| Weight loss | 19% | 25% | 1% | 2% |
| Headache | 15% | 15% | 1% | 0% |
| Chest pain | 16% | 9% | 1% | 1% |
| Chills | 8% | 30% | 1% | 2% |
| Gastrointestinal disorders | ||||
| Mucositis‡ | 41% | 10% | 3% | 0% |
| Anorexia | 32% | 44% | 3% | 4% |
| Nausea | 37% | 41% | 2% | 5% |
| Diarrhea | 27% | 20% | 1% | 2% |
| Abdominal pain | 21% | 17% | 4% | 2% |
| Constipation | 20% | 18% | 0% | 1% |
| Vomiting | 19% | 29% | 2% | 3% |
| Infections | ||||
| Infections§ | 20% | 10% | 3% | 2% |
| Urinary tract infection|| | 15% | 12% | 1% | 2% |
| Pharyngitis | 12% | 2% | 0% | 0% |
| Rhinitis | 10 % | 2% | 0% | 0% |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 20% | 14% | 3% | 4% |
| Arthralgia | 18% | 15% | 1% | 1% |
| Myalgia | 8% | 15% | 1% | 1% |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Dyspnea | 28% | 24% | 9% | 6% |
| Cough | 26% | 15% | 1% | 0% |
| Epistaxis | 12% | 4% | 0% | 0% |
| Skin and subcutaneous tissue disorders | ||||
| Rash¶ | 47% | 7% | 5% | 0% |
| Pruritus | 19% | 8% | 1% | 0% |
| Nail disorder | 14% | 1% | 0% | 0% |
| Dry skin | 11% | 7% | 1% | 0% |
| Acne | 10% | 1% | 0% | 0% |
| Nervous system disorders | ||||
| Dysgeusia# | 20% | 9% | 0% | 0% |
| Insomnia | 12% | 15% | 1% | 0% |
| Depression | 4% | 14% | 0% | 2% |
* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0.
† Includes edema, facial edema, and peripheral edema.
‡ Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis.
§ Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster.
|| Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection.
¶ Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash.
# Includes taste loss and taste perversion.
Laboratory abnormalities
In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks1
Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician's discretion1
Serum glucose, serum cholesterol, and serum triglycerides should be tested before and during treatment with TORISEL1
Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter1
| Selected laboratory abnormalities | All Grades** | Grades 3 & 4** | ||
|---|---|---|---|---|
| TORISEL 25 mg IV once weekly (n=208) |
IFN up to 18 MU 3x weekly (n=200) |
TORISEL 25 mg IV once weekly (n=208) |
IFN up to 18 MU 3x weekly (n=200) |
|
| Any | 100% | 98% | 78% | 72% |
| Hematology (checked weekly) |
||||
| Hemoglobin decreased | 94% | 90% | 20% | 22% |
| Lymphocytes decreased†† | 53% | 53% | 16% | 24% |
| Neutrophils decreased†† | 19% | 29% | 5% | 10% |
| Platelets decreased | 40% | 26% | 1% | 0% |
| Leukocytes decreased | 32% | 47% | 1% | 6% |
| Chemistry (checked every 2 weeks) |
||||
| Alkaline phosphatase increased | 68% | 56% | 3% | 7% |
| AST increased | 38% | 52% | 2% | 7% |
| Creatinine increased | 57% | 49% | 3% | 1% |
| Glucose increased | 89% | 64% | 16% | 3% |
| Phosphorus decreased | 49% | 31% | 18% | 9% |
| Total bilirubin increased | 8% | 13% | 1% | 2% |
| Total cholesterol increased | 87% | 48% | 2% | 1% |
| Triglycerides increased | 83% | 72% | 44% | 35% |
| Potassium decreased | 21% | 8% | 5% | 0% |
AST=aspartate aminotransferase.
**CTCAE Version 3.0.
†† Grade 1 toxicity may be under-reported for lymphocytes and neutrophils.
Laboratory monitoring should be performed at the physician's discretion.1
Important Safety Information
- TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1 - 1.5 x ULN or AST > ULN but bilirubin ≤ ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin > 1.5 x ULN.
- Hypersensitivity/infusion reactions, including flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, may occur very early in the first infusion or with subsequent infusions. Pretreat with an H1 antihistamine. TORISEL infusion should be interrupted in patients with infusion reactions and appropriate therapy given.
- Serum glucose, serum cholesterol, and triglycerides should be tested before and during TORISEL treatment.
- TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
- TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
- Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic or had minimal symptoms. Patients should undergo baseline radiography prior to TORISEL therapy and periodically thereafter, even in the absence of clinical respiratory symptoms. Follow patients closely and, if clinically significant respiratory symptoms develop, consider withholding TORISEL until recovery of symptoms and radiographic improvement of pneumonitis findings. Some patients required TORISEL discontinuation and/or treatment with corticosteroids and/or antibiotics.
- Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.
- Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
- Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
- 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 TORISEL.
- Live vaccinations and close contact with those who received live vaccines should be avoided.
- TORISEL may cause fetal harm. Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
- Elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema and pneumonia.
- The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
- Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).
- Pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome and extravasations have been reported during postmarketing use.
- Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
- Avoid St. John's Wort which may decrease TORISEL plasma concentrations, and grapefruit juice which may increase plasma concentrations of the major metabolite of TORISEL.
- The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).
Please see the full Prescribing Information for TORISEL.
References:
- TORISEL® Kit (temsirolimus) Prescribing Information, June 2011.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
N Engl J Med. 2007;356:2271-2281.
