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Seizures
In double-blind and open-label trials of EPOGEN (r) in zidovudine-treated HIV-infected patients, 10 patients have experienced seizures. 25 In general, these seizures appear to be related to underlying pathology such as meningitis or cerebral neoplasms, not EPOGEN (r) therapy. Cancer Patients on Chemotherapy Text Continues Below
Adverse experiences reported in clinical trials with EPOGEN (r) in cancer patients were consistent with the underlying disease state. In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with EPOGEN (r) or placebo-treated patients were as indicated below: Percent of Patients Reporting Event
Patients Treated With Placebo-treated
EPOGEN (r) Patients
Event (n = 63) (n = 68)
Pyrexia 29% 19%
Diarrhea 21% a 7%
Nausea 17% b 32%
Vomiting 17% 15%
Edema 17% c 1%
Asthenia 13% 16%
Fatigue 13% 15%
Shortness of Breath 13% 9%
Parasthesia 11% 6%
Upper Respiratory 11% 4%
Infection
Dizziness 5% 12%
Tr unk Pain 3% d 16%
a p = 0.041, b p = 0.069, c p = 0.0016, d p = 0.017
Although some statistically significant differences between patients being treated with EPOGEN (r) and placebo-treated patients were noted, the overall safety profile of EPOGEN (r) appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to EPOGEN (r) ) were treated for up to 32 weeks with doses as high as 927 Units/ kg, the adverse experience profile of EPOGEN (r) was consistent with the progression of advanced cancer.
Based on comparable survival data and on the percentage of patients treated with EPOGEN (r) and placebo-treated patients who discontinued therapy due to death, disease progression, or adverse experiences (22% and 13%, respectively; p = 0.25), the clinical outcome in patients treated with EPOGEN (r) and placebo-treated patients appeared to be similar. Available data from animal tumor models and measurement of proliferation of solid tumor cells from clinical biopsy specimens in response to EPOGEN (r) suggest that EPOGEN (r) does not potentiate tumor growth. Nevertheless, as a growth factor, the possibility that EPOGEN (r) may potentiate growth of some tumors, particularly myeloid tumors, cannot be exclud-ed.
A randomized controlled phase 4 study is currently ongoing to further evaluate this issue.
The mean peripheral white blood cell count was unchanged following EPOGEN (r) therapy compared to the corresponding value in the placebo-treated group.
Thrombotic/ Vascular Events
In three double-blind, placebo-controlled orthope-dic surgery studies, the rate of deep venous thrombosis (DVT) was similar among Epoetin alfa and placebo-treated patients in the recommended population of patients with a pretreatment hemoglobin of > 10 to 13 g/ dL. 18,20,28 However, in 2 of 3 orthopedic surgery studies the overall rate (all pretreatment hemoglobin groups combined) of DVTs detected by postoperative ultrasonography and/ or sur-veillance venography was higher in the group treated with Epoetin alfa than in the placebo-treated group (11% vs 6%). This finding was attributable to the difference in DVT rates observed in the subgroup of patients with pretreatment hemoglobin > 13 g/ dL. However, the incidence of DVTs was within the range of that reported in the literature for orthopedic surgery patients. In the orthopedic surgery study of patients with pretreatment hemoglobin of > 10 to 13 g/ dL which compared two dosing regimens (600 Units/ kg weekly x 4 and Zidovudine-treated HIV-infected Patients Hypertension Exacerbation of hypertension has not been observed in zidovudine-treated HIV-infected patients treated with EPOGEN (r) . However, EPOGEN (r) should be withheld in these patients if pre-existing hypertension is uncontrolled, and should not be started until blood pressure is controlled. In double-blind studies, a single seizure has been experienced by a patient treated with EPOGEN (r) . Cancer Patients on Chemotherapy Hypertension Hypertension, associated with a significant increase in hematocrit, has been noted rarely in patients treated with EPOGEN (r) . Nevertheless, blood pressure in patients treated with EPOGEN (r) should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease. Seizures In double-blind, placebo-controlled trials, 3.2% (n = 2/ 63) of patients treated with EPOGEN (r) and 2.9% (n = 2/ 68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/ 63) of patients treated with EPOGEN (r) occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with EPOGEN (r) also had underlying CNS pathology which may have been related to seizure activity. Thrombotic Events In double-blind, placebo-controlled trials, 3.2% (n = 2/ 63) of patients treated with EPOGEN (r) and 11.8% (n = 8/ 68) of placebo-treated patients had throm-botic events (eg, pulmonary embolism, cerebrovascular accident). Growth Factor Potential EPOGEN (r) is a growth factor that primarily stimulates red cell production.
However, the possibility that EPOGEN (r) can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Surgery Patients Thrombotic/ Vascular Events In perioperative clinical trials with orthopedic patients, the overall incidence of thrombotic/ vascular events was similar in Epoetin alfa and placebo-treated patients who had a pretreatment hemoglobin of > 10 to 13 g/ dL. In patients with a hemoglobin of > 13 g/ dL treated with 300 Units/ kg of Epoetin alfa, the possibility that EPOGEN (r) treatment may be associated with an increased risk of postopera-tive thrombotic/ vascular events cannot be excluded. In one study in which Epoetin alfa was administered in the perioperative period to patients undergoing coronary artery bypass graft surgery, there were 7 deaths in the group treated with Epoetin alfa (n = 126) and no deaths in the placebo-treated group (n = 56). Among the 7 deaths in the patients treated with Epoetin alfa, 4 were at the time of therapy (between study day 2 and 8). The 4 deaths at the time of therapy (3%) were associated with thrombotic/ vascular events. A causative role of Epoetin alfa cannot be excluded (see WARNINGS). Hypertension Blood pressure may rise in the perioperative period in patients being treated with EPOGEN (r) . Therefore, blood pressure should be monitored carefully. Drug Interaction No evidence of interaction of EPOGEN (r) with other drugs was observed in the course of clinical trials.
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