"The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved t"...
- Patient Information:
Details with Side Effects
Increased Mortality, Serious Cardiovascular And Thromboembolic Events
Anemia associated with chronic renal failure
Patients experienced greater risks for death and serious cardiovascular events when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.
In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7 p=0.03).
Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to Epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. Higher mortality (35% vs. 29%) was observed in the 634 patients randomized to a target hemoglobin of 14 g/dL than in the 631 patients randomized to a target hemoglobin of 10 g/dL. The reason for the increased mortality observed in this study is unknown; however, the incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
Anemia due to other conditions
The safety and efficacy of Mircera (methoxy polyethylene glycol-epoetin beta) have not been established for use among patients with anemia due to cancer chemotherapy or for reduction in the need for allogeneic RBC transfusion in the peri-surgical setting. In these conditions, clinical trials of ESAs have shown risks for thrombotic events and/or mortality.
In a randomized controlled study (referred to as Cancer Study 1 - the "BEST" study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75, p=0.012).
A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 3 - the "BEST" and "ENHANCE" studies) evaluating 9353 patients with cancer compared ESAs plus RBC transfusion with RBC transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk (RR) of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.
An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed. In a randomized controlled study (referred to as the "SPINE" study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received Epoetin alfa and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events.
Increased mortality was observed in a randomized placebo-controlled study of Epoetin alfa in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to Epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events.
Increased Mortality and/or Tumor Progression
A dose-ranging trial of Mircera (methoxy polyethylene glycol-epoetin beta) in 153 patients who were undergoing chemotherapy for non-small cell lung cancer was terminated prematurely because significantly more deaths occurred among patients receiving Mircera (methoxy polyethylene glycol-epoetin beta) than another ESA.
Erythropoiesis-stimulating agents, when administered to target a hemoglobin of > 12 g/dL, shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy [Cancer Studies 3 and 4 (DAHANCA 10) in Table 2]. ESAs also shortened survival in patients with metastatic breast cancer (Cancer Study 1) and in patients with lymphoid malignancy (Cancer Study 2) receiving chemotherapy when administered to target a hemoglobin of ≥ 12 g/dL. In addition, ESAs shortened survival in patients with non-small cell lung cancer and in a study enrolling patients with various malignancies who were not receiving chemotherapy or radiotherapy; in these two studies, ESAs were administered to target a hemoglobin of ≥ 12 g/dL (Cancer Studies 5 and 6 in Table 2). Although studies evaluated hemoglobin targets of ≥ 12 g/dL in these tumor types, the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of < 12 g/dL.
Table 2: Randomized, Controlled Trials with Decreased Survival and/or Decreased LocoregionaJ Control
|Primary Endpoint|| Adverse Outcome for ESA-
|Cancer Study 1 Metastatic breast cancer (n=939)||12-14 g/dL|| 12.9 g/dL
12.2, 13.3 g/dL
|12-month overall survival||Decreased 12-month survival|
|Cancer Study 2 Lymphoid malignancy (n=344)|| 13-15 g/dL(M)
13-14 g/dL (F)
| 11.0 g/dL 9.8,
| Proportion of
patients achieving a hemoglobin
|Decreased overall survival|
|Cancer Study 3 Head and neck cancer (n=351)|| > 15g/dL(M)
|Not available|| Locoregional
|Decreased 5-yearlocoregional progression-freesurvivalDecreased overall survival|
|Cancer Study 4 Head and neck cancer (n=522)||14-15.5 g/dL||Not available|| Locoregional
|Decreased locoregional disease control|
|No Chemotherapy or Radiotherapy|
|Cancer Study 5 Non-small cell lung cancer (n=70)||12-14 g/dL||Not available||Quality of life||Decreased overall survival|
|Cancer Study 6 Non-myeloid malignancy (n=989)||12-13 g/dL|| 10.6 g/dL
9.4, 11.8 g/dL
|RBC transfusions||Decreased overall survival|
Decreased overall survival:
Cancer Study 1 (the "BEST" study) was previously described [see Warnings and PRECAUTIONS]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator- attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p=0.012).
Cancer Study 2 was a Phase 3, double-blind, randomized (Darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to Darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Cancer Study 5 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04).
Cancer Study 6 was a Phase 3, double-blind, randomized (Darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the Darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.
Decreased locoregional progression-free survival and overall survival:
Cancer Study 3 (the "ENHANCE" study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobins of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14, p=0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI- 1.05, 1.84; p=0.02).
Decreased locoresional control:
Cancer Study 4 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to Darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving Darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p=0.02). Overall survival was shorter in patients receiving Darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p=0.08).
Blood pressure should be controlled adequately before initiation of Mircera (methoxy polyethylene glycol-epoetin beta) therapy. Special care should be taken to closely monitor and control blood pressure during Mircera (methoxy polyethylene glycol-epoetin beta) therapy, especially in patients with a history of cardiovascular disease or hypertension. If blood pressure is difficult to control by pharmacologic or dietary measures, the dose of Mircera (methoxy polyethylene glycol-epoetin beta) should be reduced or withheld.
In Mircera (methoxy polyethylene glycol-epoetin beta) clinical studies, approximately 27% of patients with CRF, including patients on dialysis and not on dialysis, required intensification of antihypertensive therapy. Hypertensive encephalopathy and/or seizures have been observed in patients with CRF treated with Mircera [see Warnings and PRECAUTIONS].
Seizures have occurred in patients participating in Mircera (methoxy polyethylene glycol-epoetin beta) clinical studies. During the first several months of therapy, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. While the relationship between seizures and the rate of rise of hemoglobin is uncertain, the dose of Mircera (methoxy polyethylene glycol-epoetin beta) should be decreased or withheld if the hemoglobin increases more than 1 g/dL in any 2-week period [see DOSAGE AND ADMINISTRATION].
Pure Red Cell Aplasia
Pure red cell aplasia (PRCA) and severe anemia, with or without other cytopenias, have been associated with the development of neutralizing antibodies to erythropoietin in patients treated with ESAs. PRCA occurred predominantly in patients with CRF receiving an ESA by SC administration. PRCA was not observed in clinical studies of Mircera (methoxy polyethylene glycol-epoetin beta) .
Any patient who develops a sudden loss of response to Mircera (methoxy polyethylene glycol-epoetin beta) , accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of the altered hemoglobin response, including evaluation for the development of neutralizing antibodies to erythropoietin [see Warnings and PRECAUTIONS]. Serum samples should be obtained at least a month after the last Mircera (methoxy polyethylene glycol-epoetin beta) administration to prevent interference of Mircera (methoxy polyethylene glycol-epoetin beta) with the assay. If anti-erythropoietin antibody-associated anemia is suspected, withhold Mircera (methoxy polyethylene glycol-epoetin beta) and other erythropoietic proteins. Contact Roche at 1-800-526-6367 to perform assays for antibodies. Mircera (methoxy polyethylene glycol-epoetin beta) should he permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react [see ADVERSE REACTIONS].
Lack or Loss of Response to Mircera (methoxy polyethylene glycol-epoetin beta)
The lack of a hemoglobin response or failure to maintain a hemoglobin response with Mircera (methoxy polyethylene glycol-epoetin beta) doses within the recommended dosing range should prompt a search for causative factors. Deficiencies of iron, folic acid and vitamin B12 should be excluded or corrected.
Intercurrent infections, malignancy, inflammation, occult blood loss, hemolysis, severe aluminum toxicity, osteitis fibrosis cystica, underlying hematological disease (e.g., thalassemia, refractory anemia or myelodysplastic disorders) or bone marrow fibrosis, may also compromise the hemoglobin response. In the absence of another etiology, the patient should be evaluated for evidence of PRCA, including tests for the presence of antibodies to erythropoietin [see Warnings and PRECAUTIONS].
Sufficient time should be allowed to determine a patient's response to a Mircera (methoxy polyethylene glycol-epoetin beta) dose before adjusting the subsequent doses. Because of the time required for erythropoiesis and the red blood cell (RBC) life span, an interval of 2 to 6 weeks may occur between the time of a dose adjustment (initiation, increase, decrease, or discontinuation) and a significant change in hemoglobin. In order to prevent the hemoglobin from exceeding 12 g/dL or rising too rapidly (greater than 1 g/dL in 2 weeks), the guidelines for dose and frequency of dose adjustments should be followed [see DOSAGE AND ADMINISTRATION].
Average platelet counts decreased approximately 7% among patients receiving Mircera (methoxy polyethylene glycol-epoetin beta) in clinical studies with most patients maintaining platelet counts within normal levels. The decrease in platelet counts occurred immediately following Mircera (methoxy polyethylene glycol-epoetin beta) initiation and the levels remained stable thereafter. At least one post-baseline platelet count below 100 x 109/L was observed in 7.5% of patients treated with Mircera (methoxy polyethylene glycol-epoetin beta) and 4.4% of patients treated with another ESA.
Serious allergic reactions, consisting of tachycardia, pruritus and rash, have been reported in patients treated with Mircera (methoxy polyethylene glycol-epoetin beta) . If a serious allergic or anaphylactic reaction occurs due to Mircera (methoxy polyethylene glycol-epoetin beta) , treatment should be immediately and permanently discontinued and appropriate therapy should be administered.
Patients with CRF Not Requiring Dialysis
Patients with CRF not requiring dialysis may require lower maintenance doses of Mircera (methoxy polyethylene glycol-epoetin beta) than patients receiving dialysis. Patients who are not receiving dialysis may be more responsive to the effects of Mircera (methoxy polyethylene glycol-epoetin beta) and require judicious monitoring of blood pressure and hemoglobin. Renal function and fluid electrolyte balance should also be closely monitored.
Therapy with Mircera (methoxy polyethylene glycol-epoetin beta) results in an increase in red blood cells and a decrease in plasma volume, which could reduce dialysis efficiency; patients who are marginally dialyzed may require adjustments in their dialysis prescription.
In order to ensure effective erythropoiesis, iron status should be evaluated for all patients before and during treatment. Provide supplemental iron therapy for patients whose serum ferritin is below 100 mcg/L or whose serum transferrin saturation is below 20%.
During Mircera (methoxy polyethylene glycol-epoetin beta) therapy, monitor hemoglobin every two weeks until the hemoglobin level has stabilized between 10 and 12 g/dL and the maintenance Mircera (methoxy polyethylene glycol-epoetin beta) dose has been established. The hemoglobin should then be monitored at least monthly. If a patient requires a dose adjustment or is switched to Mircera (methoxy polyethylene glycol-epoetin beta) from another ESA, monitor hemoglobin every two weeks until the hemoglobin level has stabilized [see DOSAGE AND ADMINISTRATION].
Patient Counseling Information
Information for Patients
Inform patients of the:
- Need for regular blood pressure monitoring and laboratory tests for hemoglobin in order to lessen the risks for mortality and serious cardiovascular events
- Possible side effects of Mircera (methoxy polyethylene glycol-epoetin beta) , including injection site reactions, allergic reactions and the potential problems due to excessive increases in blood hemoglobin levels [see Warnings and PRECAUTIONS]
- Signs and symptoms of injection site and allergic reactions
- Importance of compliance with any prescribed dietary restrictions, dialysis regimens or medications, including antihypertensive medications
Administer Mircera (methoxy polyethylene glycol-epoetin beta) under the direct supervision of a healthcare provider or, in situations where a patient has been trained to administer Mircera (methoxy polyethylene glycol-epoetin beta) at home, provide instruction on the proper use of Mircera (methoxy polyethylene glycol-epoetin beta) , including instructions to:
- Carefully review the Medication Guide and the Patient Instructions for Use
- Avoid the reuse of needles, syringes, or unused portions of the Mircera (methoxy polyethylene glycol-epoetin beta) vials or prefilled syringes and to properly dispose of these items
- Always keep a puncture-proof disposal container available for the disposal of used syringes and needles
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of Mircera (methoxy polyethylene glycol-epoetin beta) has not been evaluated in long-term animal studies. Mircera (methoxy polyethylene glycol-epoetin beta) did not induce a proliferative response in either the erythropoietin receptor positive cell lines HepG2 and K562 or the erythropoietin receptor negative cell line RT112 in vitro. In addition, using a panel of human tissues, the in vitro binding of Mircera (methoxy polyethylene glycol-epoetin beta) was observed only in bone marrow progenitor cells.
The mutagenic potential of Mircera (methoxy polyethylene glycol-epoetin beta) has not been evaluated.
Impairment of Fertility
When Mircera (methoxy polyethylene glycol-epoetin beta) was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
Use In Specific Populations
Pregnancy: Category C
When Mircera (methoxy polyethylene glycol-epoetin beta) was administered subcutaneously to rats and rabbits during gestation, bone malformation was observed in both species at 50 mcg/kg once every three days. This effect was observed as missing caudal vertebrae resulting in a thread-like tail in one rat fetus, absent first digit metacarpal and phalanx on each forelimb resulting in absent polex in one rabbit fetus, and fused fourth and fifth cervical vertebrae centra in another rabbit fetus. Dose-related reduction in fetal weights was observed in both rats and rabbits. At doses 5 mcg/kg once every three days and higher, Mircera (methoxy polyethylene glycol-epoetin beta) caused exaggerated pharmacodynamic effects in dams. Once-weekly doses of Mircera (methoxy polyethylene glycol-epoetin beta) up to 50 mcg/kg/dose given to pregnant female rats did not adversely affect pregnancy parameters, natural delivery or litter observations. Increased deaths and significant reduction in growth rate of Fl generation were observed during lactation and early post weaning period. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in Fl generation of any dose groups.
There are no adequate and well-controlled studies in pregnant women. Mircera (methoxy polyethylene glycol-epoetin beta) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether Mircera (methoxy polyethylene glycol-epoetin beta) is excreted into human breast milk. In one study in rats, Mircera (methoxy polyethylene glycol-epoetin beta) was excreted into maternal milk. Because many drugs are excreted in human milk, caution should be exercised when Mircera (methoxy polyethylene glycol-epoetin beta) is administered to a nursing woman.
The safety and efficacy of Mircera (methoxy polyethylene glycol-epoetin beta) in pediatric patients have not been established.
Clinical studies of Mircera (methoxy polyethylene glycol-epoetin beta) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Last reviewed on RxList: 12/20/2007
This monograph has been modified to include the generic and brand name in many instances.
Additional Mircera Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options.