NN&I - April 2010
www.nephronline.comApril 2010 Nephrology News & Issues 29 Patient Management ber of factors, independent of the individual's iron status, may influence the serum ferritin measurement. Evidence for the confounding influence of inflammation on serum fer -ritin levels is seen in studies on malnutrition-inflammation syndrome.11,12 In addition, significant interassay variability exists among currently used laboratory serum ferritin tests, and repeated tests in the same individual have been found to vary by more than 50% over a two-week time period.13Although the most recent Kidney Disease Outcome Quality Initiative guidelines state that there is insufficient evidence to recommend routine IV iron use if the serum ferritin level is >500 ng/mL,1 the guidelines do not set an upper limit for serum ferritin. Instead, they cite a number of factors that should be considered in making treatment decisions for hemodialysis patients with higher serum fer -ritin levels. These include the patient's clinical status, the presence of ESA hyporesponsiveness, and the TSAT level. In particular, a higher serum ferritin level, in combination with a low TSAT level, may reflect a state of iron-restricted erythropoiesis, in which the body has insufficient levels of storage iron to keep pace with the accelerated rate of eryth-ropoiesis caused by ESAs.1The literature currently does not provide solid evidence in support of a specific upper level of serum ferritin. There is a need for studies to evaluate the effects of treating patients with IV iron at various serum ferritin levels on clinical out -comes such as hospitalization risk, cardiovascular events, and quality of life.14 Although there is a plausible biologic basis supporting a role for iron in increasing the risk of infection, there is no convincing evidence that higher serum ferritin levels in hemodialysis patients are associated with adverse outcomes, such as infection, or with consistent increases in markers of inflammation, such as C-reactive protein.5,6,15-17Similar to the DRIVE studies,6,7 our study results showed that IV iron administration up to a serum ferritin level of 1,200 ng/mL may help improve and maintain Hb levels and reduce ESA doses. IV iron can be delivered through peri-odic repletion courses (e.g., 1 g every three to four months) whenever iron stores fall out of target ranges (a "load and hold" strategy). Alternatively, it can be delivered via smaller doses at regular intervals (e.g., 62.5 mg once weekly) in order to maintain a consistently stable iron balance.1 It has been estimated that, in patients who are iron replete, 22 mg to 65 mg per week of IV iron are needed to maintain a neutral iron balance.1 In patients with serum ferritin levels up to 1200 ng/mL, DRIVE showed the benefits of IV iron given as a repletion regimen,6 while our study showed similar ben-efits using a regular, low-dose IV iron regimen.Because of the more frequent dosing schedule, regular, low-dose regimens are more likely to ensure that the eryth- Drug related adverse events reported by 2% of Venofer ® (iron sucrose injection,USP) treated patients are shown by dose group in Table 4. Table 4.Most Common Adverse Events Related to Study Drug Reported in 2% of Patients by Dose Group (Multidose Safety Population) HDD-CKD PDD-CKD Adverse Events 100 mg 300 mg for 2 doses followed by (Preferred Term) (N=231) 400 mg for 1 dose (N=75) %% Subjects with any adverse event 14.7 10.7 Gastrointestinal Disorders Diarrhea NOS* 0.9 2.7 Dysgeusia 0.9 0 Nausea 1.7 1.3 Vascular Disorders Hypotension NOS 5.2 0 *NOS=Not otherwise specified Adverse Events Observed in Hemodialysis Dependent Chronic Kidney Disease (HDD-CKD) Patients Adverse reactions,whether or not related to Venofer ® administration,reported by >5% of treated patients from a total of 231 patients in the 3 pivotal HDD-CKD Studies were as follows:hypotension (39.4%),muscle cramps (29.4%), nausea (14.7%),headache (12.6%),graft complications (9.5%),vomiting (9.1%),dizziness (6.5%),hypertension (6.5%),chest pain (6.1%),and diarrhea (5.2%). In the first post-marketing safety study,665 chronic hemodialysis patients were treated with Venofer ® doses of 100 mg at each dialysis session for up to 10 consecutive dialysis sessions for their iron deficiency or on a weekly basis for 10 weeks for maintenance of iron stores.In this study,72% of the patients received up to 10 doses,27% received between 11-30 doses,and 1% received 40 to 50 doses of Venofer ® .Serious adverse events and drug-related non-serious adverse events were collected.In the second post-marketing safety study,386 hemodialysis patients were exposed to a single dose of Venofer ® (100 mg IV by slow injection over 2 minutes or 200 mg IV by slow injection over 5 minutes).Adverse events reported by > 1% of 1,051 treated patients were:cardiac failure congestive,sepsis NOS and dysgeusia. Adverse Events Observed in Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) Patients In the pivotal study of 121 treated PDD-CKD patients,75 patients were exposed to Venofer ® .Adverse events,whether or not related to Venofer ® reported by 5% of these patients are as follows:diarrhea,peritoneal infection,vomiting, hypertension,pharyngitis,peripheral edema and nausea. In these 75 patients exposed to Venofer ® ,9 patients experienced serious adverse events as follows:peritoneal infection (2 patients) and 1 patient each with cardiopulmonary arrest,myocardial infarction,upper respiratory infection NOS,anemia,gangrene,hypovolemia and tuberculosis.None of these events were considered drug-related.Two Venofer ® patients experienced a moderate hypersensitivity/allergic reaction (rash or swelling/itching) during the study. The only drug related adverse reaction to Venofer ® administration reported by 2% of patients was diarrhea. Three patients in the Venofer ® study group discontinued study treatment due to adverse events (cardiopulmonary arrest,peritonitis and myocardial infarction,hypertension) which were considered to be not drug-related. Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies,several patients experienced hypersensitivity reactions presenting with wheezing,dyspnea, hypotension,rashes,or pruritus.Serious episodes of hypotension occurred in 2 patients treated with Venofer ® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock,loss of consciousness or collapse,bronchospasm with dyspnea,or convulsion) associated with Venofer ® administration. One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S.trials in HDD-CKD patients (studies A,B and the two post marketing studies) had prior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product).When these patients were treated with Venofer ® there were no occurrences of adverse events that precluded further use of Venofer ® . OVERDOSAGE Dosages of Venofer ® (iron sucrose injection,USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis.Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation.Venofer ® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1].Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer ® too rapidly included hypotension,dyspnea,headache, vomiting,nausea,dizziness,joint aches,paresthesia,abdominal and muscle pain,edema,and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids,hydrocortisone,and/or antihistamines.Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer ® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation,hypoactivity,pale eyes,and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer ® is expressed in terms of mg of elemental iron.Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron,administered over sequential sessions,to achieve a favorable hemoglobin response and to replenish iron stores (ferritin,TSAT). Hemodialysis patients may continue to require therapy with Venofer ® or other intravenous iron preparations at the lowest dose necessary to maintain target levels of hemoglobin,and laboratory parameters of iron storage within acceptable limits. Administration: Venofer ® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD): Venofer ® may be administered undiluted as a 100 mg slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg,diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes per consecutive hemodialysis session for a total cumulative dose of 1,000 mg. Peritoneal Dialysis Dependent-Chronic Kidney Disease Patients (PDD-CKD): Venofer ® is administered as a total cumulative dose of 1,000 mg in 3 divided doses,given by slow intravenous infusion,within a 28 day period:2 infusions of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later.The Venofer ® dose should be diluted in a maximum of 250 mL of 0.9% NaCl. Rx Only REFERENCE: [1] National Kidney Foundation.K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease,2000. Am J Kidney Dis. 37:S182-S238,(suppl 1) 2001. IN534BS 100987-01 Iss.01/09 © 2008 Fresenius Medical Care Venofer ® is manufactured under license from American Regent,Inc.(Shirley,NY) and Vifor (International) Inc., Switzerland. Venofer ® is a trademark of Vifor (International) Inc.used by permission. Manufactured for & Distributed by: Fresenius Medical Care NA Waltham,MA 02451 1-800-323-5188 FVEN0068 RBE Effi NNI DR 3/8/10 12:31 PM Page 3 [ P A TIENT MANAGEMENT , continued from page 26 ] Patient Management_0410_7.indd 29 3/18/10 3:46:16 PM
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