January 2012 FAQs
January 2012 FAQs
Can the interval between INRs be extended in patients receiving stable doses of warfarin?
Can the interval between INRs be extended in patients receiving stable doses of warfarin?
The use of vitamin K antagonists for anticoagulation requires routine monitoring to confirm that a patient maintains a therapeutic international normalized ratio (INR). The American College of Chest Physicians recommends that the INR be measured at least every 4 weeks for patients on stable doses of warfarin.1 Limited studies conducted in stable patients suggest that longer intervals between INRs may potentially be used. One retrospective study in England found that patients with a stable INR could wait 14 weeks between prothrombin tests (PT) safely.2 In this study, 70% of INRs with a 6-week follow-up were in the target range compared with 76% using a 14-week follow-up. However, in this study, only stable patients were selected for testing at 14-week intervals. Patients only recently stable on warfarin or with recent dose changes were required to have more frequent testing, suggesting the potential for bias in these results. Another study conducted in Italy suggested no difference in INRs between 4- and 6-week assessments in patients stabilized on warfarin.3 But in this trial, the primary endpoint was to determine the risk of hemorrhage or thrombotic complications and compared the rates of INR values <1.5 or >5.0, rather than maintaining a therapeutic target range. Of note, INR values >5.0 were found more frequently in the 6-week group compared with the 4-week group (1.67% vs. 0.94%), but the difference did not reach statistical significance (p=0.06). Most recently, a randomized clinical trial was conducted to compare the safety and efficacy of evaluating INRs every 4 weeks versus every 12 weeks in patients receiving a stable dose of warfarin.4 Extending the time between visits for INR testing for warfarin could result in a significant cost savings to the healthcare system.
This was a randomized, noninferiority trial conducted at a single anticoagulation clinic in Canada.4 Patients were able to participate in the trial if they had been receiving a stable dose of warfarin (therapeutic INR range of 2.0 to 3.0 or 2.5 to 3.5) for at least 6 months prior to the trial. Patients were randomized to every 4 week assessment or every 12 week assessment using block randomization. All patients had INR measurements completed every 4 weeks, and an INR value was reported every week to the treating physician. For those randomized to assessment every 4 weeks, treating physicians received the true INR reports each week. Physicians managing patients in the every 12-week group received the true INR once every 12 weeks and received "sham" reports for the other weeks. These "sham" INR reports were given as values within or just outside of the therapeutic range (e.g., 1.8 to 3.5 for a target range of 2.0 to 3.0) to encourage continued use of the same dose. In the case of extreme true INRs, the treating physician was notified of the actual value. The primary outcome of the study was the percentage of time the patient maintained a therapeutic INR (reported as Time in Therapeutic Range [TTR]). The study also measured the number of extreme INRs, dose changes, major bleeding events, thromboembolic events, and death. Only 2 laboratories were used to conduct the INR testing to reduce variability in test results.
Based on a power analysis, a total of 214 patients were enrolled in the trial to demonstrate noninferiority; however, after a pre-planned interim analysis, the sample size was increased to 250 subjects.4 The margin for noninferiority between the 2 assessment intervals was 7.5% (as the upper limit of a 97.5% confidence interval [CI]). The investigators also evaluated the impact of clinical variables such as sex, use of antiplatelet agents, heart failure, diabetes, and the specific laboratory used.
Patients in both groups were similar at baseline.4 The median age was approximately 71 years, and 70% of the patients were male. The most frequent indications for anticoagulation were atrial fibrillation and heart valve replacement. The primary outcome, the percentage of time patients were in a therapeutic range (TTR) was 74.1% (±18.8) in the 4-week group and 71.6% (±20.0) in the 12-week group. The upper limit of the 97.5% CI for the difference was 7.3% and within the prespecified noninferiority margin (p=0.019 for noninferiority). Seventy patients (55.6%) in the 4-week group had ≥ 1 change in the dose of warfarin, while 46 patients (37.1%) in the 12-week group required ≥ 1 change (p=0.004). There were no significant differences between groups in the incidence of extreme INRs, major bleeding, thrombotic events, or death. No significant interactions were seen for any of the clinical variables analyzed.
The authors noted several limitations to this trial. The study used a surrogate endpoint of percentage of time in therapeutic range, since it was not feasible to power a study to assess clinical outcomes; a large number of patients would be needed for such a trial. Patients in both the 4- and 12-week groups had INRs measured and telephone communications with the anticoagulation clinic staff every 4 weeks. Therefore, this study did not assess a true 12-week monitoring. For ethical reasons, the actual INR value was reported (even if before 12 weeks) for patients with extreme INRs to allow for dosage adjustments. If there had been no interventions or patient-provider communication between the 12-week intervals, the outcomes may have been different. In addition, the trial was conducted at a single center, which may make it more difficult to generalize the results.
This trial suggests that INRs may be measured every 12 weeks in patients on a stable dose of warfarin. Although this would be more convenient for the patient and more cost-effective for the hospital, there are several concerns that need to be addressed before pharmacists change their practice. This study was single-blinded and all patients continued to have the INR measured every 4 weeks. Not only could compliance to the warfarin regimen be re-enforced, but if the INR was out of the therapeutic range, providers could make a dose adjustment. If patients were only seen every 12 weeks, the outcomes may have been different.
A more comprehensive trial assessing clinical outcomes should be designed to determine the benefit of extending the INR measurement to 12 weeks. The current guidelines recommend INRs be measured every 4 weeks once patients are on a stable warfarin dose. Until more comprehensive, multicenter trials assessing clinical outcomes have been conducted, providers are cautioned about changing their practice.
1. Ansell J,Hirsh J,Hylek E,Jacobson A,Crowther M,Palareti G;American College of Chest Physicians . Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):160S-198S.
2.Lidstone V, Janes S, Stross P. INR: Intervals of measurement can safely be extended to 14 weeks. Clin Lab Haematol. 2000;22(5);291-293.
3. Pengo V, Barbero F, Biasiolo A, Pegoraro C, Cucchinin U, Iliceto S. A comparison between six and four week intervals in surveillance of oral anticoagulant treatments. Am J Clin Path. 2003;120(6):944-947.
4. Schulman S, Parpia S, Stewart C, Rudd-Scott L, Julian JA, Levine M. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios. Ann Intern Med. 2011;155(10);653-659.
What is the recommended preoperative use of epoetin for blood conservation?
What is the recommended preoperative use of epoetin for blood conservation?
In the United States, surgical procedures account for the transfusion of almost 15 million units of packed red blood cells (pRBC) every year. 1 However, allogeneic blood transfusions (ABT) do carry risks to the recipient. ABTs are associated with potentially fatal complications including viral and bacterial transmission leading to infection, acute lung injury, hemolytic transfusion reactions, graft-versus-host-disease, transfusion-associated circulatory overload, anaphylaxis, and post-transfusion purpura.2 Therefore, there is an increased interest in methods to decrease bleeding and the need for ABT with surgery.
Erythropoietin (EPO) is an erythropoiesis-stimulating glycoprotein that is 90% made by the kidneys. EPO allows erythroid precursor cells in the bone marrow to mature and eventually become erythrocytes. This process takes over 1 week, and erythrocytes have a normal survival time of 120 days. 3 Epoetin alfa (Procrit®, Epogen®) is the recombinant form of EPO available in the United States. It is indicated for the treatment of anemia secondary to chronic kidney disease (CKD) or use of zidovudine or cancer chemotherapy, and to reduce need for ABT in patients undergoing elective, noncardiac, nonvascular surgery. For surgical patients, there are 2 dosing recommendations: 300 units/kg per day subcutaneously (SC) for 14 days total, administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery; or 600 units/kg SC in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.4
In practice, however, epoetin has been used for a variety of surgical patients, such as those at high risk of anemia from surgery, patients who refuse blood transfusions (eg, Jehovah's Witness), or those undergoing preoperative autologous blood donations (PABD). Dosing and duration of administration has also been variable. The following review will discuss the available information on the preoperative use of epoetin as a strategy for blood conservation.
Recommendations for blood conservation during surgery
In 2011, the Blood Conservation Clinical Practice Guidelines from the Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists provide specific recommendations for blood conservation during surgery.5 One of the recommendations includes a short-course of epoetin, plus iron, preoperatively for patients undergoing cardiac surgery, those with preoperative anemia, those refusing blood transfusions, or for those at high risk for postoperative anemia. In addition, epoetin can be used preoperatively for patients undergoing PABD, although this recommendation is based on lesser evidence.
However, no dosing recommendations are included in the guidelines, and there is discussion regarding the risks associated with epoetin use. 5 Epoetin has a boxed warning stating an increased risk of mortality, myocardial infarction, stroke, and thromboembolism.4 According to the labeling for epoetin, targeting a higher hemoglobin (13 to 14 g/dL) compared to a lower range (9 to 11.3 g/dL) increased the risk of death, myocardial infarction, stroke, and thrombotic events in patients with CKD. Additionally, the manufacturer states that there is an increased incidence of deep venous thrombosis among patients receiving epoetin and undergoing orthopedic surgery.
Several studies have provided evidence for the use of epoetin preoperatively. Earnshaw and colleagues reviewed the role of epoetin in patients undergoing orthopedic surgery.6 In the 16 studies included in the review, the epoetin regimens were inconsistent, ranging from 50 units/kg intravenously (IV) twice a week for 3 weeks, up to 10,000 units SC for 6 doses at both preoperative weeks 2 and 4. All but 4 studies included supplemental iron. In these studies, there was also a wide range of findings including increased reticulocyte count, hemoglobin and hematocrit, reduced transfusion needs, and increased PABD volume.
In a systematic review on blood management regimens for hip and knee surgery, Spahn reviewed 6 studies utilizing epoetin for reduction of blood loss. 7 Similar to the studies reviewed by Earnshaw, the dose of epoetin was variable. Doses ranged from 7500 to 45,000 units given weekly for up to 4 weeks prior to surgery with oral iron. The outcome assessed, need for ABT, was significant in favor of epoetin in 4 of the trials. The rate of ABT was lower with epoetin (3% to 21%) compared with controls (14% to 54%). The author did note that the differences between ABT rates were more pronounced when transfusion triggers were more "liberal" (generally < 8 or 9 g/dL). However, no difference was noted in other outcomes, such as postoperative infection rate, length of stay, or 30-day mortality.
In a meta-analysis, Alghamadi and colleagues included 11 controlled studies in patients undergoing cardiac surgery. 8 Again, epoetin regimens were inconsistent across all studies, ranging from 150 to 800 units/kg IV or SC. Several studies used a fixed dose of 1200 up to 10,000 units. The frequency also varied, ranging from 1 to 3 times weekly, with durations of 1 to 4 weeks preoperatively. All studies included concomitant iron supplementation. A pooled analysis found that fewer patients who received epoetin preoperatively received ABT. This reduction in the need for transfusion was seen in patients with PABD (relative risk [RR] 0.28, 95% confidence interval [CI] 0.18-0.44, p<0.00001) and in patients without PABD (RR 0.53, 95% CI 0.32-0.88, p<0.01). One study of low quality was excluded due to significant heterogeneity when it was included in the analysis. The number needed to treat (NNT) was calculated and found to be 3 for patients with PABD and 4 for those without PABD, meaning that 3 or 4 patients would need to be treated with epoetin to prevent 1 additional patient from receiving an ABT. This meta-analysis did not report the autologous transfusion requirements in the studies that included PABD.
A safety analysis of the 11 studies was not performed.8 However, the authors report that one of the studies reported an increase in mortality during the study or within 2 months of discontinuation of the double-blind therapy, though this was found to be insignificant (p=0.06). 8 This study also found no difference in nonfatal complications between the epoetin and control groups. Another study reported 2 patients were removed due to adverse events possibly related to epoetin (one patient with fatigue and the other with skin rash and hypertension).
The safety of preoperative epoetin compared with standard of care for blood conservation was assessed in an open-label trial by Stowell and colleagues. 9 Patients undergoing elective spinal surgery were randomized to either epoetin 600 units/kg weekly for 4 doses starting 3 weeks before the procedure or to standard of care. Oral iron therapy was given to all patients and no patient received perioperative anticoagulation. The primary outcome of the study was the incidence of deep vein thrombosis. A total of 680 patients were included in the trial. Deep vein thrombosis was diagnosed in 4.7% of the epoetin patients and in 2.1% of those given standard of care. The difference exceeded predefined criteria for no additional risk of deep vein thrombosis with epoetin. The authors concluded that perioperative anticoagulation needs to be considered when epoetin is used prior to major surgical procedures.
Most available trials on the use of epoetin preoperatively use a multiple-dose regimen, beginning treatment at least 1 week prior to surgery. There is, however, limited information on single-dose epoetin. A recent study conducted by Yoo and colleagues looked at the transfusion requirements of 74 anemic patients in South Korea who underwent valvular heart surgery with or without preoperative epoetin.10 Patients were randomized to receive either epoetin 500 units/kg IV bolus plus iron sucrose 200 mg IV over 1 hour at 16 to 24 hours prior to surgery or an equivalent volume of normal saline with no iron supplementation. It should be noted that all patients received a loading dose and maintenance infusion of tranexamic acid during surgery with an additional loading dose at the onset of cardiopulmonary bypass (CPB). Primary endpoints included overall incidence of perioperative transfusion and the mean number of units of pRBC transfused per patient during surgery and postoperatively. Secondary endpoints included daily postoperative pRBC requirements, serial changes in hemoglobin, reticulocyte count, iron profiles, and postoperative complications. The thresholds for blood transfusion included a hemoglobin < 7 g/dL during CPB, and < 8 g/dL after CPB and postoperatively.
There were significantly fewer patients who were transfused with pRBC postoperative total (13.5% vs. 73%), on each postoperative day (2.7% to 13.5% vs. 21.6% to 54.1%) and perioperatively (59.5% vs. 86.5%), but not intraoperatively (54.1% vs. 67.7%), in the epoetin group compared with the control group, respectively.10 For the perioperative period, the mean number of pRBC units transfused with epoetin was 1.0 per patient compared with 3.3 in the control group (p<0.001). In addition, among transfused patients, the number of pRBC units was lower with epoetin versus controls (1.6 vs. 3.7; p=0.004). However, blood loss was not significantly different between the 2 groups (624 mL vs. 766 mL for epoetin and controls, respectively). Limitations of this study include the fact that all patients received tranexamic acid, an inhibitor of plasminogen activation often used in surgical procedures to reduce bleeding.11 Additionally, the treatment group was administered both epoetin and iron supplementation. It has been shown that a relative iron-deficient state occurs during the postoperative period, 12 and the iron supplementation itself may have had an influence on the study results.
García-Erce and colleagues described a blood conservation protocol used for patients undergoing knee or hip surgery, which used a single dose of epoetin 40,000 units.13,14 The same authors evaluated this protocol in an observational, cohort study of 196 anemic patients over the age of 65 who underwent surgery for hip fracture repair.15 Anemia was defined as a hemoglobin between 10 g/dL and 13 g/dL. All patients were entered into the blood conservation protocol, which consisted of a restrictive transfusion trigger (transfusion if hemoglobin < 8 g/dL or < 9 g/dL if active cardiac disease or acute anemic symptoms were present), a single dose of epoetin 40,000 units within 24 to 48 hours of admission, 3 perioperative doses of IV iron sucrose 200 mg, intramuscular vitamin B12 at admission, and oral folic acid and oral vitamin C from admission to discharge. Patients were excluded if they did not undergo surgery within 7 days of admission; therefore, they received epoetin no more than 5 to 6 days prior to surgery. This study was not intended to be comparative; however, 81 of the 196 patients did not receive epoetin for various reasons, including difficulty in obtaining epoetin due to hospital prescribing restrictions; patients staying in the emergency department until surgery; medical residents being unaware of the protocol; and patients being transferred to the floor without printed blood counts. This allowed the investigators to evaluate the blood transfusion requirements of patients who did and did not receive epoetin according to the protocol.
Significantly fewer patients who received epoetin required ABT perioperatively compared with patients who did not receive epoetin (42% vs. 60%, p=0.013).15 When transfusion needs were evaluated as pre-, intra-, post-, or pre- plus postoperative, only the need for postoperative ABT remained significant (29.6% vs. 46.1% for epoetin and no epoetin, respectively; p=0.004). Additionally, postoperative hemoglobin levels were greater on days 7 and 30 in those who received epoetin than those in the control group, although preoperative hemoglobin levels were similar in the 2 groups. There was no difference in postoperative complications, postoperative length of stay, and 30-day mortality. Limitations of this study include the possible bias due to the non-random distribution of patients who did and did not receive epoetin.
Epoetin has been shown to decrease ABT in surgical patients when given preoperatively. Concomitant iron supplementation should be given to maintain adequate iron stores necessary for the developing erythrocytes. Additionally, deep vein thrombosis prophylaxis is strongly recommended in all surgical patients receiving epoetin.
Single-dose epoetin with iron supplementation given preoperatively has been shown to decrease the requirement of blood transfusions in anemic patients who underwent cardiac and orthopedic surgery. However, only 2 studies are available that evaluated single-dose epoetin. Both of these studies were small, and 1 was not designed as a comparative trial.
Although the Blood Conservation Clinical Practice Guidelines from the Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists considers a short-course of epoetin an acceptable strategy for select surgical patients, no dosing recommendations are provided. The current labeling for epoetin includes 2 dosing regimens-300 units/kg or 600 units/kg-given at various intervals beginning 14 to 21 days prior to elective surgery for high-risk patients.4
In patients receiving cardiac surgery or orthopedic surgery, where the risks of bleeding and vascular complications are greater, epoetin with iron supplementation may have a role in anemic patients who are at high risk of requiring ABT. Due to the increased risk of cardiovascular complications associated with epoetin, the risks and benefits should be weighed in these patients who are already at risk for these complications.
1. Sullivan MT, Cotten R, Read EJ, Wallace EL. Blood collection and transfusion in the United States in 2001. Transfusion. 2007;479(3):385-394.
2. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009 ; 113(15): 3406-3417.
3. Cook K, Ineck B, Lyons W. Anemias. In: DiPiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L, eds. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York, NY: McGraw Hill Medical; 2011:1717-1740.
4. Procrit [Package Insert]. Thousand Oaks, CA: Amgen; 2000.
5. Ferris VA et al. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91(3):944-982.
6. Earnshaw P. Blood conservation in orthopaedic surgery: the role of epoetin alfa. Int Orthop. 2001;25(5):273-278.
7. Spahn D. Anemia and patient blood management in hip and knee surgery. Anesthesiology. 2010;113(2):482-495.
8. Alghamadi A, Albanna M, Guru V, Brister S. Does the use of erythropoietin reduce the risk of exposure to allogeneic blood transfusion in cardiac surgery? A systematic review and meta-analysis. J Card Surg. 2006;21(3):320-326.
9. Stowell C, Jones S, Enny C, Langholff W, Leitz G. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery. Spine. 2009;34(23):2479-2485.
10. Yoo YC, Shim JK, Kim JC, Jo YY, Lee JH, Kwak YL. Effect of single recombinant human erythropoietin injection on transfusion requirements in preoperatively anemic patients undergoing valvular heart surgery. Anesthesiology. 2011;115(5):929-937.
11. Cyklokapron [Package Insert]. New York, NY: Pfizer; 2011.
12. Karkouti K, McCluskey SA, Ghannam M, Salpeter MJ, Quirt I, Yau TM: Intravenous iron and recombinant erythropoietin for the treatment of postoperative anemia. Can J Anaesth. 2006;53(1):11-19.
13. García-Erce JA, Cuenca J, Martínez F, Cardona R, Pérez-Sarrano L, Muñoz M. Perioperative intravenous iron preserves iron stores and may hasten recovery from post-operative anaemia after knee replacement surgery. Transfus Med. 2006;16(5):335-341.
14. García-Erce JA, Cuenca J, Muñoz M, et al. Perioperative stimulation of erythropoiesis with intravenous iron and erythropoietin reduces transfusion requirements in patients with hip fracture. A prospective observational study. Vox Sang. 2005;88(4):235-243.
15. García-Erce JA, Cuenca J, Haman-Alcober S, Martinez AA, Herrera A, Munoz M. Efficacy of preoperative recombinant human erythropoietin administration for reducing transfusion requirements in patients undergoing surgery for hip fracture repair. An observational cohort study. Vox Sang. 2009;97(3):260-267.
Written by: Melissa Kusaka, PharmD.
What are the medication guide distribution requirements as part of REMS?
What are the medication guide distribution requirements as part of REMS?
Guidance from the Food and Drug Administration
In 2007, the Food and Drug Amendments Act (FDAAA) was passed which granted the Food and Drug Administration (FDA) the authority to require postmarketing studies or clinical trials for medications as they deem necessary.1 The Risk Evaluation and Mitigation Strategies (REMS) was created by the FDA to serve as a postmarketing surveillance process that ensures medication safety. The goal is to guarantee that the benefits of a medication outweigh the risks. Components of REMS include one or more of the following: prescriber, pharmacy, and/or dispensing requirements, quantity limits, monitoring requirements, documentation, and medication guides. The REMS requirements are specific for each medication. Although medication guides may be developed separately for some medications, they are the most common component of REMS.2 Over 150 medication guides have been FDA-approved between March 2008 and January 2011 and of them, 108 guides are REMS requirements.2,3
Additional requirements of REMS include:4
- All direct-to-consumer advertisements contain information on reporting negative side effects to the FDA
- All drug labeling provide a toll-free telephone number for consumers to report adverse events
- The FDA must have a searchable website for safety information
- Information about newly approved products be posted on the FDA website
- Establishment of an FDA Advisory Committee on Risk Communication to conduct bi-weekly screenings of the Adverse Event Reporting System
Since the establishment of REMS, several questions have arose regarding the distribution of medication guides in various settings, such as inpatient and outpatient clinics, when a drug is dispensed by a healthcare professional.2 In a hospital or nursing home setting, medications are dispensed by a pharmacist and administered by a healthcare professional.3 In an outpatient setting, such as a clinic or infusion center, medications are administered by healthcare professionals, with or without the involvement of a dispensing pharmacist. In both cases, a patient may receive a drug several times a day or week. To address these concerns, in November 2011, the FDA published guidance for medication guide distribution requirements under REMS. Below is a summary of the recommendations.
The guidance, which contains nonbinding recommendations, provides information for industry, healthcare providers, and authorized dispensers of prescription medications.3 Two main topics are addressed in the guidance: when a medication guide must be provided to a patient when the medication is dispensed by a healthcare provider and when a medication guide is required under REMS.
Medication guides are not required in the inpatient setting unless requested by the patient or his or her caregiver.2,3 When drugs are administered by a healthcare professional in the outpatient setting (e.g., clinic, dialysis unit, or infusion center) medication guides should only be provided under the following circumstances: 1) at the time of first administration; 2) the first time a medication is administered after a medication guide changes; 3) if requested by the patient; or 4) if a patient must be enrolled in a REMS program. However, patient instructions must be provided by the healthcare provider addressing the appropriate use of the medication, potential adverse effects, and follow-up, if needed.3 Table 1 provides specific recommendations for medication guide provision for various settings.
Table 1: Medication Guide Enforcement Discretion Policy Setting.3
Setting Patient or patient's agent requests medication guide Medication guide provided each time drug dispensed Medication guide provided at time of first dispensing Medication guide provided when medication guide materially changed Drug is subject to an ETASU REMS that includes specific requirements for providing and reviewing a medication guide Inpatient Must provide medication guide FDA intends to exercise enforcement discretion; medication guide need not be provided FDA intends to exercise enforcement discretion; medication guide need not be provided FDA intends to exercise enforcement discretion; medication guide need not be provided Must provide medication guide as specified in REMS Outpatient when drug dispensed to healthcare professional for administration to patient (e.g., clinic, infusion center, emergency department, outpatient surgery) Must provide medication guide FDA intends to exercise enforcement discretion; medication guide need not be provided Must provide medication guide Must provide medication guide Must provide medication guide as specified in REMS Outpatient when drug dispensed directly to patient or caregiver (e.g., retail pharmacy, hospital ambulatory pharmacy, patient samples) Must provide medication guide Must provide medication guide Must provide medication guide Must provide medication guide Must provide medication guide as specified in REMS
ETASU=Elements to Assure Safe Use; FDA=Food and Drug Administration; REMS=Risk Evaluation Mitigation Strategy.
As previously stated, not all medication guides are part of REMS.3 The FDA will continue to evaluate medications and as risks associated with the use of a medication increase, the FDA may determine that a medication guide be required under REMS to ensure safe use and that the benefits of the drug outweigh the risks.
The guidance published on the distribution of medication guides required as part of a REMS represents the FDA's current stance on the topic. The guidance will not be legally enforced by the FDA and should be viewed as recommendations unless specific regulatory requirements are cited. Healthcare providers may use alternative approaches to implement the guidance. It is recommended that these be discussed with the Agency by contacting the FDA at 800-835-4709.
1. American Society of Health-Systems Pharmacists. REMS resource center. http://www.ashp.org/menu/PracticePolicy/ResourceCenters/REMS.aspx . Accessed December 21, 2011.
2. Goldman SA, Hoffman JM, Monroe CD, Stubbings J. Clinical considerations of Risk Evaluation and Mitigation Strategies in Health Care Systems. American Society of Health-Systems Pharmacists Advantage e-Newsletter. American Society of Health-Systems Pharmacists Website. http://www.remsupdates.org/docs/rems_e-newsletter_8-2011.pdf. August 2011. Accessed December 21, 2011.
3. Guidance medication guides – distribution requirements and inclusion in Risk Evaluation and Mitigation Strategies (REMS). Food and Drug Administration Website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM244570.pdf . November 2011. Accessed December 21, 2011.
4. Kishore R, Tabor E. Overview of the FDA Amendments Act of 2007: its effect on the drug development landscape. Drug Information Journal. 2010;44(4):469-475.