Frontline Pharmacist
F rontline Pharmacist Pharmacist-managed protocol to implement simvastatin labeling changes in a family medicine clinic
A
dverse drug events (ADEs) occur in approximately 27% of outpatients, with approximately 1.5 million preventable ADEs occurring each year in the United States, mostly in the outpatient setting.1,2 The Food and Drug Administration (FDA) responds to new clinically significant ADEs and risks discovered from postmarketing safety data by removing a drug from the market or by changing the prescribing information (labeling) of the implicated drug. Label changes include adding boxed warnings carrying critical information for prescribing, new dosage limitations, contraindications, or warnings.3-5 In 2009, FDA released 181 major drug safety regulatory actions: 37 boxed warnings, 23 contraindications, 120 warnings, and 1 drug withdrawal.3 In 2011, the number of boxed warnings, which are added as a result of serious adverse reactions relative to the potential benefit of the drug and in response to the most serious safety concerns, increased to 60.5 With this growth in major safety regulatory actions, often for commonly used drugs, widespread and timely implementation of medication labeling changes is difficult. Clinician response to boxed warnings has
been shown to be inadequate.6-8 In one study, more than 40% of patients were prescribed drugs such as angiotensinconverting-enzyme inhibitors, diuretics, metformin, isoniazid, and methotrexate that carried a boxed warning that applied to a contraindication with concurrent medications, a contraindication in pregnancy, or a lack of required baseline and ongoing monitoring of laboratory test values.9 Another study found that 10% of prescriptions for statin–fibrate combinations (most commonly involving simvastatin) went against package labeling.10
Prescribers may not be aware of dosage restrictions, and boxed warnings involving drug interactions may not appear in drug-interaction screening programs or resources.11 In addition, health care providers may not have systems in place to address revised FDA labeling and new dosage restrictions. Even with some systems in place, clinician adherence to FDA
The Frontline Pharmacist column gives staff pharmacists an opportunity to share their experiences and pertinent lessons related to day-to-day practice. Topics include workplace innovations, cooperating with peers, communicating with other professionals, dealing with management, handling technical issues related to pharmacy practice, and supervising technicians. Readers are invited to submit manuscripts, ideas, and comments to AJHP, 7272 Wisconsin Avenue, Bethesda, MD 20814 (301-664-8601 or [email protected]).
1248
Am J Health-Syst Pharm—Vol 71 Aug 1, 2014
boxed warnings may not be adequate. A study examining the implementation of alerts regarding FDA black-box warnings for medications in an outpatient electronic health record (EHR) found that the alerts had no impact on overall clinician adherence to the boxed warnings.12 Clearly, systems to improve adherence to FDA warnings and labeling changes are needed. Approximately 53% of adults in the United States have lipid disorders, and 19.8 million American adults use cholesterol-lowering medications.13,14 In 2012, lipid regulators were the fifth most prescribed therapeutic class of medications, and simvastatin was the fourth most prescribed drug in the United States.14 In June 2011, FDA issued a drug safety communication, which included labeling changes with new restrictions, contraindications, and dosage limitations for simvastatin and a statement that a dosage of 80 mg orally daily should be used only in patients who had taken this dosage safely for at least 12 months.15,16 Revisions to this communication were released in December 2011.17 The labeling changes were made due to an increased risk of myopathy, which was identified in the Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) collaborative group trial and evidence from FDA’s safety review of high-dose simvastatin.16-18 This article describes how new dosage limits in FDA labeling changes for simvastatin were implemented in a family medicine clinic. Development and implementation of the protocol. The Bethesda Family Medicine Clinic in St. Paul, Minnesota, is home to a family medicine residency program, where two clinical pharmacists serve on the faculty. When the FDA rec-
Frontline Pharmacist
ommendations were first released in June 2011, these pharmacists provided physician education detailing the changes. In June 2011, these pharmacists developed a detailed protocol to address FDA’s labeling changes regarding dosage limitations for simvastatin (Figure). The protocol was approved by the medical director (a physician) of the clinic and was implemented collaboratively by the clinical pharmacists and physicians in July 2011. The pharmacists were authorized to order laboratory tests, make any of the required medication changes independently, and fax the new prescriptions to the patients’ pharmacy per the protocol. Patients were eligible for inclusion in this pharmacist service if they were taking simvastatin 80 mg orally daily, a contraindicated concomitant medication, or a concomitant medication requiring a simvastatin dosage limitation, per the FDA labeling changes. All eligible patients were identified through an electronic search of the medication list in the EHR. Patients were scheduled for an appointment with the clinical pharmacist, or the changes were implemented during their physician visit, using the pharmacist-written protocol. The protocol was developed to assess patients’ current low-density-lipoprotein (LDL) cholesterol level, determine their goal LDL cholesterol range, and maintain levels already below the goal range or lower high levels into the goal range by using the relative LDL cholesterol-lowering capacities of different statins (Figure). The dose-equivalency chart provided in the FDA’s recommendations was used. The statins with a greater capacity than simvastatin 80 mg to lower LDL cholesterol are rosuvastatin 20 mg orally and atorvastatin 80 mg orally (both resulting in a 55% reduction in LDL cholesterol) and rosuvastatin 40 mg orally (resulting in a 63% reduction in LDL cholesterol).16 The FDA recommendations stated that no new prescriptions for simvastatin 80 mg daily should be initiated, but patients who have been on simvastatin for 12 months with no muscle toxicity could continue simvastatin 80 mg daily.
However, our clinic made the decision to be more conservative by no longer using the simvastatin 80-mg daily dose to avoid
any risks associated with that dosage. All other FDA recommendations were followed.
Figure. Pharmacist-developed and managed protocol. LDL = low-density lipoprotein.
If on higher simvastatin dose than recommended
If LDL cholesterol above goal: • Switch to statin with higher LDL cholesterol-lowering capacity than simvastatin dose currently taking If LDL cholesterol below goal: • Lower simvastatin to maximum recommended dose if goal LDL cholesterol will be maintained. Otherwise, switch to different statin or dose with similar LDL cholesterol-lowering capacity
If LDL cholesterol above goal: • Switch to statin with higher LDL cholesterol-lowering capacity (atorvastatin 80 mg/ day or rosuvastatin 20 mg/day)
If on simvastatin 80 mg daily
If LDL cholesterol at goal or ≤ 6% below goal: • Switch to statin with equivalent LDL cholesterol-lowering capacity (atorvastatin 40 mg/ day or rosuvastatin 10 mg/day)
If LDL cholesterol > 6% below goal: • Lower simvastatin to 40 mg/day
If LDL cholesterol > 12% below goal: • Lower simvastatin to 20 mg/day
If taking gemfibrozil, switch to fenofibrate If on interacting drug where simvastatin is contraindicated
If taking another interacting drug, switch simvastatin to another statin with appropriate LDL cholesterol-lowering capacity, depending if at goal LDL cholesterol or not
Am J Health-Syst Pharm—Vol 71 Aug 1, 2014
1249
Frontline Pharmacist
At the pharmacist visit, the patient’s lipid profile was measured, and the patient was asked about muscle symptoms. If muscle pain was present, the patient’s creatine kinase level was measured, sim vastatin was discontinued, and the patient was instructed to see his or her physician in one week. Medication adherence was assessed by chart review and patient interview; if nonadherence was suspected, the pharmacy was contacted to review refill records. The goal LDL cholesterol level was determined based on the presence or absence of coronary heart disease (CHD) or CHD risk-equivalents, or the Framingham score, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines.19 The change in statin medication was made according to the protocol, and the prescription was faxed to the patient’s pharmacy. A lipid profile and follow-up visit with the patient’s physician were scheduled to occur in six to eight weeks. If patients were unable to be reached by telephone after three attempts, letters were sent to them explaining the medication change, and their prescriptions were faxed to their pharmacy by the clinical pharmacist. Discontinuation orders for the contraindicated simvastatin dosage were also faxed to the pharmacy for all patients. Six months after the changes were implemented, chart review was performed to collect and document followup lipid profiles. Evaluation of the pharmacist service. A total of 70 patients were identified as taking simvastatin in a manner not supported by the new FDA labeling changes: 41 were taking simvastatin 80 mg/day, 2 were taking simvastatin with concomitant gemfibrozil, 23 were taking more than 20 mg of simvastatin daily with concomitant amlodipine, 3 were taking more than 10 mg of simvastatin daily with concomitant diltiazem, and 1 was taking more than 10 mg of simvastatin daily with concomitant verapamil. Regimens for all of these patients were consistent with previous simvastatin labeling but not with the new labeling. At baseline, 58 patients had a goal LDL cholesterol concentration of
F rontline Pharmacist Pharmacist-managed protocol to implement simvastatin labeling changes in a family medicine clinic
A
dverse drug events (ADEs) occur in approximately 27% of outpatients, with approximately 1.5 million preventable ADEs occurring each year in the United States, mostly in the outpatient setting.1,2 The Food and Drug Administration (FDA) responds to new clinically significant ADEs and risks discovered from postmarketing safety data by removing a drug from the market or by changing the prescribing information (labeling) of the implicated drug. Label changes include adding boxed warnings carrying critical information for prescribing, new dosage limitations, contraindications, or warnings.3-5 In 2009, FDA released 181 major drug safety regulatory actions: 37 boxed warnings, 23 contraindications, 120 warnings, and 1 drug withdrawal.3 In 2011, the number of boxed warnings, which are added as a result of serious adverse reactions relative to the potential benefit of the drug and in response to the most serious safety concerns, increased to 60.5 With this growth in major safety regulatory actions, often for commonly used drugs, widespread and timely implementation of medication labeling changes is difficult. Clinician response to boxed warnings has
been shown to be inadequate.6-8 In one study, more than 40% of patients were prescribed drugs such as angiotensinconverting-enzyme inhibitors, diuretics, metformin, isoniazid, and methotrexate that carried a boxed warning that applied to a contraindication with concurrent medications, a contraindication in pregnancy, or a lack of required baseline and ongoing monitoring of laboratory test values.9 Another study found that 10% of prescriptions for statin–fibrate combinations (most commonly involving simvastatin) went against package labeling.10
Prescribers may not be aware of dosage restrictions, and boxed warnings involving drug interactions may not appear in drug-interaction screening programs or resources.11 In addition, health care providers may not have systems in place to address revised FDA labeling and new dosage restrictions. Even with some systems in place, clinician adherence to FDA
The Frontline Pharmacist column gives staff pharmacists an opportunity to share their experiences and pertinent lessons related to day-to-day practice. Topics include workplace innovations, cooperating with peers, communicating with other professionals, dealing with management, handling technical issues related to pharmacy practice, and supervising technicians. Readers are invited to submit manuscripts, ideas, and comments to AJHP, 7272 Wisconsin Avenue, Bethesda, MD 20814 (301-664-8601 or [email protected]).
1248
Am J Health-Syst Pharm—Vol 71 Aug 1, 2014
boxed warnings may not be adequate. A study examining the implementation of alerts regarding FDA black-box warnings for medications in an outpatient electronic health record (EHR) found that the alerts had no impact on overall clinician adherence to the boxed warnings.12 Clearly, systems to improve adherence to FDA warnings and labeling changes are needed. Approximately 53% of adults in the United States have lipid disorders, and 19.8 million American adults use cholesterol-lowering medications.13,14 In 2012, lipid regulators were the fifth most prescribed therapeutic class of medications, and simvastatin was the fourth most prescribed drug in the United States.14 In June 2011, FDA issued a drug safety communication, which included labeling changes with new restrictions, contraindications, and dosage limitations for simvastatin and a statement that a dosage of 80 mg orally daily should be used only in patients who had taken this dosage safely for at least 12 months.15,16 Revisions to this communication were released in December 2011.17 The labeling changes were made due to an increased risk of myopathy, which was identified in the Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) collaborative group trial and evidence from FDA’s safety review of high-dose simvastatin.16-18 This article describes how new dosage limits in FDA labeling changes for simvastatin were implemented in a family medicine clinic. Development and implementation of the protocol. The Bethesda Family Medicine Clinic in St. Paul, Minnesota, is home to a family medicine residency program, where two clinical pharmacists serve on the faculty. When the FDA rec-
Frontline Pharmacist
ommendations were first released in June 2011, these pharmacists provided physician education detailing the changes. In June 2011, these pharmacists developed a detailed protocol to address FDA’s labeling changes regarding dosage limitations for simvastatin (Figure). The protocol was approved by the medical director (a physician) of the clinic and was implemented collaboratively by the clinical pharmacists and physicians in July 2011. The pharmacists were authorized to order laboratory tests, make any of the required medication changes independently, and fax the new prescriptions to the patients’ pharmacy per the protocol. Patients were eligible for inclusion in this pharmacist service if they were taking simvastatin 80 mg orally daily, a contraindicated concomitant medication, or a concomitant medication requiring a simvastatin dosage limitation, per the FDA labeling changes. All eligible patients were identified through an electronic search of the medication list in the EHR. Patients were scheduled for an appointment with the clinical pharmacist, or the changes were implemented during their physician visit, using the pharmacist-written protocol. The protocol was developed to assess patients’ current low-density-lipoprotein (LDL) cholesterol level, determine their goal LDL cholesterol range, and maintain levels already below the goal range or lower high levels into the goal range by using the relative LDL cholesterol-lowering capacities of different statins (Figure). The dose-equivalency chart provided in the FDA’s recommendations was used. The statins with a greater capacity than simvastatin 80 mg to lower LDL cholesterol are rosuvastatin 20 mg orally and atorvastatin 80 mg orally (both resulting in a 55% reduction in LDL cholesterol) and rosuvastatin 40 mg orally (resulting in a 63% reduction in LDL cholesterol).16 The FDA recommendations stated that no new prescriptions for simvastatin 80 mg daily should be initiated, but patients who have been on simvastatin for 12 months with no muscle toxicity could continue simvastatin 80 mg daily.
However, our clinic made the decision to be more conservative by no longer using the simvastatin 80-mg daily dose to avoid
any risks associated with that dosage. All other FDA recommendations were followed.
Figure. Pharmacist-developed and managed protocol. LDL = low-density lipoprotein.
If on higher simvastatin dose than recommended
If LDL cholesterol above goal: • Switch to statin with higher LDL cholesterol-lowering capacity than simvastatin dose currently taking If LDL cholesterol below goal: • Lower simvastatin to maximum recommended dose if goal LDL cholesterol will be maintained. Otherwise, switch to different statin or dose with similar LDL cholesterol-lowering capacity
If LDL cholesterol above goal: • Switch to statin with higher LDL cholesterol-lowering capacity (atorvastatin 80 mg/ day or rosuvastatin 20 mg/day)
If on simvastatin 80 mg daily
If LDL cholesterol at goal or ≤ 6% below goal: • Switch to statin with equivalent LDL cholesterol-lowering capacity (atorvastatin 40 mg/ day or rosuvastatin 10 mg/day)
If LDL cholesterol > 6% below goal: • Lower simvastatin to 40 mg/day
If LDL cholesterol > 12% below goal: • Lower simvastatin to 20 mg/day
If taking gemfibrozil, switch to fenofibrate If on interacting drug where simvastatin is contraindicated
If taking another interacting drug, switch simvastatin to another statin with appropriate LDL cholesterol-lowering capacity, depending if at goal LDL cholesterol or not
Am J Health-Syst Pharm—Vol 71 Aug 1, 2014
1249
Frontline Pharmacist
At the pharmacist visit, the patient’s lipid profile was measured, and the patient was asked about muscle symptoms. If muscle pain was present, the patient’s creatine kinase level was measured, sim vastatin was discontinued, and the patient was instructed to see his or her physician in one week. Medication adherence was assessed by chart review and patient interview; if nonadherence was suspected, the pharmacy was contacted to review refill records. The goal LDL cholesterol level was determined based on the presence or absence of coronary heart disease (CHD) or CHD risk-equivalents, or the Framingham score, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines.19 The change in statin medication was made according to the protocol, and the prescription was faxed to the patient’s pharmacy. A lipid profile and follow-up visit with the patient’s physician were scheduled to occur in six to eight weeks. If patients were unable to be reached by telephone after three attempts, letters were sent to them explaining the medication change, and their prescriptions were faxed to their pharmacy by the clinical pharmacist. Discontinuation orders for the contraindicated simvastatin dosage were also faxed to the pharmacy for all patients. Six months after the changes were implemented, chart review was performed to collect and document followup lipid profiles. Evaluation of the pharmacist service. A total of 70 patients were identified as taking simvastatin in a manner not supported by the new FDA labeling changes: 41 were taking simvastatin 80 mg/day, 2 were taking simvastatin with concomitant gemfibrozil, 23 were taking more than 20 mg of simvastatin daily with concomitant amlodipine, 3 were taking more than 10 mg of simvastatin daily with concomitant diltiazem, and 1 was taking more than 10 mg of simvastatin daily with concomitant verapamil. Regimens for all of these patients were consistent with previous simvastatin labeling but not with the new labeling. At baseline, 58 patients had a goal LDL cholesterol concentration of
