Jan/Feb Vol 15 No 1. Immune globulins and the risk for thrombotic events

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1 Jan/Feb 2014 Vol 15 No 1 RxPress TABLE OF CONTENTS Immune globulins and the risk for thrombotic events 1-2 Upcoming changes to the pregnancy labeling of drugs 2-3 Key features of the new hypertension treatment guidelines 3-5 Immune globulins and the risk for thrombotic events Intravenous immune globulin (IVIG) products have been used for a variety of indications since their development in 1979, most often for antibody replacement in patients with immune deficiencies. These biologic products contain human immune globulin G and quickly provide passive immunity in cases where it may not already be present (e.g., first-time exposure to an organism). Although IVIG products are generally well-tolerated, common adverse reactions are usually infusion-related and may include headache, fever, malaise, nausea, myalgias, pruritis, and urticaria. The class of IVIG products also has a boxed warning for renal dysfunction and acute renal failure. In June 2013, the Food and Drug Administration (FDA) added a boxed warning for the risk for thrombosis. The addition of this warning was based on increasing reports of both arterial (myocardial infarction, cerebrovascular accident) and venous (deep vein thrombosis, pulmonary embolism) events occurring during or shortly after the administration of IVIG. Hemolysis has also been reported, but the FDA has not required a boxed warning for this adverse event. Risk factors and the role of Factor XIa Despite the known risk for thromboembolic events (TEs) with IVIG, it is still being determined how individual products, administration techniques, and patient-specific factors contribute to the overall TE risk. Individual IVIG products are not considered pharmaceutically equivalent because they are derived from the plasma of thousands of human donors and undergo various manufacturing processes. Techniques for product purification and sterilization may differ, and sugar, sodium, amino acids, and stabilizer content may vary, as well as the osmolality of each product. Some products may carry a greater risk for TEs due to these variations. Patient-specific risk factors for TEs include advanced age, previous TEs, hypercoagulable conditions, hyperviscosity of blood, immobilization, obesity, cardiovascular conditions, and use of estrogens or tobacco. Patients with one or more of these factors receiving IVIG may be at increased risk for TEs. Higher doses of IVIG as well as faster infusion rates may increase blood viscosity, in turn predisposing patients further to TE development. One hypothesis for increased TE risk related to the manufacturing process is the unintended purification of contact-activated clotting factors during the manufacturing of IVIG, such as Factor XIa. Minute quantities of Factor XIa can result in increased thrombin generation. In a 2012 Safety Communication, the FDA discussed that elevated levels of Factor XIa were present in assays of specific IVIG products that had been associated with TE development in patients. The manufacturer of the IVIG Octagam voluntarily withdrew Octagam from the market in 2010 due to an unexpected number of TEs that occurred with its use. Analyses of lots showed high levels of procoagulant activity, and after a change in Octagam s manufacturing process (addition of an adsorption step), the product was reintroduced to the market. A retrospective analysis found that reported TE rates for Octagam decreased significantly after the change in manufacturing to reduce procoagulant activity. Evidence leading to the boxed warning of thrombolysis A retrospective claims-based cohort study was among the evidence that led to the FDA s boxed warning for thrombolysis with IVIG use. The purpose of the study was to explore TE risk with use of 6 IVIG products, including one administered subcutaneously (Vivaglobin). The study population included individuals in 13 states who were exposed to the immune globulin products from 2008 to 2010, and the study endpoint was the composite of same-day venous and arterial TEs. A total of 11,785 patients in the database were exposed, and 122 had same-day diagnosis codes for TEs (approximately 1%). Gammagard Liquid was the comparator reference because it was the most commonly administered immune globulin. 1

2 Unadjusted analyses found that odds ratios for TEs were significantly increased for Vivaglobin (2.78; 95% confidence interval [CI], 1.26 to 6.15), Octagam (2.31; 95% CI, 1.10 to 4.84), and lyophilized product (2.21; 95% CI, 1.24 to 3.94). However, significance was lost for all but Vivaglobin after adjustments were made for confounders (sex, age, dose, hypercoagulable states, prior TE). Overall, venous events were more common than arterial events (approximately 70% versus 30%). Other analyses found that risk increased with older age (>45 years), prior TE, and hypercoagulable state. Women were also more likely to have a same-day TE for certain products (Vivaglobin, lyophilized product, Gamunex) compared to Gammagard. The authors referenced studies that also showed increased Factor XIa in Vivaglobin assays, which may have contributed to the significant increased TE risk. It is still unknown how the pharmacokinetics of subcutaneous delivery of Factor XIa may impact TE risk, or if the route of delivery itself has thrombogenic potential. Another recent retrospective analysis confirmed increased TEs with Vivaglobin as well. Conclusion Within the boxed warning the FDA made recommendations regarding thrombosis with immune globulin products. The warning states that patients at increased risk include those with acquired or hereditary hypercoagulable states, prolonged immobilization, indwelling vascular catheters, advanced age, estrogen use, a history of venous or arterial thrombosis, cardiovascular risk factors (including history of atherosclerosis and/or impaired cardiac output), and hyperviscosity (including cryoglobulins, fasting chylomicronemia and/or high triglyceride levels, and monoclonal gammopathies). For those at high risk, IVIG should be administered at the minimum dose and infusion rate. Patients should also be adequately hydrated and periodically assessed for signs and symptoms of thrombosis. Although it is still unclear who is most at risk for these events and which products are of greatest concern, it is best to carefully weigh the risk/benefit ratio in each patient with risk factors, especially in those receiving immune globulins for unapproved indications. In the near future, manufacturers of immune globulin products may be doing thrombogenicity testing prior to releasing product lots. Upcoming changes to pregnancy labeling of drugs Current classification system Pharmacists are commonly consulted on the safety of medication use during pregnancy. Deficiencies in the current Food and Drug Administration (FDA) pregnancy risk categories, as well as confusion about the categories, can make answering these questions difficult. As with all pharmacotherapy decisions, risk versus benefit must be weighed when considering appropriateness of medication use in a pregnant patient. However, when data on risks are limited, these decisions become even more complex. The FDA developed the current pregnancy risk category classification system in 1979, and it consists of the letters A, B, C, D, and X, which are defined in Table 1. This classification system was initially developed to describe teratogenic risk for drug use during the first trimester only, and so the categories may not always apply to drug use in later trimesters of pregnancy. Because adverse effects to the fetus happen infrequently, there are limited pregnancy exposure data available for both old and new drugs. It has been determined that the average time to identify risk to the fetus (should it exist) is approximately 6 years. The infrequency of these events, along with the lower quality of evidence from which the data are derived (case reports, cohort studies, drug registries), do not allow for a complete understanding of how drug use during pregnancy can adversely affect the fetus. Table 1. Current Food and Drug Administration pregnancy categories and definitions. Risk category A B C D X Definition Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters). Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in humans, and the benefit of the use of the drug in pregnant women may outweigh its risk; or animal studies have not been conducted, and there are no adequate wellcontrolled studies in humans. Animal reproduction studies have shown an adverse effect on the fetus, there are no adequate well-controlled studies in humans, and the benefits from the use of the drug in pregnant women may be acceptable despite its potential risk; or animal studies have not been conducted and there are no adequate well-controlled studies in humans. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit. Another shortcoming of the pregnancy categories is that they do not address risk that may occur during childhood development into adulthood. For instance, use of selective 2

3 serotonin reuptake inhibitors during pregnancy may have neurobehavioral effects on the fetus that do not manifest until childhood development and possibly not until adulthood. The FDA categories are not adequate in describing this risk. Additionally, drugs in the same risk category may have very different risks. For example, both oral contraceptives and warfarin are pregnancy category X. Warfarin is known to result in congenital malformations of the fetus and spontaneous abortion when taken during pregnancy (especially during the first trimester), but oral contraceptives are primarily categorized as X because there is no benefit to their use during pregnancy. There have been reports of masculinization of the female fetus with the mother s use of oral contraceptives, but this risk is not the same severity as is the risk with warfarin use. The fact that oral contraceptives are categorized as X is an example of how this category (along with category D) also heavily weighs benefits to the mother. In contrast, consideration is given mostly to fetal harm when drugs are categorized as A, B, or C. A summary of limitations of the current FDA pregnancy risk categories is provided in Table 2. Table 2. Limitations of current Food and Drug Administration pregnancy categories. Classification is misleading and confusing Both new and old drugs have limited data Available data not included with categorization Different considerations for each category Maternal benefit more heavily weighed for categories D and X than A, B, and C Lack of information for Accidental exposures Nature or severity of potential fetal injury Incidence rate Exposure during all 3 trimesters Proposed labeling changes New pregnancy labeling changes were proposed by the FDA in The Pregnancy and Lactation Labeling Rule is in its final version. The Rule outlines that updated pregnancy labels will contain information on drug use in both pregnancy and lactation. Both of these will be divided into 3 subsections, including general information/ risk summary, clinical considerations, and data. The general information will provide a description of the known fetal risk and may include more than one conclusion about risk. For drugs that are systemically absorbed, the known risk based on these data will be stated, with reference to the supporting data. If only animal data are available, the likelihood of risk based on these data will be stated. Pregnancy registry contact information will also be included in this section. Clinical considerations will provide guidance for patient counseling and decisionmaking. The risk to both the mother and fetus of forgoing treatment will be described, as well as known maternal adverse reactions and neonatal complications with possible interventions. If information is available on effects of dose, timing, and duration of exposure, it will be included in this section. This section will include what is known about accidental exposure. The data section will contain separate summaries for human and animal data, with details on the study type, exposure, and identified abnormality. Human data will include details on number of patients in the studies as well as duration of the studies, and positive and negative experiences. Animal data will include species and correlate doses used to human dose equivalents. The FDA is in the process of finalizing the proposed Rule. Once this occurs, it will be available in the Federal Register. Prescription drugs that will be required to follow this rule include those with applications approved between June 2001 and June 2006, and any applications submitted or pending after June Drugs approved prior to 2001 will not be required to update their labeling. They will only be required to remove the original labeling within 3 years of the finalized Rule. Implementation of proposed labeling changes will allow pharmacists and other healthcare providers to make a more informed decision when determining appropriateness of medication use in pregnant women. Inclusion of data to support the category will allow healthcare providers to more thoroughly evaluate risks and benefits of the drug and more easily discuss these with the patient as well. Key features of the new hypertension treatment guidelines Introduction Over the last decade there has been increasing anticipation for an updated hypertension guideline following the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) released in The National Heart, Lung, and Blood Institute (NHLBI) initially commissioned the Eighth Joint National Committee (JNC 8) in 2008, but in 2013 NHLBI announced that they were no longer authoring guidelines and empowered other organizations to undertake the task. The NHLBI withdrew authorship of the JNC 8 guidelines prior to publication; however, the panel members appointed to JNC 8 released a revised set of evidence-based treatment guidelines for the management of high blood pressure (BP) in December While awaiting JNC 8, several other organizations published their own hypertension guidelines. In addition to JNC 8, the most recently published guidelines for high BP are from the American Heart Association (AHA)/American College of Cardiology (ACC)/Centers for Disease Control and Prevention (CDC) and the American Society of Hypertension (ASH)/International Society of Hypertension (ISH), released in November 2013 and December 2013, respectively. The new recommendations in each of these guidelines contain some key features that may significantly impact the management of high BP in adults. 3

4 Key features of available guidelines In contrast to JNC 7, the JNC 8 guidelines are less comprehensive and focus on answering the panel s 3 highestranked (critical) questions related to BP management. 1. Does initiating antihypertensive therapy at specific BP thresholds improve health outcomes? 2. Does treatment with antihypertensive therapy to a specified BP goal lead to improved health outcomes? 3. Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? There are 9 general recommendations made in JNC 8. For the general adult population less than 60 years of age, the panel recommends initiating pharmacologic treatment when BP is above 140/90 mm Hg. This is also the recommended goal BP for these patients. For patients 60 years of age and older it is recommended to initiate pharmacologic treatment when BP is above, and to a goal less than, 150/90 mm Hg. There is a caveat to this recommendation that those who have achieved tighter control than the stated goal and are tolerating their treatment without adverse effects can continue current treatment without adjustment. In the adult population with chronic kidney disease or diabetes the goal BP is less than 140/90 mm Hg regardless of age. The JNC 8 recommendations for initial pharmacologic treatment are summarized in the Table. If the goal BP is not reached within 1 month of treatment initiation there are several recommended strategies: the dose of the drug can be increased; a second or third agent from the recommended drug classes (thiazide-type diuretic, calcium channel blocker [CCB], angiotensin-converting enzyme inhibitor [ACEI], or angiotensin receptor blocker [ARB]) can be initiated; or the patient may be referred to a hypertension specialist. Lifestyle modification is strongly emphasized. The ASH/ISH guidelines are focused on managing hypertension in the community setting. They are more comprehensive than JNC 8 and include background information on hypertension with definitions, diagnostic measures, information, and recommendations on pharmacological and non-pharmacological treatments, and a specific section on special issues in treating high BP in black patients. While the ASH/ISH guidelines resemble JNC 8 in many ways there are some differences. The guidelines recommend 80 years as the age cutoff for the higher initiation and treatment BP goal of <150/90 mm Hg and the omission of a thiazide diuretic as an initial treatment option for non- Black adults under 60 years of age. ASH/ISH also provides additional recommendations for special populations with coronary artery disease (CAD), stroke, and heart failure (HF). Another area that the guidelines differ from JNC 8 is that they recommend initial treatment with 2 drugs for all patients with a BP >160/100 mm Hg. The AHA/ACC/CDC guidelines provide less information than the ASH/ISH guidelines, but still more than JNC 8. These guidelines are similar to JNC 7 and maintain the goal BP of <140/90 mm Hg for the general population. They mention that lower goals may be targeted for special populations, but do not state a specific goal for these patients. AHA/ ACC/CDC also makes specific pharmacologic treatment recommendations for patients with CAD/post-myocardial infarction and systolic or diastolic HF patients. They also provide detailed information on lifestyle modifications and information on antihypertensive agents. Controversies with new guidelines There has been some controversy regarding the recommendation toward a more liberal BP goal in the population over 60 years of age as stated in JNC 8, and this recommendation was not supported in other recently released guidelines. The ASH/ISH guidelines chose a higher age cut-off for a less restrictive BP goal, and the AHA/ACC/CDC chose to maintain the general goal of <140/90 mm Hg for adult patients of all ages. These variations between guidelines in ages and BP goals, along with varied pharmacologic treatment recommendations may result in differences among healthcare professionals in the management of patients with high BP. Conclusion The healthcare community has long awaited the arrival of the updated JNC 8 hypertension guidelines and has now received 3 very recently published updates. Some of the guidelines suggest that a less stringent level of BP control may be sufficient to prevent poor health outcomes in certain patient populations. However, this is controversial and not uniformly recommended in all guidelines for the treatment of hypertension. There are also differences with initial pharmacological treatment recommendations for patients in the 3 guidelines and some are more comprehensive. It may, therefore, be necessary to review multiple guideline recommendations from the different organizations prior to making treatment decisions in clinical practice. 4

5 Table 3. Guideline comparisons of goal BP and initial drug therapy for adults with hypertension Guideline Population Goal BP(mm Hg) Initial Drug Treatment Options JNC 7 No compelling indication Compelling disease indication (including diabetes and CKD) <140/90 Thiazide (most patients), ACEI or ARB, β- blocker, CCB, or combination <130/80 Diabetes: 1 st - ACEI or ARB, 2 nd -thiazide, 3 rd -βblocker or CCB CKD: 1 st -ACEI or ARB JNC 8 60 y <150/90 Non-Black: thiazide, <60 y <140/90 ACEI, ARB, or CCB Black: thiazide or CCB Diabetes <140/90 Thiazide, ACEI, ARB, or CCB CKD <140/90 ACEI or ARB ASH/ISH <80 y <140/90 Non-Black (<60 y): 80 y <150/90 ACEI or ARB Non-Black ( 60 y): CCB or thiazide (may consider ACEI or ARB) Black (all ages): CCB or thiazide CAD: β-blocker plus ACEI or ARB Stroke: ACEI or ARB HF: ACEI or ARB + β-blocker + diuretic + aldosterone antagonist Author/Editor: Lara K. Ellinger, PharmD, BCPS Authors: Tamkeen Quraishi Abreu, PharmD AHA/ACC/ CDC Diabetes <140/90 ACEI or ARB (black can consider CCB or thiazide) CKD <140/90 ACEI or ARB General population <140/90 CAD/Post MI: β- blocker, ACEI Systolic HF: ACEI or ARB, β-blocker, aldosteroneantagonist, thiazide Diastolic HF: ACEI or ARB, β-blocker, thiazide Diabetes: ACEI or ARB, thiazide, β- blocker, CCB CKD: ACEI or ARB Stroke/TIA: thiazide or ACEI Table 3 Abbreviations: ACEI, angiotensin converting enzyme inhibitor; AHA/ACC/CDC, American Heart Association/ American College of Cardiology/Centers for Disease Control and Prevention; ARB, angiotensin receptor blocker; ASH/ISH, American Society of Hypertension/International Society of Hypertension; CAD, coronary artery disease; CCB, calcium channel blocker; CKD, chronic kidney disease; HF, heart failure; JNC 7, Seventh National Joint Committee; JNC 8, Eighth Joint National Committee; MI, myocardial infarction; TIA, transient ischemic attack. 5