Unboxing Boxed Warnings and Risk Assessment for IG Products
- By Amy Ehlers, BS, PharmD, BCPS
In This Article:
BOXED WARNINGS (formerly known as black box warnings) are the highest safety related warning assigned by the U.S. Food and Drug Administration (FDA). These warnings are used to communicate potential rare but dangerous side effects or important instructions for safe use of the drug. As the name implies, a boxed warning will appear in bold font with a heading in all capital letters surrounded by a black border. This boxed warning must appear in the drug’s prescribing information, the drug’s manufacturer website and any promotional items.
A boxed warning is typically assigned to the entire class of drugs since the risk is associated with a specific action of the medication causing an undesired effect. Boxed warnings may be assigned before or after the drug comes to market and may be modified at any time. The intent of a boxed warning is not to preclude the use of the drug or class of drugs, but to make clinicians and patients aware of the potential severe side effects and ensure the benefits outweigh the risk.
More than 400 drugs contain a boxed warning. Examples include selective serotonin reuptake inhibitor antidepressants, fluroquinolone antibiotics, isotretinoin and immune globulin (IG) products. All IG products contain a boxed warning for thrombosis and those IG products administered intravenously (IVIG) also contain a boxed warning for renal dysfunction and acute renal failure (ARF).
The Use of IG Product Boxed Warnings
IVIG, subcutaneous IG (SCIG) and facilitated SCIG (fSCIG) infusions can cause arterial and/or venous blood clots that may result in myocardial infarction, cerebrovascular accidents, transient ischemia attack, deep vein thrombosis, pulmonary embolism and retinal vein occlusion. These thromboembolic events (TEs) may occur during or after an IG infusion. Patients with thrombosis risk factors appear to be at a higher risk, but TEs have been reported in the absence of known risk factors.
Why do TEs occur with IG products? After IG administration, heightened plasma viscosity and platelet aggregation may be seen. This may promote platelet, erythrocyte and leukocyte aggregation, induce arterial vasospasm or encourage release of vasoconstrictive cytokines. In addition, IG products contain contaminants, such as Factor XIa (FXIa), antiphospholipid antibodies and pre-kallikrein activator (PKA), all of which may induce clot formation, increasing the risk of thrombosis.
The boxed warning on IG products for thrombosis was added in 2013. Since 1986, there had been reports of TEs, and the number of events stayed consistent with the number of IG grams sold from 1986-2010. In 2009, an IG product had an increase of TEs reported, and it was determined FXIa had not been effectively removed. In 2010 and 2011, two additional IG products (one IVIG and one SCIG) had increased FXIa and PKA levels. After analysis of health database and post-marketing reports of serious TEs, FDA mandated the addition of a boxed warning on all IG products for thrombosis and the associated risk factors: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity and cardiovascular risk factors. This was in addition to requiring IG manufacturers to implement changes during the purification process to minimize or remove FXIa.
Mitigating Thrombosis Risk
To minimize thrombosis risk in patients receiving IVIG, adequate hydration in patients is important the day before, day(s) of infusion and the day after. While oral hydration is preferred and appropriate in most cases, IV hydration may be used. If using IV hydration, providers should consider possible compatibility issues with the IG, the increase in the required infusion time and other co-morbid conditions such as congestive heart failure, kidney dysfunction or liver disease. Antithrombotic therapy may be considered, although there are no guidelines officially endorsing this recommendation.
In patients at risk for hyperviscosity due to factors such as hypergammaglobulinemia, cryoglobulinemia, markedly increased triglycerides and paraproteinemia, blood viscosity should be assessed.
IG should be administered at the minimum dose necessary and infused at the slowest rate practicable. Large doses of IVIG may need to be split and infused over more than one day.
Patients should also be monitored for signs and symptoms of thrombosis. Myocardial infarction and pulmonary embolism symptoms include chest pain, shortness of breath or pain while breathing. Cerebral vascular accident and transient ischemic attack symptoms include confusion, slurred speech, weakness on one side, facial drooping and loss of consciousness. Deep vein thrombosis symptoms include swelling, intense pain or tenderness (often in the calf) and warm, red discolored skin.
While all forms of IG carry the boxed warning for thrombosis, the risk with SCIG and fSCIG is considered to be less than with IVIG. This is because the IG is administered into the subcutaneous tissue and is slowly absorbed over 24 to 72 hours. SCIG traditionally has smaller doses administered more frequently and with a slower infusion time per dose. Thise may make SCIG or fSCIG a better IG option for patients at higher risk for thrombotic events.
Mitigating Renal Dysfunction Risk
IVIG products also contain a boxed warning for renal dysfunction and ARF. Acute renal dysfunction includes increased serum creatinine, oliguria, ARF and osmotic nephrosis. This is usually seen within seven days of the IVIG infusion. These significant renal issues were mostly associated with IG products using sucrose as the stabilizer. It is important to note that the last sucrose-containing product was voluntarily discontinued by the manufacturer in 2018.
Risk factors for renal dysfunction and ARF include advanced age, preexisting renal disease or renal insufficiency, diabetes, obesity, hypovolemia, volume depletion, sepsis, paraproteinemia and concurrent use of nephrotoxic drugs.
To minimize renal issues, providers should obtain baseline kidney function labs such as serum creatinine and BUN, and then monitor as appropriate. Because renal issues may not present until days or weeks after the IVIG infusion, patients should be educated on the signs and symptoms of renal dysfunction/ARF. These include decreased urine output, dark or tea-colored urine, sudden weight gain due to fluid retention and shortness of breath.
The same recommendations seen with minimizing thrombosis risk are also important. IG should be administered at the minimum dose necessary and infused at the slowest rate practicable. Large doses of IVIG may need to be split and infused over more than one day. Also, because SCIG and fSCIG products do not contain the boxed warning for renal dysfunction and ARF, these products may be more suitable for patients at high risk.
The Necessity of Risk Assessment
The IgNS Immunoglobulin Therapy Standards of Practice Edition 3.2 recommends a complete and thorough risk assessment, to include screening for box warnings, upon start of care and annually at a minimum thereafter. In addition, a risk assessment should be completed if there is a significant change in the patient’s clinical status or clinical event.
This risk assessment should include a review of the patient’s history and physical, laboratory reports, diagnostic tests, recent hospitalizations, current and past medication history, and other relevant health information. Prescribers or pharmacists should also review the potential risk factors for adverse drug reactions in patients with comorbidities such as diabetes, IgA deficiency status, blood type, current infection/sepsis, history of thromboembolic events or cardiac, renal or liver dysfunction.
Based on the outcome of this risk assessment, prescribers or pharmacists should make any necessary adjustments to the drug therapy regimen. The more risk factors a patient has, the more conservative they may need to be. Adjustments to IG therapy may include lowering the maximum infusion rate, lowering the dose per day, lowering the IG concentration (5% versus 10%), more frequent monitoring of renal function and monitoring of serum viscosity. The specific IG brand may need to be considered due to the varying individual product differences, or it may be necessary to consider changing the route of administration from IVIG to SCIG or fSCIG.
Ensuring Safe, Effective Therapy
While IG products carry boxed warnings, these events are uncommon. Patients and their healthcare team should collaborate to determine an optimal therapeutic plan that minimizes risk factors and potential adverse effects while supporting the best possible clinical outcomes. Clinicians — including prescribers, nurses and pharmacists — should work together to develop an individualized treatment approach that incorporates all relevant clinical data, evaluates the appropriate IG product and route of administration, and outlines a comprehensive monitoring strategy. Such coordination helps ensure safe, effective therapy and supports the achievement of the most favorable patient outcomes.
IG and Serious Adverse Drug Reactions
In addition to boxed warnings, IG products also have several serious adverse drug reactions (ADRs) that should be considered when developing an IG therapy regimen. These include anaphylaxis, aseptic meningitis syndrome (AMS) and hemolysis/hemolytic anemia.
- Anaphylaxis. This is a rare but potentially life-threatening ADR that may, within minutes, cause rapid and severe hypotension, extreme respiratory distress and cardiopulmonary arrest that must be addressed immediately. If this occurs, the IG infusion should be stopped, emergency medical services should be contacted and epinephrine should be administered. Organization-specific policies may include other interventions that include IV fluids, antihistamines, bronchodilators or steroid administration.
The cause of anaphylaxis is thought to be due to a response to impurities in the IG such as IgG fragments, IgG aggregates and PKA. This reaction can occur in any patient, but those with IgA deficiency and IgA autoantibodies may be more susceptible. True IgE-mediated anaphylaxis with release of mediators from tissue mast cells and peripheral blood basophils is exceptionally rare. Ensuring an anaphylaxis kit is available for all IG infusions is recommended in the IgNS Immunoglobulin Therapy Standards of Practice Edition 3.2.
If a patient experiences an anaphylactic reaction, the decision to continue IG therapy should be reassessed by the healthcare team and the patient. In individuals with IgA deficiency, transitioning to SCIG or to an IVIG product with the lowest available IgA content is recommended. For patients without IgA deficiency, switching to SCIG or to an alternate IVIG product may be appropriate, provided premedications are used and therapy is administered under close monitoring in a controlled clinical setting.
- AMS. This occurs when the brain and spinal cord become inflamed, but the cerebrospinal fluid is negative for any bacterial, viral or fungal infection. Symptoms include a severe headache (rated 8+/10), nausea, vomiting, photophobia, neck stiffness and fever. These appear within hours of the infusion but may be seen for up to 48 hours post infusion. While the exact cause of AMS by IG is not known, IgG does cross the blood brain barrier, which may cause an inflammatory reaction or osmotic shift. Hypersensitivity to the various stabilizers and contaminants may also contribute to AMS. Risk factors of AMS are large doses of IG, rapid infusion rates, dehydration and those patients with a history of migraine headaches.
Possible interventions may include changing the brand of IG used or considering the use of SCIG or fSCIG in patients in whom AMS occurred with IVIG. Decreasing the maximum infusion rate, increasing the number of infusion days, possibly nonconsecutive, and adequate hydration are also important considerations. In patients who have migraine treatment prescribed, ensure the medicine if scheduled or available if needed.
- Hemolysis. This occurs when red blood cells break down faster than the body can replace them, which can lead to hemolytic anemia. Mild hemolysis may cause no symptoms or only slight tiredness, but more severe hemolytic anemia can become life-threatening. Symptoms such as dark colored urine, jaundice, increased heart rate or enlargement of the liver or spleen may appear several days to weeks after an IG infusion.
The exact cause of hemolysis from IG therapy is not fully understood, but it is believed to be related mainly to anti-A and anti-B antibodies that are not fully removed during the manufacturing process. Other possible contributors include the way IG may increase red blood cell removal by the body or activity from other types of antibodies. Hemolysis is more common in people with non O blood types because they naturally have both anti-A and anti-B antibodies.
Patients receiving high doses of IG (more than 2 g/kg) are at higher risk. When large doses are needed, spreading the total amount over several days — sometimes on nonconsecutive days — can help reduce this risk.