How much IG to prescribe differs for each individual based ...

1 14 February-March 2011 IG Living!How much IG to prescribe differs for each individual based on a variety of clinicaland non-clinical factors, as well as physician Kris McFalls15 February-March 2011 IG Living!Immune globulin (IG) is not a one-size-fits-all the proper dose to administer can be difficultand is dependent on several factors, the most importantof which is a clinical assessment. However, other non-clinical variables also are important. Understanding all ofthe factors that determine proper IG dosing will ensure thepatient is being prescribed the amount of the drug thatwill provide them with the most effective the DiseaseWhen prescribing IG, the first clinical consideration isthe patient s disease. IG was initially prescribed to treatprimary immune deficiency diseases (PIDD) and immunethrombocytopenic purpura (ITP). Over time, IG also hasproven to be an effective treatment for numerous inflam-matory and immune-mediated diseases affecting theneuromuscular system.

2 Current IG products collectivelycarry Food and Drug Administration (FDA)-approvedindications for PIDD, ITP, Kawasaki disease (KD), chronicinflammatory demyelinating polyneuropathy (CIDP) andchronic B-cell lymphocytic leukemia (CLL). Although thereare other FDA-approved indications for intravenous IG(IVIG), the products used to treat those indications are nolonger on the market. Dosing recommendations for FDA-approved indicationsfor each IG product are included in its package insert (PI).These recommendations are based on the results ofindividual clinical trials, and they change only when a newclinical trial is conducted that results in positive outcomesfor new dosing guidelines. Yet, as physicians learn moreabout diseases and patients responses to treatment, theamount of IG prescribed does vary from patient to patientand can differ from manufacturer PI addition, physicians also can prescribe IG for off-labelindications, but by law, dosing guidelines for off-labelindications cannot be included on the PI.

3 Instead, physiciansmust use peer-reviewed literature, clinical observationsand their best judgment when deciding on the properdose to prescribe for off-label indications. Having so manydynamic variables makes it easy to see why there may besome confusion and inconsistencies in IG Physician DiscretionWhether or not an indication is FDA-approved, physicianshave the option to utilize professional judgment in orderto adjust the dose and/or use a particular medication foran off-label indication. While it is illegal for manufacturersto advertise drugs for an off-label indication, once thedrug is FDA-approved, physicians can legally prescribemedications for any other purpose. And, insurance com-panies often will cover certain off-label indications as longas it is the standard of care for that particular Measuring Effectiveness PIDD associated with hypogammaglobulinemia (lowimmunogammaglobulin [IgG] levels) is an example ofhow IG replacement therapy and dosing have changedover time.

4 It was first treated with intramuscular injec-tions of IG, which were not only extremely painful forpatients, but also proved difficult to achieve high enoughserum IgG levels to adequately prevent infections. As aresult, IVIG became the preferred route of administrationin the early 1980s. Initially, IVIG replacement therapy for PIDD with low IgGlevels was dosed at 100 to 200 mg/kg. In part to assesswhether the dose was working, great reliance was placedon trough levels (the amount of serum IgG concentrationimmediately preceding the next infusion) as indicators ofeffectiveness. It was thought that an adequate troughlevel was roughly 500 mg/dL. However, it was laterlearned that not all patients have the same response whenmaintaining trough levels in this range. In addition,although trough levels can be used as a guide, a sufficienttrough level to prevent serious bacterial infections for alltypes of patients has not yet been established.

5 Accordingto recent research published in Clinical Immunology, PIDD patients receiving IVIG therapy and experiencingpneumonia are likely to be helped by increasing the IgGtrough levels to at least the mid-normal range of IgG..[And,] meta-analysis provides evidence that pneumoniarisk can be progressively reduced by higher trough IgGlevels up to at least 1000 mg/dL. 1 While trough levels can be a useful guide for PIDD associated with low IgG levels, the same cannot be saidfor patients with immune-mediated diseases affecting theneuromuscular system. These disorders are treated withWhen prescribing IG, thefirst clinical considerationis the patient s 2011 IG Living!IG, but the diagnosis is not based on IgG serum , using serum IgG trough levels as a benchmarkis not a viable option. Complicating matters is the fact thatscientists don t fully understand how IG works in CIDP andother immune-mediated neuromuscular diseases such asmultifocal motor neuropathy (MMN), myasthenia gravis (MG)and myositis.

6 For these diseases, IG is not a replacementtherapy as it is for PIDD. Instead, it is an immune-modulatingtherapy, meaning it adjusts the body s innate immuneresponse that has gone awry. Currently, CIDP is the only neuromuscular indication thatis FDA-approved to be treated with IG. The generallyaccepted dosing protocol for CIDP treatment with IG wasdetermined through clinical trials. But still more studiesare needed to gather data to establish more universallyaccepted standard protocols. Dosing for CIDP can vary from the PI and should bebased on individual response to therapy. Many insurancepolicies carry a clause in the reauthorization process thatrequires patients, once stabilized by IG, to try a lower doseof IG to see if maintenance can be attained at a lowercost. Many physicians, trying to optimize treatment and atthe same time limit the cost for patients, also may take asimilar approach. As with PIDD, the dose needs to betailored to the individual patient sneeds using the clinicalfindings as a guide.

7 For instance, before FDA approval ofProductManufacturerIndicationAdministr ationDosingRouteRecommendationsCarimune NFCSL to g/kg every 3 to 4 g/kg over 2 to 5 consecutive daysFlebogamma DIF 5%GrifolsPIDDIV300 to 600 mg/kg every 3 to 4 weeksFlebogamma DIF 10%GrifolsPIDDIV300 to 600 mg/kg every 3 to 4 weeksGammagard S/DBaxter Healthcare PIDDIV300 to 600 mg/kg infused at 3- to 4-week intervalsCLLIV400 mg/kg every 3 to 4 weeksITP IV1 g/kgKawasaki IVEither a single 1 g/kg dose, or a dose of 400 mg/kg for 4 consecutive days beginning within 7 days of the onset of feverGammagard LiquidBaxter Healthcare PIDDIV300 to 600 mg/kg every 3 to 4 weeksGammaplexBio Products Laboratory PIDDIV300 to 800 mg/kg every 3 to 4 weeksGamunex-CTalecris Biotherapeutics x IVIG dose in mg/kg/iv dose interval in weeks, weeklyPIDD IV300 to 600 mg/kg every 3 to 4 weeksITP IV2 g/kgCIDP IVLoading dose: 2g/kg Maintenance dose: 1g/kg every 3 weeksHizentraCSL BehringPIDD SCInitial dose: x IVIG dose (in grams)/ No.

8 Of weeks between IVIG dosesOctagam 5%OctapharmaPIDDIV300 to 600 mg/kg every 3 to 4 weeksPrivigenCSL BehringPIDDIV200 to 800 mg/kg every 3 to 4 weeksITPIV1g/kg IV daily for 2 consecutive days (2g/kg total)VivaglobinCSL BehringPIDD x IVIG dose (in grams)/No. of weeks between IVIG doses, weeklyDosing RecommendationsFor All Immune Globulin ProductsKey:CLL = chronic B-cell lymphocytic leukemia IVIG = intravenous immune globulin ITP = immune thrombocytopenic purpura PIDD = primary immune deficiency disease IV = intravenousSC = subcutaneous immune globulinNote: All information taken from product package inserts17 February-March 2011 IG Living!Gamunex to treat CIDP, many experienced clinicians startedtreatment using a loading dose of 2 g/kg over two to fivedays. The patient was then observed and asked to imme-diately report any signs of recurrence. Once symptomsstarted to reappear, a maintenance dose of 1 g/kg wasgiven.

9 The patient was again observed for signs ofreturned symptoms. That interval of time between theinfusion and the first sign of returned symptoms becamethe interval for maintenance therapy. For many patients,that interval was between two and four weeks. Research presented in the Journal of the PeripheralNervous Systemhas shown that dose frequency, onceestablished, should not be changed. In addition, theresearch shows that lower dose treatment is not associatedwith shorter intervals between courses, and lowest effectivedose is independent of weight and disease duration. 2 Additional studies are needed to establish standard protocolsfor CIDP patients. In the meantime, dosing for off-labelimmune-mediated indications will continue to rely onexperienced physicians and peer-reviewed data to establishstandard-of-care protocols. Too Little or Too Much Can Make a DifferenceClinical trials and scientific studies help to establishmaximum and minimum IG dosing standards.

10 The clinicaleffects of IG dosing can have significant how much is too much and how little is too littleis crucial for maximizing health outcomes and minimizingcosts. Yet, because the amount of IG to prescribe can beboth disease- and patient-specific, there are no clear-cutuniversal is not well-known how much IG is too much. Whentreating PIDD, it is believed that after a certain amount,there is no medical benefit to increasing the , there are not enough studies to determineexactly what that amount is. In general, however, the goalis to prescribe enough IG to prevent serious breakthroughbacterial infections from occurring. When treating otherdiseases, the amount of IG to prescribe is even less more IG than is medically necessary may result inincreased costs for all, increased risk of fluid volumeoverload, increased risk of side effects (especially if highdoses increase the propensity to speed up the infusion),and an artificially increased need for the limited naturalresources needed to make matter what the disease state, treating with too littleWhether or not anindication is FDA-approved,physicians have the optionto utilize professionaljudgment in order to adjustthe dose and/or use a particular medication foran off-label 2011 IG Living!