Date: May 4, 2009
To: Debbie Cordaro, RPM
Nisha Jain, Branch Chief
From: Lisa Stockbridge, Ph.D., CSO
Through: Ele Ibarra-Pratt, RN, MPH, Branch Chief
Subject: BLA 125329 Gammaplex (Immune Globulin Intravenous, Human)
Comments on Draft Product Labeling
On November 14, 2008, Bio Products Laboratory submitted a new BLA with a proposed package insert (PI) for Gammaplex (Immune Globulin Intravenous, Human). Proposed carton and container labels were submitted on January 9, 2009. The proposed PI is in conformance with the Physician’s Labeling Rule. In addition, the BLA appears to contain an xml file with Structured Product Labeling. APLB has reviewed the proposed PI, as well as the carton and container labels, and has the following comments and recommendations.
- Refrain from the use of the trademark symbol in the PI. It may only appear once, at first use, in the full prescribing information (FPI) section of the PI.
- Use command language whenever possible.
- Whenever possible, refrain from describing adverse events as “associated with” Gammaplex. Instead, describe adverse reactions as “reported with” Gammaplex or describe that Gammaplex “increases the risk” of a particular adverse reaction.
- Assure that page headers and footers are not in the final PI.
- There are too many unnecessary references in the PI. Common knowledge does not require references.
- We recommend that you revise the boxed warning subsection to the following:
WARNING: ACUTE RENAL DYSFUNCTION/FAILURE
See full prescribing information for complete boxed warning
- Immune globulin intravenous (IGIV) products, particularly those with sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.
- For patients pre-disposed to renal dysfunction or failure, administer Gammaplex at the minimum concentration available and the minimum infusion rate practicable.
- Gammaplex does not contain sucrose.
- We recommend that you revise the Indications and Usage subsection to the following:
Gammaplex is an immune globulin intravenous (human) indicated for the treatment of primary immunodeficiency.
- Add the bolded statement, “Intravenous Use Only” directly following the heading for the Dosage and Administration subsection.
- The second bullet in the Contraindications subsection of the Highlights should be revised to be more specific to the contraindication itself. For example,
IgA deficient patients with antibodies against IgA and a history of hypersensitivity.
- We recommend that you revise the Warnings and Precautions subsection of the Highlights and the Warnings and Precautions section of the FPI to list the risks in decreasing order of importance. For example: Hypersensitivity, Renal Failure, Serum Osmolality, Thrombotic Events, Aseptic Meningitis Syndrome, Hemolysis, Transfusion-related Acute Lung Injury, Volume Overload, Transmissible Infectious Agents, Laboratory Tests. Assure that the Highlights Warnings and Precautions subsection matches that in the FPI and that the cross-reference links are in ascending order.
- The proposed contact information for reporting suspected adverse events does not meet the contact information requirement for labeling. The manufacturer’s phone number to report suspected adverse events must be a U.S. phone number and should be toll-free.
- Pregnancy must be addressed in the Use in Specific Populations subsection of the Highlights. Since Gammaplex is Pregnancy Category C, we suggest that the first bullet in this subsection is
Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
- Geriatrics is a specific sub-subpart of the Use in Specific Populations subsection of the Highlights. Thus, the statement regarding use in patients over age 65 should be a second bullet following Pregnancy. For example
Geriatrics: In patients over age 65 at risk of developing renal insufficiency, do not exceed the recommended dose and infuse Gammaplex at the minimum rate practicable (8.5)
Table of Contents
- The heading – FULL PRESCRIBING INFORMATION: CONTENTS must appear at the beginning of the table of contents in upper case letters and bold type.
- Assure that the section headers and numbering in the Table of Contents correspond to the sections in the FPI.
Full Prescribing Information (FPI)
- The heading – FULL PRESCRIBING INFORMATION should be bold.
- The company name should not be in the FPI.
- Delete “Rx Only” from the FPI.
- Prepare boxed warning in bulleted format (see above suggestion on boxed warning in Highlights).
- Revise the first sentence of Indications and Usage section of FPI to include the product class reference. For example
Gammaplex is an immune globulin intravenous (Human) 5% preparation that is indicated for the treatment of primary immune deficiency.
- Place the bolded statement “For Intravenous Use Only” directly below the Dosage and Administration section header.
- For ease of retrieving information, we suggest using bulleted lists in the subsections of the Dosage and Administration section.
- Revise the Contraindications section as follows:
- Gammaplex is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.
- Gammaplex is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity.
- We suggest that hypersensitivity reactions be listed as the first subsection Warnings and Precautions. The second subsection should be Acute Renal Dysfunction and Renal Failure.
- Include a subsection on hyperproteinemia, increased serum viscosity, and hyponatremia in the Warnings and Precautions section. This section on serum osmolality is placed appropriately between the Acute Renal Dysfunction and Renal Failure subsection and the Thrombotic Events subsection.
- Simplify the Thrombotic Events subsection of the Warnings and Precautions section. We suggest the following language
Thrombotic events may occur following IGIV treatment. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Gammaplex at the minimum rate of infusion practicable.
- Simplify the Transmissible Infectious Agents subsection of the Warnings and Precautions section and include a toll-free U.S. phone number for reported infections. For example
Gammaplex is made from human plasma. Due to effective donor screening and product manufacturing processes, it carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for Gammaplex. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bio Products Laboratory at 1-800-000-0000.
- Interference with live attenuated vaccines should be discussed in the Drug Interactions section of the PI. Inclusion of this information in Warnings and Precautions is unnecessary.
- It is unnecessary and distracting to include cross references to the Patient Counseling Information section in the Warnings and Precautions section. The Patient Counseling Information section is reserved for a list of discussion points that the doctor should address with the patient. It is not intended to be a summary of the Warnings and Precautions.
- Vague terms of frequency (i.e., “may occur occasionally,” “rarely,” “very rarely,” and “in isolated cases”) are misleading and should be deleted from the Adverse Reactions section. The actual number of observations is included in the Clinical Studies Experience subsection. Furthermore, the actual rate of an observed serious adverse reaction is greater than any rate observed in small, controlled clinical studies. Serious adverse reactions from IGIV therapy will apply to Gammaplex in a clinical setting.
- Include a cutoff frequency (i.e., ≥ 5%) in the list of common adverse reactions.
- Separate the list of common adverse reactions from the paragraph of serious adverse reactions. Keep all information about serious adverse reactions together so that it is easily retrievable from the front of the Adverse Reactions section.
- Vague terms of intensity (i.e., “mild,” “moderate,” and “severe”) are misleading in the absence of definition.
- The discussion regarding the differences of adverse reactions between the two infusion protocols (21- and 28-day) is misleading. In particular, the statement, “This may be expected since the subjects on the 21-day infusion cycle had more infusions of Gammaplex,” minimizes the importance of the reported adverse reactions. The actual rate of adverse reactions will be higher in clinical practice, thus attempts to minimize the importance of the finding should be deleted. Factual differences between the two protocols may be presented as two columns in Table 1.
- Table 2 is unnecessarily redundant. Consider combining the temporal relationship (or time to event) with the adverse reactions by including the information on Table 1. For example, Table 1 could include adverse reactions occurring within 72 hours after the infusion of Gammaplex. Under no circumstances should the temporal relationship of the “product-related” adverse reactions be remotely discussed in a separate sub-subsection. Furthermore, the information on the temporal relationship of the adverse reactions is unnecessarily detailed, which may lead to reduced comprehension of the overall risk of the serious adverse reactions. Thus, we recommend that, if included at all, the information be condensed to a brief few lines under Table 1.
- The inclusion of the single-center, randomized, parallel-group, single dose comparative study in 36 selected patients given Vigam or Gammaplex, is misleading because this study was not adequate to provide any substantive information regarding the safety or efficacy of Gammaplex. Moreover, the subsequent paragraph regarding the lack of “clinically significant changes” in vital signs, electrocardiographic intervals, laboratory values or viral screen results, the lack of serious adverse reactions, and the “trend” towards treatment-related headaches with faster infusion rates in this study, is misleading because it discusses “safety” that is not supported by a study that lacked statistical significance. We recommend that discussion of this study be deleted.
- The first paragraph in the Postmarketing Experience subsection of the Adverse Reactions section is misleading because it minimizes the findings of adverse reactions with the terminology “mild to moderate.” Furthermore, the paragraph is inconsistent with the regulations requiring the following statement of limitation at the beginning of this subsection
The following adverse reactions have been identified during post approval use of intravenous immune globulins. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.
We note that a similar statement is included at the end of this subsection, but it is further minimized by the inclusion of the following statement “Evaluation and interpretation of these post-marketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance.” We recommend that this second sentence be deleted from the sentence including the required language.
- All of the adverse reactions provided in the Postmarketing Experience subsection should be combined in the organized list by body system. Furthermore, it is not necessary to include references to this information.
- Under Drug Interactions, there is no need to have a separate subsection if there is only the one drug interaction with live virus vaccines.
- The Mechanism of Action subsection of the Clinical Pharmacology section should include the statement that the mechanism of action in primary immunodeficiency has not been fully elucidated.
- Only describe clinically significant information in the Clinical Pharmacology section.
- Nonclinical toxicology may be deleted from this label.
- In the Clinical Studies section, avoid the use of the terms “primary efficacy variable” and “secondary efficacy variable.”
- The Clinical Studies section is limited to the discussion of clinical studies that are important to a prescriber’s understanding of the safe and effective use of Gammaplex, including primary support for effectiveness and prospective safety evaluations. However, studies that were not adequate and well-controlled should be avoided.
- References are overused in this label. Only include references when labeling summarizes or otherwise relies on recommendation by an authoritative scientific body, a standardized methodology, scale, or technique because this information is necessary for safe and effective use. Do not use guidances as references.
- The Patient Counseling Information is a section designed to give the physician discussion points with the patient. It should be written in command language and should not be used as a re-iteration of the Warnings and Precautions section. We recommend that this section be revised to simple list or set of brief paragraphs. For example
- Inform patients to report the following signs and symptoms to the doctor or healthcare provider because these may be signs of serious adverse reactions
- Decreased urine output, sudden weight gain, fluid retention/edema, shortness of breath [See Renal Dysfunction and Renal Failure (5.2)]
- Shortness of breath, chest pain, leg pain and swelling, difficulty walking [See Thrombotic Events (5.3)]
- Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movement, nausea and vomiting [See Aseptic Meningitis (5.5)]
- Increased heart rate, fatigue, yellowing of skin or eyes, dark-colored urine [See Hemolysis (5.6)]
- Trouble breathing, chest pain, blue lips or extremities, fever [See TRALI (5.7)]
- Inform patients that Gammaplex is made from human plasma and may contain infectious agents that can cause disease. While the risk that Gammaplex can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them.
- Inform patients that Gammplex can interfere with their immune responses to live vaccines (i.e., MMR) and that they should tell their healthcare provider of this potential when receiving vaccinations.
Carton and Container Labels
- The bar code is missing from the proposed carton and container labels.
- Increase the prominence and readability of the dosage strength/volume to prevent potential dosing errors.
The above comments are provided from a comprehension and an advertising and promotional labeling perspective to assist you in revising the proposed labeling materials. If you have any questions, please contact Lisa Stockbridge at 301-827-6226.