


Review Memorandum - May 4, 2009 - Gammaplex




REVIEW MEMORANDUM

 

Date:               May 4, 2009

To:                  Debbie Cordaro, RPM

                        CBER/OBRR/DBA/LRPM/HFM-380

                        Nisha Jain, Branch Chief

                        CBER/OBRR/HFM-392

From:                         Lisa Stockbridge, Ph.D., CSO

CBER/OCBQ/DCM/APLB/HFM-602

Through:        Ele Ibarra-Pratt, RN, MPH, Branch Chief

CBER/OCBQ/DCM/APLB/HFM-602                                          


Subject:          BLA 125329 Gammaplex (Immune Globulin Intravenous, Human)

                                    Comments on Draft Product Labeling

Background

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.

Comments

General
  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.

Highlights Section
  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.
 
