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September 23, 2013 Approval Letter - FLEBOGAMMA 5% DIF

Our STN: BL 125077/276                            
 
Instituto Grifols, S.A.
Attention:  Mr. Vicente Blanquer
2 Can Guasch St., Poligono Levante
08150 Parets del Valles
Barcelona
Spain
 
Dear Mr. Blanquer:
 
Please refer to your supplemental Biologics License Application (sBLA), dated July 8, 2013, received July 9, 2013, and as amended on August 29, 2013, submitted under section 351 of the Public Health Service Act for Immune Globulin Intravenous (Human), FLEBOGAMMA 5% DIF and FLEBOGAMMA 10% DIF.
 
We also refer to our letter dated June 10, 2013, notifying you, under Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA), of new safety information pertaining to the risk of thrombosis that we believe should be included in the labeling for the entire class of intravenous, subcutaneous, and intramuscular immune globulin (human) products. In addition, please refer to our letter dated August 13, 2013, notifying you of revisions to the final required safety labeling.
 
This sBLA, as amended, provides for revisions to the labeling for Immune Globulin Intravenous (Human), FLEBOGAMMA 5% DIF and FLEBOGAMMA 10% DIF, consistent with our August 13, 2013 Revised Safety Labeling Changes Letter.
 
We have approved your sBLA for Immune Globulin Intravenous (Human), FLEBOGAMMA 5% DIF and FLEBOGAMMA 10% DIF, to include the following new safety information on the risk of thrombosis in the package insert:
 
1.     HIGHLIGHTS OF PRESCRIBING INFORMATION
 
Thrombosis may occur with immune globulin products, including [your product]. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

For patients at risk of thrombosis, administer [your product] at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before  administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
 
2.   FULL PRESCRIBING INFORMATION (FPI)
 
Thrombosis may occur with immune globulin products, including [your product]. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors.   Thrombosis may occur in the absence of known risk factors. (see WARNINGS AND PRECAUTIONS [5.x], PATIENT COUNSELING INFORMATION [17.x]).
 
For patients at risk of thrombosis, administer [your product] at the minimum dose and infusion rate practicable.  Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity (see DOSAGE AND ADMINISTRATION [2.3], WARNINGS AND PRECAUTIONS [5.x]).
 
3.   WARNINGS AND PRECAUTIONS
 
            Thrombosis
 
Thrombosis may occur following treatment with immune globulin products, including [your product]. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
 
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 at risk of thrombosis, administer [your product] at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity (see BOXED WARNING, DOSAGE AND ADMINISTRATION [2.3], PATIENT COUNSELING INFORMATION [17.x]).
 
4.   Additional language for the PATIENT COUNSELING INFORMATION Section as follows. (Please note that this section was not included in the original Safety Labeling Change Requirement letter dated June 10, 2013):

Thrombosis
           
Instruct patients to immediately report symptoms of thrombosis. These symptoms may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.
 
All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h.
 

As soon as possible, but no later than 14 days from the date of this letter, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.

You may submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448.  You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 [21 CFR 601.12(f)(4)].
 
All promotional materials for your drug product that include representations about your drug product must be promptly revised to make it consistent with the labeling changes approved in this supplement, including any new safety information [21 CFR 601.12(a)(4)]. The revisions to your promotional materials should include prominent disclosure of the important new safety information that appears in the revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent to comply with 21 CFR 601.12(a)(4) to the address above.
 
All promotional claims must be consistent with and not contrary to approved labeling.  You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims [21 CFR 202.1(e)(6)].
 
Also within 14 days, please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that include these changes.
 
We will include information contained in the above-referenced supplement in your biologics license application file.
 
Sincerely,
 
 /s/
 
Basil Golding, MD
Director
Division of Hematology
Office of Blood Research and Review
Center for Biologics
 Evaluation and Research
  
ENCLOSURES:
Content of Labeling

 

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