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warnings and cautions
5 WARNINGS AND PRECAUTIONS IgA deficient patients with antibodies against IgA may develop severe hypersensitivity and anaphylactic reactions ( 5.1 ). May carry a risk of transmitting infectious agents such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite manufacturing steps designed to minimize the risk of viral transmission ( 5.2 , 11 ). 5.1 Hypersensitivity to IgA GLASSIA may contain trace amounts of IgA. Patients with selective or severe IgA deficiency and with known antibodies to IgA, have a greater risk of developing severe hypersensitivity and anaphylactic reactions. Monitor vital signs continuously and observe the patient carefully throughout the infusion. IF ANAPHYLACTIC OR SEVERE ANAPHYLACTOID REACTIONS OCCUR, DISCONTINUE THE INFUSION IMMEDIATELY . Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. 5.2 Transmissible Infectious Agents Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and removing certain viruses during the manufacturing process (see Description [ 11 ] for viral reduction measures). Despite these measures, such products may still potentially transmit human pathogenic agents. There is also the possibility that unknown infectious agents may be present in such products. The physician should weigh the risks and benefits of the use of this product and discuss the risks and benefits with the patient. 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 Kamada Ltd. at 1-866-GLASSIA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. No seroconversions for hepatitis B or C (HBV or HCV) or human immunodeficiency virus (HIV) or any other known infectious agent were reported with the use of GLASSIA during the clinical studies.
6 ADVERSE REACTIONS Two serious adverse reactions observed on two separate occasions during clinical studies with GLASSIA were cholangitis and exacerbation of chronic obstructive pulmonary disease (COPD). The most common drug-related adverse reactions considered by the investigator to be at least possibly related to GLASSIA administration observed at a rate of >3% in subjects receiving GLASSIA were headache and dizziness. The most common product-related adverse reactions (>3%) in clinical studies were headache and dizziness ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Kamada Ltd. at 1-866-GLASSIA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 65 subjects have received treatment with intravenous GLASSIA in two clinical studies, both performed in the US. Three subjects participated in both studies. However, because of the large temporal difference between studies (> 5 years) and major difference in study designs, each study was analyzed separately without excluding these three subjects who participated in both trials from either study analysis. Thus, safety and efficacy of GLASSIA are reported on all 18 subjects in a Phase I study and all 50 subjects who received GLASSIA in a Phase II/III study, for a total of 68 subjects, representing 65 unique subjects. In an open label, Phase I non-parallel, dose-escalation study, 18 subjects received a single infusion of GLASSIA at dosages of 30, 60 or 120 mg/kg. In a randomized, Phase II/III double-blind, active-control study, 50 subjects were scheduled to receive weekly infusions of GLASSIA or the comparator Alpha 1 -PI product, Prolastin, at a dosage of 60 mg/kg for a total of 12 doses after which all subjects remaining in the study were treated for another 12 weeks with GLASSIA only. Overall, 17 subjects received 12 doses and 21 subjects received 24 doses of GLASSIA during the study. Eleven subjects received either 22 or 23 doses and one subject did not receive any treatment with GLASSIA during the last 12 weeks of the study. The population treated with GLASSIA in these two studies was 40-74 years old, 54% male, 100% Caucasian and had congenital Alpha 1 -PI deficiency with clinical evidence of emphysema. Table 1 compares the adverse events reported during the initial 12 weeks (double-blind portion) of the Phase II/III study occurring in all subjects treated with GLASSIA with events in the concurrent Prolastin control group. Table 1: Number of Subjects/Infusions/Adverse Events Occurring during the First 12 Weeks of Treatment GLASSIA Prolastin No. of subjects treated 33 17 No. of infusions 393 190 No. of subjects with adverse events regardless of causality (%) 27 (82%) 16 (94%) No. of subjects with related adverse events according to investigator causality assessment(%) 6 (18%) 6 (35%) No. of subjects with related serious adverse events 0 0 No. of subjects experiencing an adverse event within 24 hours of infusion, regardless of causality (%) 19 (58%) 14 (82%) No. of adverse events regardless of causality (mean rate of adverse events per infusion) 70 (0.18) 46 (0.24) No. of adverse events, regardless of causality, occurring within 24 hours of infusion (% of all adverse events) 35 (50%) 30 (65%) No. of infusions associated with adverse events occurring within 24 hours of infusion, regardless of causality (% of infusions) 32 (8%) 28 (15%) Table 2: Adverse Events Occurring in > 5% of Subjects during the First 12 Weeks of Treatment (Irrespective of Investigator Causality Assessment) GLASSIA No. of subjects: 33 Prolastin No. of subjects: 17 Adverse Event (AE) No. of subjects with AE (percentage of all subjects) No. of subjects with AE (percentage of all subjects) Cough 5 (15%) 4 (24%) Upper respiratory tract infection 4 (12%) 0 (0%) Headache 3 (9%) 4 (24%) COPD Exacerbation 4 (12%) 5 (29%) Table 3: Adverse Event Frequency as a % of all Infusions (> 0.5%) (Irrespective of Investigator Causality Assessment) a Throughout entire 24-week double-blind plus open-label trial period b Throughout initial 12-week double-blind period GLASSIA a No. of infusions: 960 Prolastin b No. of infusions: 190 Adverse Event (AE) No. of AEs (percentage of all infusions) No. of AEs (percentage of all infusions) Upper respiratory tract infection 14 (1.5%) 0 (0.0%) Headache 8 (0.8%) 4 (2.1%) Nasopharyngitis 8 (0.8%) 0 (0.0%) Cough 7 (0.7%) 4 (2.1%) Pharyngolaryngeal pain 7 (0.7%) 1 (0.5%) COPD 6 (0.6%) 2 (1.1%) Table 4: Adverse Events Occurring in > 5% of Subjects during or Within 72 Hours of the End of an Infusion, in the First 12 Weeks of Treatment (Irrespective of Investigator Causality Assessment) GLASSIA No. of subjects: 33 Prolastin No. of subjects: 17 Adverse Event (AE) No. of subjects with AE (percentage of all subjects) No. of subjects with AE (percentage of all subjects) Cough 3 (9%) 4 (24%) Upper respiratory tract infection 3 (9%) 0 (0%) Headache 3 (9%) 3 (18%) Sinusitis 2 (6%) 1 (6%) Chest discomfort 2 (6%) 0 (0%) Dizziness 2 (6%) 0 (0%) Hepatic enzyme increased 2 (6%) 0 (0%) During the 12-week double blind portion of the Phase II/III trial, 4 subjects (12%) had a total of 7 exacerbations of chronic obstructive pulmonary disease (COPD) during GLASSIA treatment and 5 subjects (29%) had a total of 6 exacerbations of COPD during Prolastin treatment. Seventeen additional exacerbations in 14 subjects (28%) occurred during the 12-week open-label treatment period with GLASSIA. The overall rate of pulmonary exacerbations during treatment with either product was 1.3 exacerbations per subject per year. Most adverse events were mild to moderate in severity, although two episodes of headache and one episode of cholangitis were severe. Two subjects experienced treatment emergent serious adverse events (cholangitis and infective exacerbation of COPD), both of which were considered by the investigator to be unrelated to treatment with GLASSIA. Out of 68 subjects treated with GLASSIA during clinical studies, 14 (21%) experienced one or more adverse events that were assessed by the investigator as possibly or probably related to treatment ( Table 5 ). A total of 3 subjects (approximately 5%) receiving GLASSIA reported urticaria, irrespective of the investigator's opinion of cause. Table 5: Adverse Reactions Assessed by Investigator as Possibly or Probably Related to Treatment with GLASSIA (No. of subjects: 68*: combined data from single-dose PK study and 24-week clinical study) Adverse Event (AE) No of subjects experiencing a related event according to investigator causality assessment (percentage of all subjects) *Three (3) subjects participated in both the single-dose PK study and the 24-week trial, such that 65 unique subjects were administered GLASSIA. Any event 14 (21%) Headache 4 (6%) Dizziness 2 (3%) Dysgeusia, Influenza-like illness, Lethargy, Pyrexia, Decreased platelet count, Joint swelling, Erythema marginatum, Pruritis, Rash, Urticaria, Hypertension, 1 (1.5%) Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either study. 6.2 Post-Marketing Experience No spontaneous adverse event reports have been received.
adverse reactions table
<table ID="id_16e8b355-bbf5-4df6-8db0-04f81ddacc41"> <caption ID="id_a4d1fb82-3229-4561-976a-6799dcc5f40e">Table 1: Number of Subjects/Infusions/Adverse Events Occurring during the First 12 Weeks of Treatment </caption> <col align="left" width="64.067%"/> <col align="left" width="17.967%"/> <col align="left" width="17.967%"/> <tbody> <tr ID="id_64c05f17-a79f-43ed-a866-a424b0bb14db"> <td align="left" styleCode="Botrule Toprule Rrule Lrule" valign="top"/> <td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">GLASSIA</content> </td> <td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">Prolastin</content> </td> </tr> <tr ID="id_9df19ac1-5a33-4012-be0c-da3b494fb17e"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of subjects treated </td> <td align="center" styleCode="Botrule Rrule" valign="top">33 </td> <td align="center" styleCode="Botrule Rrule" valign="top">17 </td> </tr> <tr ID="id_8a324b7e-5120-4409-8655-f7aa0d579c68"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of infusions </td> <td align="center" styleCode="Botrule Rrule" valign="top">393 </td> <td align="center" styleCode="Botrule Rrule" valign="top">190 </td> </tr> <tr ID="id_e3698fac-df17-426f-b97d-c934df9917fc"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of subjects with adverse events regardless of causality (%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">27 (82%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">16 (94%) </td> </tr> <tr ID="id_5050668a-52a4-4729-9011-a924f88ad179"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of subjects with related adverse events according to investigator causality assessment(%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">6 (18%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">6 (35%) </td> </tr> <tr ID="id_d6d695db-1fda-4977-9872-ea5325acbbc9"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of subjects with related serious adverse events </td> <td align="center" styleCode="Botrule Rrule" valign="top">0 </td> <td align="center" styleCode="Botrule Rrule" valign="top">0 </td> </tr> <tr ID="id_565e4316-9103-482a-94d4-fb3f0176195c"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of subjects experiencing an adverse event within 24 hours of infusion, regardless of causality (%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">19 (58%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">14 (82%) </td> </tr> <tr ID="id_4221622e-71fe-4f0b-9727-8ba39d982db2"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of adverse events regardless of causality (mean rate of adverse events per infusion) </td> <td align="center" styleCode="Botrule Rrule" valign="top">70 (0.18) </td> <td align="center" styleCode="Botrule Rrule" valign="top">46 (0.24) </td> </tr> <tr ID="id_9371d0d4-fbbe-4565-afa8-735699b61cdd"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of adverse events, regardless of causality, occurring within 24 hours of infusion (% of all adverse events) </td> <td align="center" styleCode="Botrule Rrule" valign="top">35 (50%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">30 (65%) </td> </tr> <tr ID="id_909bb472-906c-4af1-99ee-99280df4bdf8"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">No. of infusions associated with adverse events occurring within 24 hours of infusion, regardless of causality (% of infusions) </td> <td align="center" styleCode="Rrule" valign="top">32 (8%) </td> <td align="center" styleCode="Botrule Rrule" valign="top">28 (15%) </td> </tr> </tbody> </table>