Adverse reactions : תופעות לוואי

8. ADVERSE REACTIONS
The most serious adverse reaction observed in patients receiving HAEMATE P is anaphylaxis.
Thromboembolic events have also been observed in patients receiving HAEMATE P for the treatment of VWD . Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical studies.

In patients receiving HAEMATE P in clinical studies for treatment of VWD, the most commonly reported adverse reactions observed by >5% of subjects are allergic-anaphylactic reactions 
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(including urticaria, chest tightness, rash, pruritus, and edema). For patients undergoing surgery, the most common adverse reactions are postoperative wound and injection-site bleeding, and epistaxis.

8.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates obseved cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Treatment of Bleeding Episodes in VWD
Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study. Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to HAEMATE P. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus.

In a prospective, open-label safety and efficacy study of HAEMATE P in VWD subjects with serious life- or limb-threatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were one occurrence each of mild vasodilation and mild pruritis; two occurrences of mild paresthesia; and one occurrence each of moderate peripheral edema and extremity pain and severe pseudothrombocytopenia (platelet clumping with a false low reading).
HAEMATE P was discontinued in the subject who experienced the peripheral edema and extremity pain.

Prevention of Excessive Bleeding During and After Surgery in VWD
Among the 63 VWD subjects who received HAEMATE P for prevention of excessive bleeding during and after surgery, including one subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with five subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Table 6 presents the postoperative hemorrhagic adverse events.

Table 6.     Hemorrhagic Adverse Events in 63 Surgical Subjects

Adverse Event        Surgical       Number            Onset*                   Severity Procedure          of           (Number of             (Number of Events) Category        Subjects/         Events)
Events
On       Post       Mild       Mod        Severe
Major          8/11          7           4         9         –          2 Wound/injection
Minor          2/2           2           –         1         1          – site bleeding
Oral           2/6           –           6         3         3          – Major          4/4           2           2         3         1          – Epistaxis
Minor          1/1           1           –         1         –          – Cerebral                Major          1/2           2†          –         –         2          – hemorrhage/ subdural hematoma
Gastrointestinal        Major           1/3          3‡          –          –          2         1 bleeding
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Menorrhagia                   Major               1/1             1§              –           –           1         – Groin bleed                   Oral                1/1             –               1           1           –         – Ear bleed                     Major               1/1             1               –           1           –         – Hemoptysis                    Major               1/1             1               –           1           –         – Hematuria                     Major               1/1             1               –           1           –         – Shoulder bleed                Major               1/1             1               –           1           –         – * On = on-therapy; onset while receiving HAEMATE P or within 1 day of completing HAEMATE P administration. Post = post-therapy; onset at least one day after completing HAEMATE P administration.
† Reported as serious adverse events following intracranial surgery.
‡ Two of these events were reported as serious adverse events following gastrojejunal bypass.
§ Reported as a serious adverse event requiring hysterectomy following hysteroscopy and dilation and curettage.

Table 7 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to HAEMATE P. Pulmonary embolus considered possibly related to HAEMATE P occurred in one elderly subject who underwent bilateral knee replacement.

Table 7.      Non-Hemorrhagic and Possibly Related Adverse Events in 63 Surgical Subjects 
Body System                Adverse Event (AE)               Number of Subjects              Number of Subjects with an AE Possibly                with an AE
Related to                   Regardless of
HAEMATE                        Causality*
P
Pain                                        –                               11 Fever                                       –                                4 Body as a whole                   Abdominal pain                              –                                3 Infection                                   –                                3 Surgery                                     –                                3 


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Body System                Adverse Event (AE)    Number of Subjects    Number of Subjects with an AE Possibly      with an AE
Related to         Regardless of
HAEMATE P             Causality*
Back pain                     –                    2
Facial edema                  –                    2
Chest pain                    –                    3
Cardiovascular                    Pulmonary embolus†            1                    1 Thrombophlebitis†             1                    1
Nausea                        1                   15
Constipation                  –                    7
Digestive
Vomiting                      1                    3
Sore throat                   –                    2
Hemic and lymphatic               Anemia/decreased              –                    2 system                            hemoglobin
Metabolic/nutritional             Increased SGPT               1                       1 Dizziness                    1                       5
Headache                     1                       4
Nervous
Increased sweating           –                       3
Insomnia                     –                       2
Pruritus                     –                       3
Skin and appendages
Rash                         1                       1
Urinary retention            –                       4
Urogenital                        Urinary tract                –                       2 infection
* Events occurring in two or more subjects.
† Events occurring in separate subjects.

Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus.

8.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of HAEMATE P.
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 HAEMATE P exposure.

Adverse reactions reported in patients receiving HAEMATE P for treatment of VWD or hemophilia A are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to FVIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia.


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Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
 https://sideeffects.health.gov.il/ a d e ailed to the Registratio Holder’s Patie t Safety U it at: PV-IL@cslbehring.com