Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS
5.1   Risk of QT Prolongation with Higher-Than-Recommended Dosages
ORLADEYO should not be used for treatment of acute attacks of HAE. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended. An increase in QT was observed at dosages higher than the recommended 150 mg once daily dosage and was concentration dependent [see Clinical Pharmacology (12.2)].

5.2 Effects on ability to drive and use machines
ORLADEYO does not affect the ability to drive or use machines.

6       ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in the labeling: •   QT Prolongation [see Warnings and Precautions (5.1)]
6.1   Clinical Trials 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 practice.
The safety of ORLADEYO is primarily based on 24-week (Part 1) data from a 3-part, double-blind, parallel-group, placebo-controlled study (Trial 1) in 120 patients with Type I or II HAE randomized and dosed with either ORLADEYO 110 mg, 150 mg, or placebo, once daily with food. After Week 24, patients who continued in the study received active treatment through 48 weeks.
In Trial 1, a total of 81 patients aged 12 years and older with HAE received at least one dose of ORLADEYO in Part 1. Overall, 66% of patients were female and 93% of patients were Caucasian with a mean age of 41.6 years. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 7% and 3% for patients treated with 110 mg and 150 mg ORLADEYO, respectively, and 3% for placebo-treated patients. No deaths occurred in the trial.
The safety profile of ORLADEYO was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region.
Table 1 shows adverse reactions occurring in ≥10% of patients in any ORLADEYO treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1.


Table 1: Adverse Reactions Observed in ≥10% of Patients in any ORLADEYO Treatment Group (Trial 1)

ORLADEYO
Placebo
Adverse Reaction                                                110 mg               150 mg      Total (N=39)
(N=41)               (N=40)     (N=81) n (%)              n (%)                 n (%)    n (%)

Abdominal Pain*                              4 (10)              4 (10)               9 (23)    13 (16) 
Vomiting                                      1 (3)              4 (10)               6 (15)    10 (12) 
Diarrhea†                                        0               4 (10)               6 (15)    10 (12) 
Back Pain                                     1 (3)              1 (2)                4 (10)     5 (6) 
Gastroesophageal Reflux Disease                  0               4 (10)                2 (5)     6 (7) * includes Abdominal pain, Abdominal discomfort, Abdominal pain upper, and Abdominal tenderness †   includes Diarrhea and Frequent bowel movements

Gastrointestinal reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These reactions generally occurred early after initiation of treatment with ORLADEYO, became less frequent with time, and typically self-resolved. No patients in the ORLADEYO 150 mg dose group and 1 patient in the ORLADEYO 110 mg dose group discontinued treatment due to a gastrointestinal adverse reaction.
Less Common Adverse Reactions
Other adverse reactions that occurred in Part 1 of Trial 1 with an incidence between 5% and <10% at a higher incidence in ORLADEYO-treated patients compared to placebo included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%).
A maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in subjects who continued dosing.
Safety data are also available from 227 patients enrolled in an ongoing, open-label, long-term safety study (Trial 2) who received ORLADEYO 110 mg (N=100) or 150 mg (N=127) once daily with food and are consistent with the 24-week controlled safety data from Trial 1 (Part 1).
Laboratory Abnormalities
Transaminase elevations
In Part 1 of Trial 1, a single 150 mg ORLADEYO-treated patient discontinued treatment due to asymptomatic elevated transaminases (ALT >8x the upper limit of normal [ULN] and AST >3x ULN).
Total bilirubin was normal. No subject receiving 110 mg or placebo developed transaminase levels >3x ULN. In addition to this patient, 2 ORLADEYO-treated patients developed laboratory-related hepatic adverse events compared to 1 placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.
6.2    Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ORLADEYO.
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 drug exposure.
Gastrointestinal Disorders: nausea

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 and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com 

Effects on Driving