Merck Sharp & Dohme Limited

- Section 4.8 of the Summary of Product Characteristics has been updated based on newly-available clinical data concerning hypersensitivity in healthy volunteers that is also part of the updated Risk Management Plan Version 4.1. Furthermore, within the MAH Response to the CHMP Request for Supplementary Information the opportunity was taken to include the most recent safety update: that hypersensitivity reactions, including acute anaphylactic reactions, may lead to a fatal outcome.

- Sections 4.4 and 4.5 of the Summary of Product Characteristics have been updated from the current information on haemostasis. These changes are also part of the updated Risk Management Plan Version 4.1.

- Section 4.6 of the Summary of Product Characteristics has been adapted to implement QRD template Version 7.3.

Approval of a type II variation on drug hypersensitivity, have amended the following sections of the SmPC:

4.4.    The section currently titled 'Allergic reactions' has been amended to reflect the Drug hypersensitivity reactions submission as     follows:
        Drug hypersensitivity reactions:
        Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions (see section 4.8).

4.8     A new paragraph has been added specifically about drug hypersensitivity reactions and other reference to allergic reactions removed:
Drug hypersensitivity reactions:
Hypersensitivity reactions have occurred in some patients and volunteers. In clinical trials these reactions were reported uncommonly and for post-marketing reports the frequency is unknown.
These reactions varied from isolated skin reactions to serious systemic reactions (i.e. anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to sugammadex.
Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia and swelling of tongue and pharynx.

In Section 4.4 a new paragraph detailing the Effect of sugammadex on hemostasis has been added. Greater detail has been included in the section titled ‘Interference with laboratory tests’ interference of the serum progesterone assay is observed at sugammadex plasma concentration of 100µg/ml. Reference is also made to prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT) and pharmacodynamic interactions seen in in vitro experiments as explained in the new paragraph on hemostasis.

This variation was the result of the fulfilled Follow-Up Measure on re-occurrence of neuromuscular blockade through displacement and involved clinical study 19.4.112 the SmPC has been amended in the following way:

4.4     Special warnings and precautions for use: under the heading Displacement reaction flucloxacillin has been removed as a potential drug for displacement reactions.

4.5     Interaction with other medicinal products and other forms of interaction: ‘No interaction studies have been conducted in adults with sugammadex and other medicinal products’ has been deleted. Reference to Clinical studies has been added. Flucloxacillin has been removed as a potential for Displacement reactions. The following text on Intravenous administration has been adapted to reflect this:

Intravenous administration of fusidic acid:

The use fusidic acid in the pre-operative phase may give some delay in the recovery of the T₄/T₁ ratio to 0.9. No re-occurrence of neuromuscular blockade is expected in the post-operative phase, since the infusion rate of fucidic acid is over a period of several hours and the blood levels are cumulative over 2-3 days. For re‑administration of sugammadex see section 4.2.