PRESERVATIVES
`
`Are they safe?
`
`31 May 2010
`
`Piotr Kozarewicz
`European Medicines Agency
`
`An agency of the European Union
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 1
`
`
`
`Are they safe?
`
`31 May 2010
`
`Piotr Kozarewicz
`European Medicines Agency
`
`An agency of the European Union
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 1
`
`
`
`Key Principles - Excipients
`
`Most experts agree that formulations for the paediatric
`population may need to be different to those for adults:
`
`(cid:190) Formulations should be as simple as possible
`
`(cid:190) Number of excipients should be reduced to a minimum
`
`(cid:190) No unnecessary additives
`
`(cid:190) Excipient levels should be reduced to a minimum
`
`2
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 2
`
`
`
`Key Principles - Preservatives
`
`According to Guideline on Excipients in the Dossier for
`Application for Marketing Authorisation of a Medicinal Product
`(Doc. Ref. EMEA/CHMP/QWP/396951/2006):
`
`“Antimicrobial preservatives are normally added to prevent
`microbial proliferation arising under in use conditions. The
`properties are due to certain chemical groups which are
`usually harmful to living cells and might therefore be
`associated to certain risks when used in man.“
`
`3
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 3
`
`
`
`Key Principles - Preservatives
`
`“Inclusion of antimicrobial preservatives or antioxidants in a
`finished product needs special justification.
`
`The use of these substances should be avoided in
`general, especially when considering the suitability of
`related formulations to the paediatric population.”
`
`4
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 4
`
`
`
`Problem?
`
`We have the Guideline …
`
`so what is the problem?
`
`5
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 5
`
`
`
`Problem with Preservatives
`
`Safety concerns?
`
`Are the accumulated safety data relevant to the paediatric
`population?
`
`Should we ban them in paediatric formulations?
`
`What about existing formulations?
`
`6
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 6
`
`
`
`Problem with Preservatives
`
`(cid:190) Preservatives
`
`(cid:190) May cause their own undesirable effects
`
`(cid:190) They may be tolerated in adults but what about the
`paediatric population?
`
`(cid:190) It is nearly always technically possible to re-think the
`product development to remove them or minimise their
`use
`
`7
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 7
`
`
`
`Policy making
`
`No simple answer - difficult to deliver a single dogmatic view
`on the problem.
`
`Strong Negative position
`(cid:190) Banned in ALL paediatric age groups? Or only in the Lower
`age groups e.g. neonates & infants?
`(cid:190) Banned for Long-term continuous use only?
`
`Relaxed position
`(cid:190) OK for older children – but how old?
`(cid:190) For Short term use are we not concerned?
`
`8
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 8
`
`
`
`Safety of Preservatives
`
`(cid:190) Look at EU Food Legislation as a possible indicator of
`long-term safety
`
`(cid:190) Look at EU Food Safety Agency (EFSA) Scientific
`Committee Reports
`
`Example:
`Propyl paraben is not recommended in the food legislation.
`
`Provisional conclusion – parabens should not be used in
`paediatric medicines for long term use. An extreme position
`considering many medicines already on the EU market with
`parabens - but do we want to keep on repeating this? A
`worthy aim to keep in mind.
`
`9
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 9
`
`
`
`Safety of Preservatives
`
`Methyl & Ethyl parabens
`EFSA has assigned ADI of 10mg/kg/day
`
`Propyl paraben
`EFSA has not assigned an ADI
`
`Reports of developmental problems in juvenile animals.
`Failure of testicular development. Must be seen as relevant
`to paediatric use, esp. lower age groups.
`
`Optimal approach - propyl paraben should not be used in
`paediatric medicines for neonates, infants and small children.
`Not even in the short term.
`
`10
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 10
`
`
`
`Safety of Preservatives
`
`Other preservatives
`
`Benzoic acid and its salts
`Signals suggesting effect on activity and attention in
`children, however their relevance has not been evaluated nor
`confirmed.
`
`Currently approved for use as food additive.
`
`Sorbic acid and its salts
`Currently approved for use as food additive.
`
`11
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 11
`
`
`
`Preservatives in eye drops
`
`Ophthalmic preparations without preservatives are
`strongly recommended for use in paediatric patients,
`especially neonates. Therefore, pharmaceutical companies
`should develop preparations without preservatives wherever
`possible in order to cater for the diversity of patients’ needs.
`
`Nevertheless, based on a review of available safety evidence,
`a general recommendation not to use preservatives in eye
`drops cannot be supported.
`
`EMEA Public Statement on Antimicrobial Preservatives in Ophthalmic Preparations for
`Human Use (Doc. Ref.: EMEA/622721/2009)
`
`12
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 12
`
`
`
`Current approach …
`
`(cid:190) Preservative free formulations whenever possible should be
`considered.
`Instead of developing multidose liquid formulations
`requiring preservation alternatives such as solid dosage
`forms (granulates, granules in sachets, bulk granules in
`bottles with measuring devices, individual “dry” doses that
`can be converted to liquid immediately prior to use, etc)
`should be investigated
`
`13
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 13
`
`
`
`Current approach …
`
`(cid:190) When preservatives are required, the concentration should
`be at the minimum level consistent with satisfactory
`antimicrobial function in each individual preparation and a
`thorough justification for the choice of the preservative
`should be provided.
`
`(cid:190) Non-clinical and clinical studies of appropriate design and
`duration are needed to give reassurance that the proposed
`formulations are optimal in term of benefit/risk balance.
`
`14
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 14
`
`
`
`Future …
`
`A lot of unanswered questions:
`
`We have to find a balance between a strong and relaxed
`position on formulation issues, keeping in mind:
`
`(cid:190) The need to have high quality appropriate pharmaceutical
`formulations for a sensitive population with special needs
`(cid:190) The “precautionary principle”
`(cid:190) Benefit/Risk arguments
`(cid:190) The need to be consistent
`
`15
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 15
`
`
`
`Discussion …
`
`Thank you for the attention
`
`Opiant Exhibit 2077
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 16
`
`
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