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Registration of products containing phenylephrine in place of pseudoephedrine
In view of the proposed rescheduling of pseudoephedrine, the TGA will adopt a modified approach to the registration of products that contain phenylephrine hydrochloride in place of pseudoephedrine. This will only apply to products that are intended to be marketed instead of or in parallel to equivalent registered products of the same sponsor that contain pseudoephedrine.
This approach is justified by the pharmacological similarity between pseudoephedrine and phenylephrine, the long history of marketing of cough and cold products containing phenylephrine and the NDPSC's request to the TGA to facilitate the registration of phenylephrine hydrochloride combination products. Details of this modified approach follow.
1. Safety and efficacy data
Specific safety and efficacy data will not be required for phenylephrine hydrochloride alone or in combination with the following substances:
This will only apply where the dose is 10mg every 4 hours to a maximum of 60 mg in 24 hours1. Sponsors wanting to use a different dose will need to provide adequate supporting data with the application.
This will only apply to medicines that are presented in dosage forms that have already been accepted for existing registered products containing phenylephrine or pseudoephedrine. It will not apply to 'new' dosage forms (i.e. a dosage form which does not exist in Australia for a similar product containing phenylephrine or pseudoephedrine) or to modified release dosage forms. For these products, the sponsor will need to establish the safety and efficacy and quality (including full stability data) of the product according to the requirements in ARGOM.
Products containing other active ingredients that have not been evaluated in combination with phenylephrine (e.g. the low-sedating antihistamines) will continue to require efficacy and safety data (or an acceptable justification) as detailed in the 'multi-component products' guideline in ARGOM.
Sponsors providing a justification in place of clinical data should address the potential for cardiac toxicity as well as the potential for drug-drug interactions (this could include in vitro high throughput screening studies for cytochrome P450s, glucuronidation and sulphation enzymes and p-glycoprotein transporter).
1 This dose is consistent with previous Medicines Evaluation Committee recommendations, standard pharmaceutical references and with the FDA monograph for OTC Nasal Decongestant Drug Products.
2. Stability data
For products which have phenylephrine hydrochloride replacing pseudoephedrine as the only change (apart from adjustments in the quantities of excipients), the TGA will accept an 18 month shelf life on the basis of 6 months of acceptable stability data generated on 2 batches of the proposed formulation, tested in real time and under accelerated conditions, as described in ARGOM. The sponsor will need to provide an assurance that the first two production batches will undergo full stability testing and that any adverse trends will be immediately reported to the TGA.
3. Product development
Manufacturing process validation should be carried out according to the requirements of the Australian Code of Good Manufacturing Practice for Medicinal Products. Information should be included in the application to indicate what action has been taken or will be taken to demonstrate the suitability of the manufacturing method for routine processing of the product.
Many products will contain <2% by weight of phenylephrine. Sponsors and manufacturers should hold evidence that the manufacturing process is adequate to ensure that the active is uniformly distributed in each dosage unit.