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ARGOM Appendix 5: Guidelines on OTC applications for specific substances
Note: This guidance document contains references to warning statements that are being included in the current updating of the RASML document. Warning statements marked with an (*) which are included in the updated version of the RASML document will be removed from this guidance document once the updated RASML is implemented.
Metered dose inhalers
A statement consistent with the following should be included in the Product Information of metered dose inhaler products used in the treatment of respiratory disorders such as asthma and chronic obstructive airways disease:
- Children and many other people will benefit from the consistent use of a spacer device with their metered dose inhaler (MDI or 'puffer'), particularly those with poor inhaler technique. Use of a spacer will also decrease the amount of medicine deposited in the mouth and back of the throat, and therefore reduce the incidence of local side effects such as mouth and throat irritation.
- In those people using a spacer, a change in formulation of the medicine used, or a change in the make of spacer may be associated with alterations in the amount of medicine delivered to the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the person should be monitored for any loss of asthma control.
- If using a spacer, the patient should be instructed to breathe in and out several times after each release into the spacer. Any delay should be kept to a minimum.
- Because of electrostatic charge, leading to adherence of medicine particles to the walls of the spacer, spacers should be washed in warm water with kitchen detergent and left to drain dry (without rinsing) before initial use and at least monthly thereafter. A cloth should not be used to dry the spacer, as this can produce more static electricity.
The Product Information should include information on compatible spacers, and should recommend that patients are directed to read the instructions that come with the spacer.
Consistent advice should also be included on the label and/or in the CMI (or other package insert).
Mouth ulcers, relief
Product labels should include a statement such as:
- If symptoms persist, seek medical or dental advice.
The efficacy of any antiseptic active ingredient in products indicated for the relief of mouth ulcers must be justified.
See also 'Teething products'
Claims of antiseptic activity must be accompanied by evidence of efficacy. Any claims relating to the duration of action will require justification.
Local anaesthetics and boric acid are not acceptable in any form for the treatment of nappy rash.
Nicotine replacement therapy
Nicotine Replacement Therapy (NRT) products are modified release products, and are considered to be formulation and delivery system dependent. Applications to register new NRT products should generally include a full data package, unless otherwise justified.
A full data package comprises:
- Preclinical (toxicology) data
- Formulation-specific pharmacokinetic data
- Local tolerance data
- Clinical efficacy and safety studies (to justify the intended dosage of the product, including the dose size, frequency and duration of use).
Full data package
The following are examples of cases where a full data package will be required:
New NRT dose forms
NRT dose forms that are not currently registered in Australia will require a full data package. Formulation-specific clinical data should be provided to justify the efficacy and safety of the proposed product, and the intended dosage size, frequency and duration of use of the product.
New nicotine molecule
NRT products that contain forms of nicotine (e.g. salts, complexes) that are not currently registered in Australia will require a full data package to justify the efficacy and safety of the proposed products.
Products containing the following forms of nicotine have been approved by the TGA:
- Anhydrous nicotine
- Nicotine polacrilex
- Nicotine betadex complex
- Nicotine bitartrate dihydrate.
The ARTG should be checked for the most current information.
Sponsors who propose to provide an application for registration of a new NRT product without clinical efficacy and safety data should discuss the application with the TGA prior to submission.
Justification for not submitting clinical efficacy data
A justification for not submitting clinical efficacy and safety data may be acceptable in some situations, including the following:
New form of nicotine, registered dosage form
In the case of a product containing a new form of nicotine and a dosage form that has been approved in Australia, clinical efficacy data may not be required. However, the following data will be required:
- Preclinical toxicology data;
- Formulation-specific pharmacokinetic data; and
- Local tolerance data.
Bioequivalence or bioavailability data may also be required (see ARGOM Appendix 1 - Guidelines on efficacy and safety aspects of OTC applications).
Modified release oral (buccal/sublingual) products, other than chewing gums
Single dose and multiple dose pharmacokinetic studies should be provided to support the registration of modified release oral NRT dosage forms intended for buccal/sublingual absorption.
Where the dosage form of a new modified release oral (buccal/sublingual) NRT product differs from the dosage forms currently approved for use in Australia, clinical efficacy and safety data should be provided, unless otherwise justified.
In place of clinical efficacy and safety data, submission of bioequivalence or other bioavailability/pharmacokinetic data comparing the proposed product and a relevant currently registered Australian product may be acceptable, if the sponsor can justify that the proposed and comparator products have the same methods of administration / absorption. The sponsor must justify any differences in the directions for use between the proposed and comparator products, if clinical efficacy and safety data are not provided.
See ARGOM Appendix 1 - Guidelines on efficacy and safety aspects of OTC applications for information on bioequivalence/bioavailability data requirements.
Local tolerance data using the proposed formulation should also be provided, unless otherwise justified.
Higher strength NRT products
For applications to register new NRT products with the same dosage form, but higher strengths than those currently approved for use in Australia, sponsors should provide the following data:
- Preclinical safety data, unless otherwise justified;
- Local tolerance data using the proposed formulation (to demonstrate that the higher nicotine strength does not adversely affect local tolerance), unless otherwise justified; and
- Clinical safety data using the proposed higher strength product formulation.
Lower strength NRT products
For applications to register new NRT products with the same dosage form, but lower strengths than those currently approved for use in Australia, sponsors should provide the following data:
- Bioavailability data and/or clinical efficacy data comparing the proposed formulation with a formulation currently registered in Australia; and
- Local tolerance data using the proposed formulation, unless otherwise justified.
Bioequivalence or pharmacokinetic data, but not clinical efficacy/safety data, may be acceptable as support for some applications, including the following:
Reformulation of an existing product, or addition of a new flavour of a currently registered product
Data showing bioequivalence of the new product with a relevant formulation/flavour currently registered by the sponsor in Australia should be provided. The TGA may consider a justification for not providing bioequivalence data, only if the proposed changes to the formulation are minor.
Local tolerance data using the proposed formulation should also be provided (to demonstrate that the changes to the flavour and/or other formulation details do not adversely affect local tolerance), unless otherwise justified.
Where a new product contains the same dosage form, same strength and same form of nicotine as a currently registered Australian NRT product (e.g. a generic 2 mg or 4 mg nicotine chewing gum containing nicotine polacrilex), data showing bioequivalence of the proposed and comparator products should be provided. Clinical efficacy data will not be required.
Where registration of two or more different strengths of a generic dosage form is proposed, the sponsor should submit bioequivalence data for each strength, or a justification for not providing these data.
Local tolerance data using the proposed formulation should also be provided (to demonstrate that any formulation differences do not adversely affect local tolerance), unless otherwise justified.
Single NRT product types have been approved for use in Australia for the following standard indications:
- Use as an aid in the cessation of smoking in smokers with nicotine dependence; and
- Relief of nicotine withdrawal symptoms, including nicotine cravings, associated with smoking cessation.
Other indications approved for specific NRT products
In addition to use of single NRT product types for the standard indications above, the TGA may consider other indications that have been approved in Australia for specific NRT dosage forms or NRT combinations, without requiring additional formulation-specific clinical data or a literature-based submission. Applications for the following indications will currently be considered:
- Combination therapy using nicotine transdermal patches and intermittent use products:
- Nicotine transdermal patches plus 2 mg nicotine gums, where both components are currently registered in Australia or are shown to be bioequivalent to relevant originator products currently registered in Australia.
- Nicotine transdermal patches plus 1.5 mg or 2 mg nicotine lozenges, where both components are currently registered in Australia or are shown to be bioequivalent to relevant originator products currently registered in Australia.
- Smoking reduction prior to stopping smoking – use of intermittent dosing nicotine products by smokers who are unable or not ready to stop smoking abruptly, as a step towards stopping completely:
- Nicotine chewing gums that are currently registered in Australia, or are shown to be bioequivalent to nicotine 2 mg or 4 mg chewing gum products currently registered in Australia.
- Nicotine inhalers that are bioequivalent to the originator inhalers providing nicotine for buccal absorption registered in Australia.
- Nicotine lozenges that are bioequivalent to the originator lozenges registered in Australia.
- Pre-cessation use of nicotine transdermal patches (use by smokers for two weeks, prior to quitting smoking):
- Nicotine transdermal patches that are considered to be bioequivalent to the relevant originator transdermal patches currently registered in Australia.
Applications for approval of combination NRT or use of NRT for smoking reduction should include formulation-specific clinical efficacy and safety data, or a justification for not providing these data (which could include a literature-based submission), to justify:
- Directions for use that differ from those approved for currently registered Australian products; or
- Use with other NRT products, or different strengths of the NRT products listed above.
Sponsors wishing to include new indications and/or directions for use of currently registered NRT products should provide clinical efficacy and safety data, or a literature-based submission, to justify the requested amendments (see ARGOM Appendix 1 - Guidelines on efficacy and safety aspects of OTC applications).
Labelling and other product documentation
Primary pack labels of unscheduled NRT products should include the statement "Keep out of reach of children" prominently on the main panel of the label as a stand-alone statement (on a line by itself). It is preferable for this statement to be located above the product name.
A Product Information (PI) document is required for all NRT products, regardless of poisons scheduling. A package insert, which could be in the form of CMI, should be provided for all NRT products, unless all relevant information (including all the contraindications, precautions and detailed instructions for use) are included on the label of the primary pack.
Some NRT transdermal patch products contain traces of aluminium or other metals to help them stick to the skin. Patches may contain enough of the metal to conduct electricity, overheat and cause a burn similar to bad sunburn, if the patches are worn during procedures such as Magnetic Resonance Imaging (MRI) scans. The PI and CMI (or other package insert) for nicotine transdermal patches that may contain traces of aluminium or other metals should include warnings that the patch should be removed prior to undergoing any MRI procedures.
In vivo scientific evidence will be required to support any application for registration of products containing nonoxinol 9 as anti-viral agents.
Nonoxinol 9 is considered to have spermicidal activity provided it is in an appropriate delivery system.
Package inserts (or carton labels if there is no package insert) of products containing nonoxinol 9 for use as a spermicidal contraceptive should include warnings consistent with the following:
- For vaginal use only.
- This product should not be used rectally.
- Sexually transmitted diseases (STDs) alert: This product does not protect against the AIDS virus (HIV) or other sexually transmitted diseases (STDs).
- Ask a doctor before use if you have a new sex partner, multiple sex partners, or unprotected sex. Frequent use (more than once a day) of this product may increase vaginal irritation, which may increase the risk of becoming infected with the AIDS virus (HIV) or other STDs from infected partners. Ask a doctor or other health professional for your best birth control method.
- Stop use and ask a doctor if you or your partner get burning, itching, a rash, or other irritation of the vagina or penis.