Adverse drug reactions bulletin

The February 2003 issue of the Australian Adverse Drug Reactions Bulletin <http://www.tga.gov.au/adr/aadrb/aadr0302.htm> is available on the TGA website.

Articles in this issue include:

• Tramadol - four years' experience
• Minocycline and not so benign intracranial hypertension
• Acute neuropsychiatric events with celecoxib and rofecoxib
• Linezolid and peripheral neuropathy
• Kava

Adverse drug reactions reporting online

New electronic system for reporting of adverse drug reactions in Australia

The reporting of suspected adverse reactions to medicines from Australian doctors, pharmacists, hospitals, pharmaceutical companies and other health professionals is set to enter a new era.

The Adverse Drug Reactions Advisory Committee (ADRAC) has been receiving reports of suspected adverse reactions to medicines from a range of health professionals in Australia since 1963. ADRAC currently receives about 12,000 reports a year and its database holds details on over 175,000 cases. To date, these reports have been submitted in hardcopy, based primarily on the ADRAC reporting card, otherwise known as the "blue card".

The opportunity now exists for Australian health professionals to submit reports electronically using an electronic form based on the blue card. While a description of the adverse reaction, the medicines involved, the dates and other key information will need to be entered on the form, many other pieces of information such as outcome, severity, dosage form and route of administration of the medicines can be chosen from dropdown lists.

It is anticipated that completing the electronic form will be faster than using the paper-based form and being sent electronically to ADRAC will result in a far more efficient process. The expansion of the electronic capabilities of the Therapeutic Goods Administration is another part of the project known as the Strategic Information Management Environment (SIME) designed to improve the way in which regulatory information is managed by the TGA.

This expansion is just the first step in an ongoing program of improvement of the electronic capabilities of Australian pharmacovigilance activities regulated by the TGA. One of the next steps will involve the development of middleware to accept electronic reports developed using ICH specifications from sponsors.

The electronic form is accessible from the TGA website. Select "Online Services" <http://www.tga.gov.au/sime/sime.htm> and follow the links to report adverse reactions.

AGRD2 updated

Two more chapters of the Australian Guidelines for the Registration of Drugs, Volume 2, have now been updated following consultation with stakeholders. These are Chapter 9 "Safety" and Chapter 10 "Efficacy".

The new guidelines have been published as Supplement 4 to the Australian Guidelines for the Registration of Drugs, Volume 2.

These guidelines have been updated to reflect current evaluation practice as recommended by the Medicines Evaluation Committee while remaining consistent with existing guidelines for prescription medicines.

The next chapters of AGRD2 to be revised will be Labelling (Chapter 6), Product Information (Chapter 7) and Consumer Medicines Information (Chapter 8).

The final document will be published in July 2003 as Australian Regulatory Guidelines for OTC Medicines (ARGOM) <http://www.tga.gov.au/docs/html/argom.htm>. Until this document is published sponsors should continue to refer to AGRD2 in conjunction with Supplements 1 to 4.

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Analgesics review

The TGA will soon release the Review of Non-prescription Analgesics - an update <http://www.tga.gov.au/docs/html/analgupd.htm>. The Update was undertaken at the request of the Medicines Evaluation Committee following ongoing reports of liver toxicity from paracetamol overdose in children. The Update extends the TGA's earlier Review of Non-prescription Analgesics <http://www.tga.gov.au/docs/html/analgesics.htm> that reviewed the scientific literature on OTC analgesics and information from Australian hospitals on admissions for analgesic toxicity. It also examined regulatory action that has been taken in other countries to date.

The original Review of Non-prescription Analgesics was published in 1998 following "concern about various public health issues associated with the use of the popular analgesic drug paracetamol and the complications that have developed in the labelling of analgesic drugs in general".

The Update will be released as a "draft for comment" and will be available from the TGA website. All comments will be considered by the MEC at its meeting on 3 April 2003. The final report will be published on the TGA website. The TGA will then follow through with implementing the recommendations in consultation with stakeholders.

Application deficiencies

Common deficiencies in category one applications identified in the Application Entry Phase

Deficiencies in applications submitted to the Drug Safety and Evaluation Branch may result in questions being raised during the Application Entry Phase and may lead to rejection of the application in this phase. When an application is accepted despite deficiencies, a Section 31 letter is usually sent, which will stop the "clock", prolonging the calendar time to a final decision as to registration.

The following is a list of common deficiencies identified during the Application Entry Phase in applications to register new products or to vary the registration of existing products. This is not a complete list of all possible deficiencies.

Administrative deficiencies
The Australian requirements for presentation of application data are outlined in Module 1 of the Common Technical Document (CTD), which can be accessed on the TGA website.

The following are some of the most commonly encountered administrative deficiencies.

• Binders that are overfilled or break easily.
• Inconsistent pagination within each volume and/or across each part/module.
• Illegible photocopies of documents.
• Non-English documents with no translation.

Data deficiencies
The requirements for presentation of application data are outlined in EU Modules 2-5 of the Common Technical Document (CTD) <http://www.tga.gov.au/docs/html/eugctd.htm>, which can be accessed on the TGA website.

The following are some of the most commonly encountered data deficiencies.

• Expert reports that are more than three years old.
• Expert reports that do not correctly cross-reference submitted studies and/or refer to studies that are absent from the relevant data package.
• Failure to ensure that a Drug Master File and letter of access has been supplied to the TGA by an intended supplier of the active pharmaceutical ingredient.
• Failure to provide adequate bioavailability/bioequivalence data or a justification for the absence of such data.

A detailed list of deficiencies associated with Part II (pharmaceutical chemistry and quality) data can be found in the document entitled Common Deficiencies in Part II Data Submitted for Category 1 Applications.

Sponsors are strongly encouraged to check applications carefully before lodgement to ensure that they comply with TGA requirements. This practice can lead to reduced calendar time to acceptance of applications.

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Certificate of free sale

The Advertising and Export Section of the TGA has recently received requests from some sponsors to issue certificates of free sale for medicines listed on the Australian Register of Therapeutic Goods for export only. Please note that the TGA does not issue certificates of free sale. Instead, the TGA issues a Certificate of Pharmaceutical Product (CPP) or a Certificate of Listed Product (CLP).

If a medicine is listed for supply in Australia, sponsors have the choice of either requesting a CPP or a CLP for it. The CLP includes a statement from the TGA that "This product has been approved by the TGA and is permitted for free sale (in that it can be legally supplied) in Australia".

For medicines listed on the ARTG solely for export purposes, the TGA issues a CPP for a Solely Export Medicine. This CPP cannot include the above comment regarding sale, as the product has not been approved for supply in Australia. In this situation, sponsors may include a comment that "This product has been developed exclusively for overseas markets. It meets the Australian legislative requirements for therapeutic goods for export purposes".

Colloidal silver

In 1998, the Complementary Medicines Evaluation Committee recommended that the TGA investigate the availability of colloidal silver products because of their potential toxicity and the lack of evidence to support the therapeutic claims being made. Unfortunately, the TGA was not able to take action against colloidal silver making therapeutic claims because of their role in the purification or treatment of drinking water. Products used for such purposes are excluded goods by virtue of the Therapeutic Goods (Excluded Goods) Order (the Order).

So that the TGA could take action against colloidal silver products making therapeutic claims, it proposed to amend the Order and undertook broad stakeholder consultation. With the support of complementary medicine industry bodies, the water quality industry and relevant government agencies, the Order was amended on 20 December 2002.

From that date, all substances used in the purification or treatment of drinking water but marketed with therapeutic claims are no longer excluded goods and are subject to the normal regulatory requirements for therapeutic goods before supply in Australia.

The TGA has not approved any colloidal silver-containing medicines and is in the process of taking action to stop any illegal supply of such medicines in Australia.

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European Union guidelines

Guidelines adopted by the TGA are sourced from the Committee for Proprietary Medicinal Products (CPMP) and International Conference on Harmonisation (ICH). Once a particular guideline has been adopted in Australia, it shall be regarded as part of Volume 1 of the Australian Guidelines for the Registration of Drugs (AGRD).

Since October 2002, thirty-four new EU Guidelines have been adopted in Australia, in addition to the publication of the Common Technical Document (CTD) - TGA Module 1 - Administrative and Prescribing Information for Australia.

• EU guidelines published as adopted in Australia <http://www.tga.gov.au/docs/html/euguidead.htm>
• EU guidelines published as NOT adopted in Australia <http://www.tga.gov.au/docs/html/euguidenotad.htm>
• EU guidelines replaced or superseded <http://www.tga.gov.au/docs/html/euguidsup.htm>

Other prescription medicine guidelines <http://www.tga.gov.au/pmeds/pmeds.htm> are also available from this website.

Kava update

In early 2002, the TGA issued an alert to health professionals and consumers, advising of potential concerns about kava-containing medicines used in the northern hemisphere. Following a report in July 2002 of the death, from complications of liver failure, of a woman in Australia who had been taking a kava-containing medicine for four months, the TGA initiated a consumer level recall of the suspected medicine.

Following advice from both the Complementary Medicines Evaluation Committee and the Adverse Drug Reactions Advisory Committee, the TGA decided in August 2002 that, as a safety precaution, a voluntary recall of medicines containing kava should commence immediately. Consumers were advised to discontinue use of kava-containing medicines and to return or dispose of any kava-containing medicines they have. Sponsors of kava-containing medicines were asked by the TGA to provide evidence of the safety of their products.

Internationally, there have been eighty-two reports of potential liver toxicity (hepatotoxicity) associated with the use of kava-containing medicines, including four deaths. The severity of the liver damage varies from abnormal liver function tests to liver transplantation. The Medicines Control Agency in the United Kingdom has recently completed a review of the safety of kava-containing medicines and recommend the prohibition of these medicines.

The TGA is currently reviewing data on the safety of kava-containing medicines and it is expected that a report will be available for the CMEC meeting in May.

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New complementary medicine substance

As foreshadowed in TGA News Issue 38 (July 2002) <http://www.tga.gov.au/docs/html/tganews/news38/med.htm>, L-arginine has been recommended as an ingredient suitable for use in listed medicines applied to the skin. The approval required a change (item 10A) to Schedule 4 of the Therapeutic Goods Regulations and also included a number of conditions that apply to the use for L-arginine in therapeutic goods. The amendment appears in the Regulations as follows:

10A medicines containing L-arginine singly or in combination with other substances and intended for application to the skin for a localised effect, if a warning label is attached to the medicine stating that the medicine is to be applied only to the skin, and not to the mucosa, vagina or rectum, unless:

1. the medicine also contains an amino acid, other than L-arginine, mentioned in paragraph (a) of item 10; or
2. the other substances are included in Schedule 3; or
3. the goods are included in a Schedule to the Poisons Standard; or
4. the goods are in a form required to be sterile; or
5. the indications proposed by the sponsor of the goods are in the treatment of a disease, condition, ailment or defect specified in Part 1 or 2 of Appendix 6 to the Therapeutic Goods Advertising Code.

New sunscreen active ingredient

The TGA has approved a new sunscreening agent for inclusion as an active ingredient in listed sunscreens.

This ingredient has been added to the list of Sunscreening agents permitted as active ingredients in listed products and can now be included as an active ingredient in listed sunscreens.

Review of medicines labelling

In March 2002 the TGA released the Review of the Labelling Requirements for Medicines, Consumer Focused Labelling - A Way Forward? <http://www.tga.gov.au/docs/html/labelrev.htm> as a consultation report. Copies of this report are available from the TGA website.

The major recommendations of the Review were:

• that label warning statements be transferred from the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) to the Medicines Labelling Order
• that consideration should be given to introducing CMI for all registered medicines
• that a "consumer focused" approach to the labelling of non-prescription medicines be adopted under an industry Code of Practice with the aim of improving the performance of labelling for the benefit of consumers.

A steering committee and two working parties (the Label Legislation working party and the Code of Practice working party) have been formed to oversee the implementation of these proposals. These groups include representatives of consumers, OTC, complementary and prescription medicine sponsors, pharmacists, APAC, Medsafe and the TGA.

Detailed proposals for the transfer of label warning statements were considered by the steering committee and issued in October as the consultation document Medicine Label Advisory Statements <http://www.tga.gov.au/docs/html/labeladv.htm>. This document is available from the TGA website.

Proposals for an industry Code of Practice have been considered by the Steering Committee and are to be further developed by the Code of Practice working party.

Progress with the implementation of these proposals will be reported in future editions of TGA News and on the TGA website.