Your questions to the PBAC

Readers are invited to write in with their questions about decisions of the Pharmaceutical Benefits Advisory Committee (PBAC). Australian Prescriber publishes selected questions from readers, together with answers from the PBAC. Questions may address issues such as regulatory decisions, pharmaceutical benefits listings and withdrawals.

This exclusive arrangement helps Australian Prescriber readers understand how the contents of the Pharmaceutical Benefits Scheme (PBS, see www.pbs.gov.au) are determined.

Letters and responses are reviewed by the Editorial Executive Committee and may be edited before publication. It may not be possible to reply to all individual questions.

Warfarin tablets

Sir, - With reference to the PBAC response about the two brands of warfarin both produced by Boots but not bioequivalent ('Your questions to the PBAC' Aust Prescr 1996;19:6-7), this is not only confusing but has the potential to be dangerous.

I wonder who will be held responsible if a brand is substituted by some unwitting pharmacist and the patient comes to grief. Would it be the pharmacist, or the doctor who fails to mark the prescription not to be substituted? Perhaps the PBAC may like to comment.

F.K. Fry
General Practitioner
Wynnum, Qld

PBAC response:
The situation to which Dr Fry refers (two brands of warfarin) has arisen through a historical 'accident' and, though unsatisfactory, is difficult to deal with. It is really an issue to do with registration for marketing rather than subsidy listing on the PBS. As noted in the response from the Boots Company, the two brands were marketed in Australia before bioavailability testing was required; thus their relative bioavailability is unknown. Changes in the industry have led to the unusual and unsatisfactory situation where the same company markets two brands of the same drug in overlapping dose ranges and with unknown relativities. In fact, the equivalence or not of different strengths of the same brand is also unknown.

What are the options? One is to remove one or other brand from the market. This would then require a large number of patients to be switched from one brand to another of unknown relative bioavailability with the attendant re-titration and risks that this would entail. Another is to require the company to do a relative bioavailability study of the two brands. For a drug with such a low therapeutic index, this would require large numbers of subjects and, even if the two brands were shown to be equivalent within limits, generic substitution of brands of a drug such as warfarin is essentially undesirable. If the two brands were shown to have different bio availabilities, we would still be in the same position as at present, albeit with the problem better defined.

Advice from the Drug Safety and Evaluation Branch of the Therapeutic Goods Administration is that they are aware of the problem and also do not have a simple answer. I understand from them that the sponsor is being requested to include an appropriate 'Warning' statement on the label, product information and consumer product information which will alert doctors and patients to the unknown bioequivalence of the two brands.

Brand substitution is only legal where identified in the Schedule of Pharmaceutical Benefits. Pharmacists should be well aware of this, particularly in relation to warfarin. Nevertheless, the PBAC has recommended that a cautionary note be added to the PBS listing for all warfarin brands and strengths as follows:

'Caution: The listed brands have not been shown to be bioequivalent and should not be interchanged.'

The responsibility of the doctor is to prescribe by brand name (not generic name) to ensure patients continue to receive the same brand of warfarin. If Dr Fry has a satisfactory solution to the conundrum, we would be delighted to hear it.

The Boots Company response:
First, it needs to be clarified that the bioequivalence of Marevan and Coumadin has never been tested, rather than they are not bioequivalent. It is on the basis that there are no data to confirm bioequivalence that they have been deemed not to be interchangeable, since it is conceivable that differences in bioavailability might seriously affect the level of anticoagulation.

It is understandable that practitioners would prefer to deal with only one brand of warfarin, and this may be of some benefit to the patient in terms of compliance. However, the present position is a consequence of a historical situation where different formulations with different excipients have co-existed in the Australian market-place for many years. The fact that the two products are now manufactured by the same company does not change that situation because the formulations and manufacturing methods of Marevan and Coumadin are significantly different.

If there is any difference in bioequivalence between the different strengths of Coumadin and Marevan, it is most likely due to different dissolution rates. Therefore, it is questionable whether there will be any clinical significance given warfarin's long half-life and the wide range of half-lives for the significant clotting factors.

The ideal situation is to maintain a patient on the same brand of warfarin. If this is not possible, it is recommended that, given the nature of the drug, the multiplicity of factors that can impinge on INR values and the seriousness of the conditions being treated, intensified INR testing is conducted in the period following a switch in brand.
It is important to consider the possible effect switching brands may have on patient compliance particularly as the strengths of Coumadin tablets are 1 mg, 2 mg and 5 mg and for Marevan they are 1 mg, 3 mg and 5 mg. Useful guidelines on the management of patients taking warfarin are available.1

Deletion of glucose injection 50%

Sir, - I was interested to read Professor J. Murtagh's comment that glucose 50% should be available as a 'Doctor's Bag' item ('Drugs for the doctor's bag' Aust Prescr 1996;19:89-92). The de-listing of this drug in December 1994 is indefensible. I have been informed by the Secretary of the PBAC that the drug was de-listed after it was found that few prescriptions were written for it. Because of the low demand for prescriptions, it was felt unnecessary for it to be supported by the PBS. Accordingly, it then became unavailable as a 'Doctor's Bag' item as these are only selected amongst PBS drugs. This is the sort of logic which may satisfy bureaucrats, but it will leave some people untreated due to the lack of a life-saving drug in urgent circumstances.

I have pointed out to the PBAC that:

  • – glucose 50% is a cheap life-saving drug
  • – the use of this drug is specific. As far as I am aware, its only therapeutic use is in the resuscitation of an unconscious hypoglycaemic diabetic
  • – because of this drug's specific use, it is not unexpected that few, if any, PBS scripts are written for it
  • – if current legislation does not allow for this drug to be listed in the 'Doctor's Bag' due to its limited use on the PBS, then surely there is a very strong argument for legislative changes to be made to enable this anomaly to be corrected. This inquiry only led to a re-statement of the ridiculous logic above!

  • Glucagon is a relatively expensive drug. For approximately $16.00, it is only possible to resuscitate one mildly hypoglycaemic patient. For less cost, glucose can far more effectively treat two or three patients.

    We are left with an expensive, less efficacious drug in our 'Doctor's Bag' when a cheaper one is easily available. Glucagon injections in our emergency kits are going out of date just as quickly as the glucose 50% did, at significant cost to the community. Glucose 50% is an essential life-saving drug and should be available again.

    Gordon Taylor
    General Practitioner
    Yarrawonga, Vic.

    PBAC response:

    The PBAC noted at its November 1993 meeting that the volume of prescriptions dispensed for glucose injection 50%, 10 mL was very low and considered if this item should be deleted from the Schedule of Pharmaceutical Benefits. This raised the issue of whether or not there was a continued need for it in the Emergency Drug (Doctor's Bag) Supplies list as, under the legislation, items to be included in the Doctor's Bag list must also be listed in the general Schedule. After careful consideration, the view of the PBAC, including its general practitioner members, was that, since glucagon became available, glucose injection was now rarely used and the inclusion of it as a routine item in the Doctor's Bag would result in most of it being wasted through going over the expiry date. The PBAC noted that glucagon injection is included in the Doctor's Bag and is more suited to the emergency situation, being able to be given by subcutaneous or intramuscular injection.

    The PBAC accepted that some doctors may find glucose injection a useful item in their emergency supply list. However, it was considered preferable and reasonable for those doctors to buy this inexpensive item on an 'as needed' basis, rather than to include it as a routine item in the Doctor's Bag with the attendant wastage. The PBAC reconsidered the matter at its March 1995 and March 1996 meetings, but remained of the same view.

    Schedule of Pharmaceutical Benefits - ATC classification

    Sir, - I am writing in response to the letter from Dr J. Ziegler (`Your questions to the PBAC' Aust Prescr 1996;19:101-3) relating to the Schedule of Pharmaceutical Benefits.

    I write in support of his (and many others') criticisms of the ATC classification used in the Schedule. The PBAC apparently considers the Schedule as having an 'important educational role'. Any examination of the publication will reveal that it contains an alphabetical list of drugs currently available for subsidy, supplemented with some information about costs, the manufacturers of the drugs and the rules and regulations pertaining to the PBS. Even with the ATC groupings, the amount of educational content is minimal. If prescribers do not already possess the very basic pharmacological knowledge contained within the classification, then one should seriously consider their right to prescribe! The ATC groupings may be appropriate in a publication such as MIMS where a prescriber might be looking for therapeutic alternatives for a particular indication; however, this is not the role of the Schedule of Pharmaceutical Benefits.

    The point of difference is that the PBAC considers, or wishes to make, the Schedule something that it is not. Any time and motion study would confirm that a simple alphabetical listing would allow the most efficient use of the Schedule. It is unfortunate that a learned body such as the PBAC, entrusted with the task of making objective evaluations of drugs submitted for subsidy, should turn such a deaf ear to reasoned criticism of the ATC format in the Schedule. It would seem that they are trying to make a silk purse out of a sow's ear.

    John Bandouvakis
    Medical Specialist
    West Perth, W.A.

    References

    1. Barnett NL. Bioequivalence of proprietary warfarin: review of the literature and current practices. Aust Pharmacist 1991;10:115-7.