E-drug: Re: Industry Control over Information (contd)
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As an example of misinformation in publications like the CPS and PDR (drug
monograph compilations), I would suggest that many of the recommended doses
in the product monographs are inappropriate (almost always too high) and
basically "wrong". The rationale for this statement is as follows:
[this information was taken from a newsletter we (The Therapeutics
Initiative) published in late 1995 (http://www.interchg.ubc.ca/jauca)]
What is the problem with using product monograph or CPS dosing
recommendations?
There are numerous examples of recommended introductory doses which are
larger than those eventually needed. These larger "recipe" doses increase the
chance of adverse effects as well as cost. A classic example, still seen in
the 1995 CPS, is the dose recommendation for the antihypertensive drug
Hydrodiuril (hydrochlorothiazide) of 50-200 mg/day.. We have known for a
long time that doses as low as 6.25 mg or 12.5mg/day are often effective
and that the dose should rarely exceed 25 mg/day.(1) The 1995 CPS
recommended dose for Capoten (captopril) is 25-150 mg TID. We know now that
6.25 mg BID is a good starting dose and doses greater than 25 mg TID are
seldom needed. Two years ago, Imitrex (sumatriptan), was marketed in Canada
only as a 100 mg tablet. In recognition of the need for lower doses it has
just been approved in the USA as a 25 and a 50 mg tablet.
Why are "recommended" drug doses often excessive for your patients?
Several factors appear to influence initial drug dosage recommendations.(2)
The Federal Health Protection Branch requires that drug companies show that
a drug has an "effect", often compared to placebo, before it can be
approved. The way to show that a drug has a significant effect in the
smallest number of study patients is to use doses of the drug that will work
in most study patients. Study patients are highly selected and often include
only middle-aged, Caucasian males, who are receiving no other drugs and have
no concomitant disease. Once approved, the company must base dosing
recommendations on the available
study data. Unfortunately, these study patients may have little in common
with your patients, particularly the elderly who are more likely to have
altered drug handling and responses.
What can we learn from the classic dose response curve?
The typical "population" log dose-response curve provides an example of the
cumulative percentage of patients who respond to incremental doses of a
drug. It is clear that different patients have similar therapeutic responses
to very
different drug doses.
Starting at the lower left portion of the efficacy curve, about 25% of
patients achieve the desired effect with "low" doses and a very low
likelihood of a toxic response. At the top right end of the curve, a point
is reached where additional dose increases may not increase the number of
people who achieve the desired effect. In other words, there a significant
number of patients (10-30%) who are nonresponders and "pushing" the dose
will be futile, adding only to adverse effects and cost.
How do you determine the best dose for your patients or how do you help
your patient determine their best dose?
For those patients who do not require an immediate response (hypertension,
NIDDM, osteoarthritis, hyperlipidemia), start with a dose that is a 1/4 to
1/2 the recommended starting dose in the CPS. Then titrate the daily dose
every two to four weeks (if this is a useful interval) to the desired
effect. To use this approach, discussion with the patient must take place
before starting drug
therapy. The patient must be told not to be disappointed if an immediate
effect is not seen and that over the next few weeks the dose will be
titrated to achieve an effective dose. Tell the patient that this approach
reduces the chance of adverse effects and may reduce the cost of the drugs..
A titration approach can also apply to more "acute" conditions such as
short-term insomnia, headache, allergies, or the common cold etc. For these
"acute" conditions one should start with the lowest available dose and
titration should occur over hours to days rather than days to weeks.
What about patients presently receiving chronic standard CPS doses?
This is a real challenge since the tendency is "don't rock the boat." There
are ample successful studies of gradual dose reduction and even
discontinuation of such agents as antihypertensives(3) and
anticonvulsants(4). As long as the dose reduction is small (reduce the dose
by 1/4 each time) and at wide enough intervals (to avoid unnecessary office
visits), there should be little patient
anxiety. If the signs or symptoms reemerge, the diagnosis and the
effectiveness of the drug are verified and the dose may again be increased.
When patients are symptomatic they can often titrate the dose themselves as
long as they are given the appropriate guidelines.
What if you require a more rapid response to drug therapy?
Start with the product monograph recommended dose, hopefully obtaining a
response, and later gradually reduce the dose according to the patient's
beneficial/toxic effects. The advantage of this approach is that an effect
will likely be seen more quickly than with the titrating up approach.
However, the titrating down approach is rarely considered since clinicians
and patients are often reluctant to decrease the dose if a benefit has been
achieved. Even in the face of a drug benefit without signs of toxicity, drug
therapy should be slowly tapered to the lowest effective dose. Sometimes
this turns out to be no drug at all. This may be the result of an initial
incorrect diagnosis, fluctuating
disease state, or effective non-drug therapy such as lifestyle changes.
How do I use lower doses if they are not readily available?
Many tablets and caplets can be broken in 1/2 or � (a community or hospital
pharmacist can provide guidelines for specific dosage manipulation). Tablets
can be broken either by placing the tablet on a hard surface and pressing
down on either side or by getting your patient to purchase a pill cutter
(available in most pharmacies). Capsules or hard coated tablets are more
difficult to work with. In some cases, even these can be reduced by 1/2 the
daily dose by giving the tablet every other day rather than daily (e.g.
omeprazole 20 mg every other day). This is only feasible for drugs with a
duration of activity in the order of days rather than hours.
What conditions cannot be treated with a titration approach?
For cases where an immediate effect is wanted (acute alcohol withdrawal,
severe pain, severe asthma, severe angina, status epilepticus, etc.) or the
consequences of underdosing are potentially dangerous (acute bacterial
infections), it is worth erring on the side of giving "too much", as long as
the drug has an acceptable toxicity profile, rather than using a slow
upwards titration.
REFERENCES
1.Johnston GD. Dose-response relationships with antihypertensive drugs.
Pharmac Thera. 55:53-93; 1992.
2.Sheinen LB, et al. Study designs for dose ranging. Clin Pharmac Ther.
46:63-77; 1989.
3.Finnerty F. Step down therapy for hypertension. Post Graduate Medicine.
77:78-85; 1985.
4.Chadwick D. Randomized study of antiepileptic drug withdrawal in
patient in remission. Lancet. 337:1175-80; 1991.
James McCormack, Pharm.D.
Associate Professor
Clinical Division Chair
Faculty of Pharmaceutical Sciences
c/o Pharmacy Department
St. Paul's Hospital
1081 Burrard St.
Vancouver, B.C.
Canada V6Z 1Y6
604-631-5150 Fax 604-631-5154
jmccorma@unixg.ubc.ca
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