E-drug: Consumer reports on medicines (cont)
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In respect to consumers' needs for drug information, there is a clear
need for information on "what do I do if I miss doses?". Something
like 80% of patients miss a dose at some time or other during
long-term pharmacotherapy -- one often, two in a row less often,
three in a row still less often, and so forth. Of course the longer
lapses in dosing, though less frequent, have greater likelihood to
trigger rebound effects in drugs that are so-prone, or to make it
likely that a recurrent first-dose effect will occur if the patient
suddenly resumes dosing with the usual dose. Then there are some
drugs whose actions are strongly adversely impacted by dosing errors
that would be trivial for
other agents. Two groups of such very unforgiving agents are the
combined estrogen-progestin oral contraceptives and the current group
of protease inhibitors. See figure 1 in the paper by Paterson, et
al. in the July 4 issue of Annals of Internal Medicine, vol 133:
21-30, 2000.
An editorial in this week's BMJ (321:719-720 ( 23 September, 2000 )
summarizes the complications that occur when drugs are suddenly
stopped as a patient undergoes surgery. That is a special case of
conflicting polices ("nothing by mouth after midnight before general
anesthesia" vs "continuity of oral pharmacotherapy") and limitations
of use of the oral route in instances where post-operative ileus
precludes the oral route. It is a special case of the drug
'holidays' that spontaneously recur frequently in ca 15% of patients,
occasionally in another ca 15%, and more or less never in the
remaining two-thirds, who nevertheless sometimes miss one or two
doses (a holiday being 3
or more, by arbitrary definition). Iatrogenic discontinuation of oral
pharmacotherapy at the time of hospitalization goes beyond just the
"NPO after midnight" order, as Walter Nimmo and colleagues showed for
emergency surgical admissions 15 years ago and van Hessen, et al.
showed for elective, nonsurgical admissions to hospital a decade ago
(Van Hessen P, Petri H, Urquhart J. Do prescribed drugs always
follow the patients to hospital? Pharm Weekbl Sci Ed 12: 66-70,
1990.)
I think it is still true that the only prescription pharmaceuticals
which have explicit information on what to do when you miss pills are
the combined estrogen-progestin oral contraceptives. "Call your
doctor" is not a satisfactory answer, because the answer is drug
specific, may vary somewhat with the indication and its severity, and
in any case has to be provided by specific studies.
One way to study the question is to do as was done with the oral
contraceptives, namely controlled substitutions of placebos for
active 'pills' and concomitantly to look for the consequences (for
the oral contraceptives it was surges in plasma levels of LH,
signifying breakthrough ovulation). Five such studies were done in
the 1980's (1-5), which provided the evidence for the information in
US and UK labeling for oral contraceptives. It is a model for all
chronic-use prescription drugs, although the details will of course
vary widely from drug to drug. The first such study was done with
two antihypertensive agents in 1994 (6), with several more having
been done more
recently (7-9). One such study was reported in 1998 with the leading
SSRI anti-depressants (10), with rather surprising results.
So there is progress, coming from the academic side, as was the case
with the oral contraceptives. In the absence of regulatory action on
this point, the manufacturers sit by, although there is potential
promotional advantage to be found with agents that are more
'forgiving' than their competitors of the most common lapses in
dosing.
One might think it apt for several of the major regulatory
authorities to begin to suggest the advisability for such information
as part of the registration package. A helpful perspective is to
look at the overall potential for harm, and rank order the regulatory
agenda accordingly. As the pioneer of statistical quality control,
W.E. Deming, taught, one must then re-order the list according to
'tractability', and then take action from the top down on the
highest-risk problems that are also technically tractable, waiting on
technical advances to confer tractability on those that must be
deferred. Pharmaceutical scientists, who tend to dominate these
matters, seem generally innocent of a
'systems perspective', which is the center-piece of Deming's
teachings on quality improvement. The result, when a systems
perspective is lacking, is to allow the intellectual excitement of
latest discoveries to re-order the list of problems in need of
attack. Compared to some of the evidently low-risk exotica in
biopharmaceutics that have excited strenuous regulatory efforts,
missed doses have both high incidence and considerable potential for
mischief, as the editorial in Saturday's BMJ summarizes for the
surgical subset of the problem.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University, Maastricht, NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug CH & Union City, CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
home office: 975 Hamilton Ave, Palo Alto, CA 94301 USA
tel: +1-650-321-3961; fax: +1-650-324-9739
email: urquhart@ix.netcom.com
References:
1. Morris SE, Groom GV, Cameron ED, Buckingham MS, Everitt JM, Elstein M.
Studies on low dose oral contraceptives: plasma hormone changes in
relation to deliberate pill ('MICROGYNON 30') omission.
Contraception 20: 61-9, 1979.
2. Chowdry V, Joshi UM, Gopalkrishna K, Betrabet S, Mehta S, Saxena BN.
'Escape' ovulation in women due to the missing of low dose
combination oral contraceptive pills. Contraception 22: 241-7, 1980.
3. Wang E, Shi S, Cekan SZ, Landgren B-M, Diczfalusy E. Hormonal
consequences of "missing the pill". Contraception 26: 545-66, 1982.
4. Landgren B-M, Diczfalusy E. Hormonal consequences of missing the
pill during the first two days of three consecutive artificial cycles.
Contraception 29: 437-46, 1984.
5. Smith SK, Kirkman RJE, Arce BB, McNeilly AS, Loudon NB, Baird DT.
The effect of deliberate omission of TRINORDIOL� or MICROGYNON� on
the hypothalamo-pituitary-ovarian axis. Contraception 34: 513-22,
1986.
6. Johnson BF, Whelton A. A study design for comparing the effects
of missing daily doses of antihypertensive drugs. Am J Therapeutics
1: 260-7, 1994.
7. Vaur L, Dutrey-Dupagne C, Boussac J et al. Differential effects
of a missed dose of trandolapril and enalapril on blood pressure
control in hypertensive patients. J Cardiovasc Pharmacol 26:
127-131, 1995.
8. Leenen FHH, Fourney A, Notman G, Tanner J. Persistence of
anti-hypertensive effect after �missed doses� of calcium antagonist
with long (amlodipine) vs short (diltiazem) elimination half-life.
Br J Clin Pharmacol 41: 83-8, 1996.
9. Hernandez-Hernandez R, Armas de Hernandez MJ, Armas-Padilla MC,
Carvajal AR, Guerrero-Pajuelo J. The effects of missing a dose of
enalapril versus amlodipine on ambulatory blood pressure. Blood
Pressure Monitoring 1: 1121-6,
1996.
10. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective
serotonin reuptake inhibitor discontinuation syndrome: a randomized
clinical trial. Biol Psychiatry 44: 77-87, 1998.
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