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NEW DRUGS VI
To lower blood glucose in
patients with type 2 diabetes not controlled by diet and
exercise alone: 1) as monotherapy or 2) in addition to
maximum doses of metformin.Mechanism of action:
Agonist for the peroxisome
proliferator-activated receptor by which it decreases
insulin resistance in muscle and adipose tissue and
inhibits hepatic gluconeogenesis.Pharmacokinetics:
Well absorbed. Extensively
metabolized in the liver. Half-life is 3-4 hours. Evidence of effects on surrogate markers:
Relief of symptoms in
week RCTs have compared rosiglitazone to placebo1,2.
patients with overactive bladder, defined as
Pooled results comparing rosiglitazone (8 mg) to
increased urinary frequency (> 7/day) plus urgency
placebo show a 2.9 mmol/L decrease in fasting glu-
cose, no significant effect on plasma insulin, a 14.7%
Mechanism of action:
increase in LDL cholesterol, no significant effect on
HDL cholesterol, a 0.9 kg increase in weight and a
Well absorbed and extensively
2.4% decrease in hematocrit. One 26 week RCT com-
metabolized in the liver by CYP 2D6 to an active
pared rosiglitazone to placebo in 348 patients with
metabolite. Average half-life for tolterodine is 2.3 h
inadequate glucose control while receiving 2.5 g of
metformin daily 3. Rosiglitazone (8 mg) as compared
Evidence of efficacy:
Two double-blind RCTs are
to placebo decreased HbA1C by 1.2%, decreased fast-
available comparing the effectiveness of tolterodine,
ing glucose by 2.9 mmol/L, had no effect on plasma
2 mg BID, with oxybutynin (Ditropan®), 5 mg TID,
insulin, increased LDL cholesterol by 14.8%, increased
and placebo6,7. As compared to placebo, tolterodine
HDL cholesterol by 9%, increased weight by 3.1 kg,
and oxybutynin decreased frequency of micturition
by 1.0 and 0.8 per day, respectively, and episodes of
Major adverse effects:
In the trials edema occurred
urge incontinence by 0.6 and 0.8 per day, respective-
more commonly with rosiglitazone as compared to
ly. There was no significant difference in the
placebo (ARI=2.5%, NNH=40 for 0.5 yr). There was no
proportion of patients who perceived an
significant hepatotoxicity reported in the published
improvement in bladder symptoms: placebo
RCTs. The US FDA review states that 11 patients in pre-
47%, tolterodine 50%, and oxybutynin 49%7.
marketing trials had ALT levels greater than 3 times the
Major adverse effects:
Dry mouth was the most
upper limit of normal. Two case reports of severe hepa-
common adverse effect: placebo 18%, tolterodine 40%,
totoxicity in patients taking rosiglitazone have been
and oxybutynin 78%. Withdrawal due to adverse
published4,5. The first drug in this class, troglitazone,
effects (primarily dry mouth) were greater with oxy-
was withdrawn from the US market after reports of 90
butynin 19%, than tolterodine 7%, and placebo 8%.
cases of liver failure, including 63 deaths, in the USA.
Dose and cost:
Tolterodine 1-2 mg BID, $1.75 daily,
Dose and cost:
Rosiglitazone 4–8 mg daily (either
oxybutynin 5 mg BID to TID $0.54-$0.81.
once daily or BID). Daily cost: $2.46 - $2.76.
Tolterodine and oxybutynin have sim-
Conclusion: In patients with type 2 diabetes
ilar but limited efficacy in patients with overactive
rosiglitazone improves some surrogate markers
bladder symptoms. Dry mouth is a common side
and worsens others.
Long-term trials are required to
effect and occurs more frequently with oxybutynin
know whether this class of drugs reduces morbidity
Department of Pharmacology & Therapeutics
(all Therapeutics Letters, Course Information)
New Data on Old Drugs
(Wellbutrin SR®, Zyban®)
Doxazosin (Cardura®) arm terminated in RCT
1) Symptomatic relief of
ALLHAT is a large double blind RCT comparing
depressive illness (effectiveness for use > 8 weeks
four first-line drugs (chlorthalidone, 12.5-25 mg, doxazosin,
has not been evaluated in controlled trials). 2) As an
2-8 mg, lisinopril, and amlodipine) in patients > 55 yrs with
aid to smoking cessation (6-7 weeks).
elevated blood pressure and at least one other CHD risk fac-
Mechanism of action:
Bupropion is chemically
tor. In January 2000, due to increased cardiovascular events,
related to sympathomimetic drugs and unrelated to
the doxazosin arm was terminated. The 3.3 year results of
other antidepressants. It blocks reuptake of noradren-
doxazosin versus chlorthalidone have been published13.
aline and dopamine, but the mechanism for its clini-
Evidence of effects on surrogate markers:
was lower by 2-3 mmHg in patients receiving chlorthalidone.
It is extensively metabolized by
Total cholesterol and mean serum glucose were both lower by
the liver to at least 3 active metabolites. Half-life of
parent drug and active metabolites is 20 to 37 hrs.
Morbidity and mortality:
The primary outcome, fatal and
Evidence of efficacy:
Bupropion was introduced in
non-fatal MI, was not different in the two groups, RR=1.03
the USA in 1985 and was withdrawn in 1986 because
(0.9-1.2). The secondary outcome, combined vascular dis-
of an unacceptable incidence of seizures. In 1989 it
ease, was significantly higher in the doxazosin group
was reintroduced in the USA (maximum dose of 450
RR=1.25 (1.2-1.3), ARI=2.9%, NNH=34 in 3.3 years. This
mg daily). Bupropion was first approved in Canada in
combined worse outcome was due to a significantly increased
1998 as an SR twice-daily formulation. In one RCT
incidence of congestive heart failure, angina and stroke in
buproprion SR, 150 mg daily and 150 mg BID, were
similar and more effective than placebo based on
Conclusion: Doxazosin and other alpha-blockers (tera-
physician rated scores of depression at 8 weeks 8. In
zosin, Hytrin® and prazosin, Minipress®) should not be
2 RCTs bupropion (150-400 mg/day) was similar in
used as first-line drugs in the management of elevated
effectiveness to sertraline (50-200 mg/day) at 8
weeks, but the incidence of satisfaction with sexual
ARR=Absolute Risk Reduction, NNT=Number Needed to Treat to prevent one event,
functioning was less with sertraline (63%) than
ARI=Absolute Risk Increase, NNH=Number Needed to cause one Harmful event
buproprion (79%) and placebo (78%) 9,10.
In an RCT of 615 smokers, bupropion,whether taken
1. Nolan JJ, Jones NP, Patwardhan R and Deacon LF. Rosiglitazone taken once
daily provides effective glycaemic control in patients with type 2 diabetes
as 150 mg daily or 150 mg BID, was associated with
Diabet. Med. 2000;17: 287-294.
the same 1 year lower point-prevalence abstinence
2. Raskin P, Rappaport EB, Cole ST et al. Rosiglitazone short-term monothera-
py lowers fasting and post-prandial glucose in patients with type II diabetes.
rate (no smoking in the previous 7 days) of 23% as
compared to placebo 12.4%, ARR=10.6%, NNT=9 11.
3. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and
Major adverse effects:
Withdrawals due to adverse
rosiglitazone combination therapy in patients with type 2 diabetes mellitus. Arandomized controlled trial.
events in the 4 trials occurred in 7.1% of patients on
4. Al-Saman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a
bupropion as compared to 2.7% of patients on place-
patient receiving rosiglitazone. A case Report
. Ann Intern Med 2000;132(2):121-4.
bo, ARI= 4.4%, NNH=23 for 8 weeks. The Canadian
5. Public Citizen Health Research Group. Liver toxicity reported with the new
Adverse Drug Reaction Monitoring program as of
diabetes drug rosiglitazone (Avandia)
. Worst Pills Best Pills News.
Sept 1999 has received 407 reports of which 256 were
6. Drutz HP, Appell RA, Gleason D et al. Clinical efficacy and safety of toltero-
serious (64 convulsions, 52 psychiatric reactions and
dine compared to oxybutynin and placebo in patients with overactive blad-der
. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:283-289.
128 allergic reactions including 14 cases of serum
7. Abrams P, Freeman R, Anderström C and Mattiasson A. Tolterodine, a new
antimuscarinic agent: as effective but better tolerated than oxybutynin in
Dose and cost:
100 mg daily to 150 mg BID for
patients with an overactive bladder.
Br J Urol 1998;81:801-810.
8. Reimherr FW. Cunningham LA. Batey SR. et al. A multicenter evaluation of the
depression. 150 mg daily for smoking cessation.
efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets
versus placebo in depressed outpatients.
Clin Ther 1998;20(3):505-516.
9. Coleman CC, Cunningham LA, Foster VJ et al. Sexual dysfunction associat-
Bupropion has antidepressant and
ed with the treatment of depression: a placebo-controlled comparison of
smoking cessation effects through a unique
bupropion sustained release and sertraline treatment.
Ann Clin Psychiatry1999;11:205-15.
mechanism of action. The adverse effect profile is
10. Croft H, Settle E, Houser T et al. A placebo-controlled comparison of the
different from other antidepressants and includes
antidepressant efficacy and effects on sexual functioning of sustained-release
convulsions and serious allergic reactions.
bupropion and sertraline.
Clin Ther 1999;21(4):643-658.
11. Hurt RD, Sachs DP, Glover ED et al. A comparison of sustained-release
bupropion and placebo for smoking cessation.
N Engl J Med 1998;337:1195-1202.
This Letter contains an assessment and synthesis of published (and whenever
12. Dunlop H. Bupropion (Zyban , sustained-release tablets):
possible peer-reviewed) publications up to June 1, 2000. We attempt to main-tain the accuracy of the information in the Therapeutics Letter by extensive lit-
erature searches and verification by both the authors and the editorial board. In
13. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
addition this Therapeutics Letter was submitted for review to 55 experts and
Research Group. Major cardiovascular events in hypertensive patients ran-
primary care physicians in order to correct any identified shortcomings or inac-
domized to doxazosin vs chlorthalidone. The antihypertensive and lipid-low-
curacies and to ensure that the information is concise and relevant to clinicians.
ering treatment to prevent heart attack trial (ALLHAT).
The Therapeutics Initiative's objectives are unbiased review and dissemination of therapeutic evidence. Our recommendations are intended to apply to most
patients; exceptional patients require exceptional approaches. We are committed to evaluate the effectiveness of our educational activities using thePharmacare/PharmaNet databases without identifying individual physicians, pharmacies or patients. The Therapeutics Initiative is funded by the BC Ministryof Health through a 5-year grant to the University of BC. The Therapeutics Initiative provides evidence based advice about drug therapy, and is not respon-sible for formulating or adjudicating provincial drug policies.
Associação Portuguesa de Projectistas e Consultores TOMADAS DE POSIÇÃO LEGISLAÇÃO E QUALIDADE DOS ACTOS A APPC entende que o Estado, na qualidade de produtor de Legislação, deve reduzir a sua intervenção. É desejável que exista menos legislação e mais fácil de compreender e usar e que sobretudo seja bem aplicada e adequada à realidade nacional. A APPC deseja que o Es
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