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New Drugs III
- Alendronate (Fosamax®)
- Dorzolamide (Trusopt®)
- Acarbose (Prandase®)
- Olanzapine (Zyprexa®)
Alendronate is a bisphosphonate bone resorption inhibitor in
the same class as etidronate and clodronate.
- Indication: Treatment
of osteoporosis or Paget's disease of the bone.
- Mechanism of action:
Alendronate inhibits osteoclastic bone resorption.
- Pharmacokinetics:
Oral bio-availability is very low (0.7%)
and is substantially diminished by food or fluids. A
proportion of absorbed drug becomes incorporated into
bone. Inactivated primarily by renal elimination.
- Evidence of effectiveness:
Two trials compare the effectiveness of alendronate
to placebo in postmenopausal women. In one
methodologically weak trial (1) 994
women, with extremely low bone mineral density (BMD) of
the lumbar spine (>2.5 SD below the mean) were
randomized to placebo or alendronate and followed for 3
years. In those with no previous fracture (79% of total),
alendronate reduced the incidence of new vertebral
fractures detected by xray from 2% to 1%, absolute risk
reduction (ARR)
= 1%, number needed to treat (NNT) =100 for 3 years. In the other
trial (2) 2027 women with
pre-existing pathologic fractures were randomized to
placebo or alendronate. Alendronate reduced the incidence
of symptomatic (painful) fractures from 18.2% to 13.6%, ARR = 4.6%, NNT = 22
for 3 years. In Paget's disease one randomized trial (3) in 89 patients, compared 6 months of
alendronate, 40 mg/day, with etidronate, 400 mg/day.
Decrease in alkaline phosphatase, the primary measure of
effect, was greater with alendronate, 79%, than
etidronate, 44%.
- Major adverse effects:
The placebo-controlled trials (1),(2) reported no increased evidence of
adverse events including upper gastrointestinal problems
with alendronate. Adverse events from post-marketing data
(4) reveal a major concern with
severe esophageal injury (51 reports) most often
occurring during the first month of therapy.
- Dose and cost: Osteoporosis:
10 mg daily ($1.75/day). Take on an empty stomach with
>200 ml of water in AM; remain upright for > 30
minutes after ingestion to prevent esophageal injury. Paget's
disease of bone, 40 mg daily ($4.66/day) for 6 months.
- Conclusions: In
women with extremely low BMD, 100 need treatment for 3
years to prevent 1 fracture detected on x-ray. In women
with a previous pathologic fracture, 22 need treatment
for 3 years to prevent one symptomatic fracture.
Dorzolamide is a carbonic anhydrase inhibitor for topical
ocular administration.
- Indication: Chronic
treatment of elevated intraocular pressure in patients
with ocular hypertension or open-angle glaucoma.
- Mechanism of action: Dorzolamide
is a sulfonamide which inhibits carbonic anhydrase II in
the ciliary processes of the eye resulting in decreased
aqueous humor secretion.
- Pharmacokinetics: Dorzolamide
acts locally and is absorbed systemically. The systemic
effect accumulates over time, but there is no evidence in
trials to date that this leads to significant metabolic
acidosis. Inactivated primarily by renal elimination.
- Evidence of efficacy:
Dorzolamide 2% TID has been shown in double-masked
placebo controlled trials to lower intraocular pressure
by 3-5 mm Hg (5). When compared with
timolol 0.5% BID, in a large multicentre trial (n = 184),
the mean per cent reduction in intraocular pressure was
greater for timolol, 29%, than for dorzolamide, 24% (6). Dorzolamide efficacy is similar to
pilocarpine when used as adjunctive therapy to timolol (7).
- Major adverse effects:
Bitter taste occurs frequently (25%) but is usually
transient. Local irritation (incidence 10%), stinging,
itching, and conjunctivitis occur more frequently than
with timolol (6) and may necessitate
stopping therapy.
- Dose and cost: Dorzolamide
2% TID ($0.90/day) as compared to timolol 0.5% BID
($0.34/day) and pilocarpine 2% TID ($0.06/day).
- Conclusions: Dorzolamide
provides a clear therapeutic advantage over oral carbonic
anhydrase. It should be reserved for patients in whom
topical beta blockers or pilocarpine are not tolerated or
ineffective. More safety and effectiveness evidence
is needed.
Arcarbose is a new antidiabetic drug that acts by a unique
mechanism of action. It inhibits hydrolysis of complex starches
to glucose in the small intestine.
- Indication: As
adjunctive therapy to diet in the treatment of patients
with non-insulin dependent diabetes mellitus (NIDDM).
- Mechanism of action:
Acarbose lowers postprandial glucose concentrations
by competitive inhibition of pancreatic alpha-amylase and
intestinal membrane-bound
alpha-glucoside hydrolases.
- Pharmacokinetics:
Acts locally in the gastrointestinal tract and less than
2% is absorbed in active form. Inactivated by metabolism
by intestinal bacteria or eliminated unchanged in feces.
- Evidence of efficacy:
Over 50 published controlled trials of the effects of
acarbose dating back to 1979, have examined the effects
of acarbose. In a Canadian multicenter randomized
controlled trial (8) (354 NIDDM
patients), for example, acarbose decreased HbA1C levels
by 0.9% as compared to placebo over a 1 year period in 3
groups of patients already treated with diet,
sulfonylureas or metformin. Acarbose has more effect on
post-prandial than fasting glucose and does not lead to
increase in insulin concentrations or weight gain.
- Major adverse effects:
Mainly gastrointestinal side effects. In the Canadian
trial for example: flatulence, absolute risk increase (ARI) =34%, diarrhea, ARI
= 23%, and abdominal cramps and discomfort, ARI = 16%. Also noted: a low incidence
of reversible elevations of serum transaminases and
bilirubin.
- Dose and cost: Acarbose
25-100 mg TID taken with the first bite of meals ($0.34 -
$0.94/day). Metformin 0.5-2.5 g/day ($0.14 - $0.69/day).
Glyburide 2.5 mg daily to 10 mg BID ($0.04 - $0.29/day).
- Conclusions: Acarbose
can be used as an adjunct to diet and other oral agents
to achieve glucose control in patients with NIDDM. Its
main disadvantages are cost and the high incidence of
gastrointestinal side effects.
Olanzapine is an atypical antipsychotic drug that structurally
resembles and binds to some of the same receptors as clozapine
(Clozaril®).
- Indication: Treatment
of schizophrenia and other psychotic disorders.
- Mechanism of action: The
drug binds to multiple receptors: serotonergic,
dopaminergic, histaminergic H1, alpha1-adrenergic, and
muscarinic. The role these actions play in its efficacy
and toxicity is unknown.
- Pharmacokinetics: Oral
bioavailability is good. Inactivated primarily by liver
metabolism. Elimination half-life of about 30 hours.
- Evidence of effectiveness:
There are two published randomized controlled
six-week trials. One (N=335) compared three doses of
olanzapine, 7 ± 1 mg/day, 12 ± 2 mg/day and 16 ± 2
mg/day, to placebo and haloperidol, 16±4 mg/day (9). The other (10)
(N=1,996) compared a titrated dose of olanzapine (13.2
mg/day) with a titrated dose of haloperidol (11.8
mg/day). The first study showed modest efficacy for the
highest dose of olanzapine (48% with >40 % improvement
in Brief Psychiatric Rating Scale) which was similar to
that with haloperidol (47%). In the second study the
response to olanzapine was better than to haloperidol,
however, the efficacy of both drugs was less than the
first. The poor response to haloperidol in the second
study was likely because 77% of the patients entered were
intolerant or unresponsive to their last course of
antipsychotic therapy. Olanzapine (mean modal dose 17
mg/day) has also been compared to risperidone (mean modal
dose 7 mg/day) in an unpublished 8-week interim analysis
of a 28-week double-blind trial. The response rates at 8
weeks (> 40% improvement) were similar for olanzapine,
29% and risperidone, 26%.
- Major adverse effects:
In the RCTs with haloperidol the incidence of
extrapyramidal side effects (dystonia, akathesia,
tremor,and hypertonia) was less for olanzapine than that
with haloperidol, however, the incidence of other side
effects (constipation, dry mouth, weight gain and
elevated ALT values) were greater for olanzapine. In the
RCT with risperidone the incidence of any extrapyramidal
event at 8 weeks was greater with risperidone (27%) than
with olanzapine (17%). Neutropenia has been documented
with olanzapine in at least 3 cases in Vancouver (11).
- Dose and cost: Single
daily doses of 10 to 20 mg. ($6.75 - $13.50/day) as
compared to haloperidol (Haldol®) 5-20 mg daily
($0.16-0.52/day), risperidone (Risperdal®), 1-4 mg BID
($2.09-8.35/day), and clozapine (Clozaril®), 100 mg BID
to 200 mg TID ($7.58-22.74/day).
- Conclusion: Olanzapine
is effective in the symptomatic management of schizophrenia and has fewer
extrapyramidal side effects in short-term trials.
Long-term effectiveness and safety remain to be
established. In the meantime it should be reserved for
patients who are refractory to or demonstrate significant
intolerance to standard antipsychotic therapy.
- Note:
see Therapeutics Letter 15 for definition and calculation
of ARR, ARI and NNT.
References:
- Liberman UA, Weiss SR,
Broll J, et al. Effect of oral alendronate on bone
mineral density and the incidence of fractures in
postmenopausal osteoporosis. N Engl J Med
1995;333:1437-1443.
- Black DM, Cummings SR,
Karpf DB, et al. Randomised trial of effect of
alendronate on risk of fracture in women with existing
vertebral fractures. Lancet 1996;348:1535-1541.
- Weinstein SE, Altman R,
Conte JM, et al. Comparative study of alendronate versis
etidronate for the treatment of Paget's disease of bone.
J Clin Endocrin Metab 1996;81:961-967.
- de Groen PC, Lubbe DF,
Hirsch LJ, et al. Esophagitis associated with the use of
alendronate. N Engl J Med 1996;334:1016-21.
- Wilkerson M, Cyrlin M,
Lippa EA, et al. Four week safety and efficacy study of
dorzolamide, a novel, active topical carbonic anhydrase
inhibitor. Arch Ophthal 1993;111:1343-1350.
- Heijl A, Strahlman E,
Sverrisson T, et al. A comparison of dorzolamide and
timolol in patients with pseudoexfoliation and glaucoma
or ocular hypertension. Ophthalmology 1997;104:137-142.
- Strahlman ER, Vogel R,
Tipping R, et al. The use of dorzolamide nad pilocarpine
as adjunctive therapy to timolol in patients with
elevated intraocular pressure. Ophthalmology
1996;103:1283-1293.
- Chiasson JL, Josse RG,
Hunt JA, et al. The efficacy of acarbose in the treatment
of patients with non-insulin-dependent diabetes mellitus.
Ann Intern Med 1994;121:928-935.
- Beasley CM, Tollefson
G, Tran P, et al. Olanzapine versus placebo and
haloperidol. Acute phase results of the North American
double-blind olanzapine trial. Neuropsychopharmacology
1996;14: 111-123.
- Tollefson GD, Beasley CM,
Tran PV, et al. Olanzapine versus haloperidol in the
treatment of schizophrenia and schizoaffective and
schizophreniform disorders: Results of an international
collaborative trial. Am J Psychiatry 1997;154: 457-465.
- Shalansky K.
Olanzapine: Atypical antipsychotic. Drug and Therapeutics
Newsletter 1997;4: 2-3.
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1997.