Clozapine
Clinical Update
Drug treatment for schizophrenia is
considered essential in managing acute,
violent psychotic episodes and reducing
their recurrence, while providing longterm
stabilization of the condition. Firstgeneration,
or typical, antipsychotic
drugs for schizophrenia are limited by
their predisposition to cause extrapyramidal
symptoms (EPSs).
The emergence of second-generation,
or atypical, antipsychotic drugs, beginning
with clozapine, has provided relatively
rapid-acting treatment for schizophrenia
with far less risk of inducing
effects associated with previous agents.
Pharmacology
Although the specific correlation
remains unclear, current wisdom implies
that interfering with dopamine at D2
receptors, especially at times when
these fluctuating sites are in a "high-affinity"
mode, yields the best results.
Interference with dopamine at these
sites also contributes to the side effects
associated with earlier therapies.
The first-generation treatments for
schizophrenia (ie, haloperidol, chlorpromazine)
are tightly bound to the D2
receptors, regardless of the amount of
unbound dopamine present. This binding
affects dopamine transmission at the
basal ganglia, causing motor function disruption.
This action gives rise to EPSs,
including muscle stiffness and peripheral
tremors that can evolve into tardive
dyskinesia and uncontrolled, spasmodic,
peripheral movements.
In general, a 65% binding capacity at
the D2 receptors treats schizophrenia,
whereas an 80% binding results in the
development of EPSs. Older agents not
only adhere more tightly to the D2 receptors,
but they maintain their hold for
longer durations—at least 1 to 2 days following
an oral dose. The eventual accumulation
of the drug almost ensures the
development of EPSs, especially as
doses are titrated upward.
Atypical antipsychotic agents such as
clozapine also bind to the D2 receptors.
Their binding, however, is described as
"loose"—meaning that they easily
detach from the receptor and allow
periodic, if reduced, transmission of
dopamine to take place. In addition,
whereas the 65% binding capacity is still
necessary for effective treatment, studies
indicate that this level is not required
at all times. The net effect of this looser
binding is to provide effective treatment
while minimizing the EPSs.
Administration and Dosing
Clozapine is given orally. Food has no
effect on absorption or clinical effect.
Dosing for schizophrenia begins with
12.5 mg once or twice daily. If the drug
is tolerated, the dosing is increased in
25-to 50-mg increments daily over a 2-
week period, until a daily dose between
300 and 450 mg is reached. Gradual
increases in dosing are necessary to
prevent the possibility of hypotension,
generalized seizures or myoclonic jerking,
and sedation.
Subsequent increases in dosing should
not be more often than once or twice
weekly. Most patients respond to daily
ranges of 300 to 600 mg; some may
require daily dosing of 600 to 900 mg.
Because clozapine readily detaches
from the D2 receptors, proper compliance
with therapy is essential. If a patient misses
just 1 or 2 daily doses, he or she can
experience a rapid decompensation, or
reemergence, of psychiatric symptoms.
Discontinuation should be over a 1-to 2-week period, with careful observation for
recurrence of psychotic symptoms.
Stress can pose
another challenge.
With increased dopamine
present, clozapine
will be more
rapidly displaced,
causing a drop from
the minimal 65%
binding needed for
effectiveness. During
such stressful episodes,
an agent with
greater D2 receptor affinity can be added
only for the duration of the episodes and
then removed. Increasing the dose of
clozapine during these times can be effective
but will increase the likelihood of
unwanted side effects.
Clozapine has been used successfully
in childhood-onset schizophrenia in a limited
number of treatment-resistant situations,
with a maximum daily dose of 525
mg. Its safety, however, has not been
established in children or adolescents
under the age of 16.
Side Effects and Drug Interactions
Contraindications to the use of clozapine
include concurrent myeloproliferative
disorders, preexisting bone marrow
depression, or a history of clozapineinduced
agranulocytosis.
Since its initial clinical trials, clozapine
has been associated with potentially lifethreatening
agranulocytosis. As a result,
this drug is available only through distribution
channels that ensure that periodic
blood tests are given prior to the dispensing
of each supply of medication,
and that patients are registered in a single,
national master database.
The supply of clozapine generally is
limited to 1-week quantities. When a
patient has a record of normal weekly
white blood counts (WBCs) and absolute
neutrophil counts (ANCs) for a 6-month
period, however, the frequency of testing
and the amount of drug dispensed may
be changed to 2-week intervals. If, after 1
year, all remains normal, this interval may
be further extended to 4 weeks.
In cases of moderate leukopenia (WBC
between 2000 and 3500 cells/mm3),
clozapine use is suspended while daily,
then twice weekly, WBCs and ANCs are
performed until blood counts reach normal
levels. Clozapine dosing may then
be reinstated, with weekly blood work
for a year.
In cases of severe leukopenia (WBC
under 2000 cells/mm3) or agranulocytosis
(ANC under 500 cells/mm3), clozapine
is discontinued. The patient must be
monitored daily, then twice weekly, and
then weekly for at least 4 weeks after
laboratory values return to normal.
Clozapine use during pregnancy,
although prolactin-sparing, is considered
unwise because of the (theoretical) possibility
of agranulocytosis and seizure
induction in the developing fetus.
Clinical Outlook
Whereas newer, atypical antipsychotic
drugs provide broad-spectrum treatment
for schizophrenia with fewer side effects
than earlier agents, the side effects they
do produce may be equally severe and
require careful monitoring.
Clozapine is available as 25-and 100-
mg tablets from Caraco Pharmaceutical
Laboratories, IVAX Laboratories Inc,
Mylan Pharmaceuticals Inc, and UDL
Laboratories Inc.
Finasteride Tablets
Benign prostatic hypertrophy (BPH)
remains one of the most common medical
conditions among men past the age
of 70. BPH represents a collection of urinary
symptoms including the sensation
of an incompletely empty bladder,
impairment of the urine stream, nocturia,
and daytime frequency.
Research has identified a limited population
of men with genetically low levels
of testosterone-converting enzymes
who have smaller prostate glands
throughout life and never develop BPH.
Regulating that enzyme in the rest of the
population has become a method for
treating the symptoms of BPH.
By obstructing the activity of the
steroid enzyme type II 5-α
reductase, finasteride inhibits
the conversion of testosterone
to dihydrotestosterone
(DHT). DHT, a more
potent androgen, is associated
with hyperplasia of the
prostate gland, with the additional
pressure on the bladder
and the urethra contributing to the
symptoms of BPH. During treatment,
finasteride reduces serum concentrations
of DHT by ~70%, while average circulating
testosterone levels increase
from 10% to 20% (yet remain within
physiologic parameters).
Finasteride is indicated for the
improvement of symptoms associated
with BPH, to reduce the risk for acute urinary
retention, and to diminish the
potential need for prostatectomy or
transurethral resection of the prostate.
Dosing
The dose for finasteride is 5 mg daily,
with DHT suppression noted within 8
hours after the first dose. The product
may be taken as a single-drug treatment
for BPH, but it can work synergistically
with the α-blocking agent doxazosin
(urethral tone being modulated by aadrenergic
receptors).
Adverse Effects
Whereas finasteride can result in a
decrease in serum PSA of ~50%, this
effect will occur even in the presence of
prostate cancer. During treatment with
finasteride, therefore, it is important to
understand that the PSA values can be
artificially low and that subsequent elevations
should be inflated by a factor of
2, because this increase may be due to
the presence of a less-benign prostatic
condition. It also should be noted that
the use of finasteride has no significant
effect on the overall incidence of
prostate cancer, nor does its use provide
any clinical benefit in the treatment of
prostate cancer.
During the first year of treatment with
finasteride, sexual dysfunction (impotence
and decrease in libido) appears to
occur more often than in placebo groups
used in comparative studies. It is interesting
to note, however, that after the
first year the active and the placebo
groups describe the same frequency
of dysfunction.
Pregnant or potentially pregnant
women should not handle broken or
crushed finasteride tablets because of
the potential for transdermal drug
absorption and the probability of risk to a
developing male fetus.
Outlook
The goal in treating BPH is to reduce
urinary symptoms, prevent the progression
of the condition, and improve the
quality of life despite recommended
lifestyle restrictions—cutting back on
fluid intake after 7 pm and limiting the
overall use of salt, spices, caffeine,
chocolate, and alcohol.
Finasteride is available in 5-mg tablets
from Teva Pharmaceuticals.
Meloxicam Tablets
The well-publicized shortcomings of
cyclooxygenase-2 (COX-2) inhibitors
have prompted clinicians to seek alternatives
for providing pain relief to patients
suffering from osteoarthritis or other inflammatory
conditions. Meloxicam actually
is classified as a COX-2 inhibitor in
other countries. In the United States,
however, it remains in the category of
nonsteroidal anti-inflammatory drugs
(NSAIDs), with its COX-2 inhibition being
considered more "preferential" than
"selective," when compared with conventional
agents such as ibuprofen.
Meloxicam has analgesic, antipyretic,
and anti-inflammatory properties. It provides
only symptomatic relief for
osteoarthritis and, like other NSAIDs,
does not reverse the destruction of joint
tissues as the disease progresses.
Dosing
Meloxicam has a one-time daily dose
of 7.5 to 15 mg, taken with or without
food or milk. Doses above 15 mg have not
been shown to have added benefit for
pain relief. Children with juvenile rheumatoid
arthritis are dosed by weight at 0.125
mg/kg, to a daily maximum of 7.5 mg.
Adverse Effects
The addition of a blackbox
warning from the
FDA may have dampened
some of the enthusiasm
for meloxicam as a COX-2
alternative. The warning
states that "NSAIDs may
cause an increased risk of serious cardiovascular
thrombotic events, myocardial
infarction, and stroke, which can be fatal.
This risk may increase with duration of
use. Patients with cardiovascular disease
(CVD) or risk factors for CVD may be at
greater risk." The risk for heart attacks
from meloxicam, in fact, has been reported
as higher than that of the discontinued
COX-2 inhibitor rofecoxib (Vioxx).
Meloxicam also can result in hypertension
or a worsening of hypertensive
symptoms. It should be used with caution
in patients with preexisting gastric ulcers
or a history of gastric bleeding. It may
contribute to renal dysfunction with prolonged
use. The potential for increased
gastrointestinal (GI) bleeding requires
additional monitoring if the patient also is
being treated with warfarin.
Patients should be educated on and
advised to report signs of CV reactions
(angina, dyspnea), GI bleeding, or hepatotoxicity
(fatigue, jaundice, lethargy).
Because of these potential adverse
effects, the lowest possible effective
dose and the shortest possible duration
of therapy to achieve treatment goals
should be employed in using meloxicam.
Outlook
The resurgence of interest in meloxicam
as a COX-2 "selective" inhibitor alternative,
along with the substantial cost savings
from its generic form, may increase
the popularity of this particular NSAID.
Meloxicam is available as 7.5-and 15-
mg tablets from companies including
Teva Pharmaceuticals, Mylan Pharmaceuticals,
and Caraco Pharmaceuticals.
Metronidazole Vaginal Gel
0.75%
Clinical Update
Bacterial vaginosis is a noninflammatory
condition in which the normal vaginal
flora (ie, Lactobacillus) is
replaced by a synergistic
mixture of Gardnerella vaginalis,
various anaerobic bacteria,
and Mycoplasma
hominis. Up to 40% of
women affected are asymptomatic.
Thus the absence or
presence of a vaginal discharge is an
unreliable indicator of infection.
Symptomatic bacterial vaginosis (amineodor
discharge) should be treated,
regardless of pregnancy status.
Metronidazole is a bactericidal treatment
commonly employed to treat bacterial
vaginosis. Five-day intravaginal
therapy results in cure rates comparable
with those of 7-day oral regimens.
Dosing
Intravaginal use of metronidazole
employs a 0.75% concentration of the
drug, in gel form. Commercial preparations
include a vaginal applicator, which
dispenses approximately 37.5 mg of
metronidazole with each 5 g of gel. For
once-daily dosing, intravaginal administration
should be done at bedtime for 5
consecutive days'. The drug also may be
administered twice daily (morning and
evening), also over 5 consecutive days.
Precautions and Adverse Effects
The most common adverse effects
include vaginal discharge and localized
irritation. Undiagnosed vaginal Candida
infections may become prominently
symptomatic during treatment with the
product. This effect occurs in 6% to 10%
of patients. Abdominal or pelvic discomfort
also is possible, and darkened urine
is a rare occurrence. Dizziness and
headache have been reported 2% to 5%
of the time. Leukopenia has been reported
in less than 2% of patients.
Patients suffering from severe hepatic
disease will have a slower rate of
metronidazole metabolism, causing drug
and metabolite accumulation. Although it
is generally well-tolerated otherwise, the
manufacturers recommend cautious use
of metronidazole vaginal gel in the presence
of hepatic impairment.
If the vaginal infection is caused by
Trichomonas vaginalis, intravaginal treatment
is less than half as effective as oral
treatment. The reason is that vaginal
applications produce subtherapeutic
serum concentrations, and systemic
effectiveness is necessary to control
Trichomoniasis. Whereas combination
therapy with oral metronidazole often is
employed in refractory cases, evidence is
lacking to demonstrate that concurrent
oral and vaginal administration is more
effective than oral therapy alone.
Women should be instructed not to
engage in vaginal intercourse or to use
douches during the entire course of therapy,
because these activities reduce the
effectiveness of the metronidazole gel.
Although systemic absorption is slight
with the use of the vaginal preparation,
the concurrent use of oral anticoagulants
may still be affected. Similarly, whereas a
disulfiram-like interaction would seem
unlikely with the vaginal preparation of
metronidazole, there has been at least
one case of such a reaction following
ingestion of alcohol during treatment.
Outlook
Bacterial vaginosis is the most common
form of infectious vaginitis, although
it may often be asymptomatic. Among
pregnant women, it has a prevalence rate
of 12% to 50%, and it has been identified
as a potential risk factor for premature
delivery. Thus treatment of symptomatic
cases is essential.
The bactericidal agent metronidazole is
effective as an oral and intravaginal treatment
for bacterial vaginosis. The intravaginal
route offers a more rapid recovery
with a lower likelihood of systemic
adverse effects.
Metronidazole is available as an intravaginal
gel in concentrations of 0.75%
from Upsher-Smith Laboratories (Vandazole).
Mr. Middleton is an instructor of pharmacology
at Kellogg Community College in Battle Creek, Mich.
