Some time ago someone asked me to post some info on Clozapine. Here is some
info about it from the Medical Letter, the first part of which is an article
about the treatment of Parkinsons that mentions Clozapine. There is also a
lot more detailed info regarding adverse effects in the Physicians Drug
Reference, but it is longer, and the Medical Letter gives a good synopsis
(even if the info is a year or two old now).
 
DRUGS FOR PARKINSON'S DISEASE [35:894]
Vol. 35 (Issue 894) - April 16, 1993
 
Approaches to treatment of Parkinson's disease have changed in recent years.
Previously, the only goal was to treat symptoms with levodopa or other drugs.
A new approach is to try to slow progression of the disease.
 
LEVODOPA AND CARBIDOPA -- Parkinson's disease is associated with progressive
degeneration of dopamine-containing neurons in the substantia nigra. Dopamine
itself does not cross the blood-brain barrier and cannot be used to treat
Parkinson's disease. Levodopa, the immediate precursor of dopamine, is
decarboxylated to dopamine in brain and peripheral tissues. This reaction can
be blocked in peripheral tissues by combining levodopa with carbidopa, a
peripheral decarboxylase inhibitor. This combination, marketed as Sinemet, is
the most effective treatment available for symptomatic relief of Parkinson's
disease.
 
Limitations - Levodopa is most effective in the first two to five years of
treatment. Later, as the disease progresses, the benefit from each dose
becomes shorter (the "wearing off " effect), and still later some patients
develop sudden fluctuations between mobility and immobility (the "on-off "
effect). After about five years of levodopa therapy, 75% of patients have
either dose-related clinical fluctuations, dose-related dyskinesias (chorea,
dystonia), inadequate response, or toxicity at subtherapeutic dosage.
Peripheral adverse effects of levodopa include anorexia, nausea, vomiting,
and orthostatic hypotension. Vivid dreams, hallucinations, delusions, and
confusion may occur, especially in older patients. Sudden discontinuation of
levodopa for several days may cause not only a recrudescence of parkinsonian
symptoms, but also fever, rigidity, and confusion resembling a neuroleptic
malignant syndrome. Most experts recommend, therefore, tapering the drug over
three to four days if possible, rather than stopping it abruptly.
 
Dosage - The usual daily dosage range is 300 to 1000 mg of levodopa divided
into three or four doses; some patients may require up to 2000 mg. Relatively
complete inhibition of peripheral decarboxylase requires 75 to 100 mg/day of
carbidopa; some patients require larger doses to suppress nausea completely.
Supplemental carbidopa is available at no cost to the patient from the
manufacturer of Sinemet. Dietary amino acids can decrease the effectiveness
of levodopa by competing with the drug for absorption from the intestine and
for transport into the brain. The drug may be more effective, therefore, if
taken at least 30 minutes before eating.
 
In patients with advanced Parkinson's disease, Sinemet CR, a
controlled-release formulation (Medical Letter, 33:91, 1991), may increase
"on" time, but may also increase dyskinesias. Switching to Sinemet CR may be
difficult for some patients, and concurrent therapy with standard Sinemet may
be necessary during the transition. Some specialists use Sinemet CR instead
of standard Sinemet when levodopa is first introduced. New Parkinson's
patients may begin with one half tablet (25/100 mg) of Sinemet CR twice a
day, in the morning and six hours later in the early afternoon. Dosage can be
increased over a few days or weeks to 50/200 mg b.i.d.; some patients may
require higher doses. The scored tablets can be split in half, but should not
be chewed or crushed. Sinemet CR takes longer than Sinemet to reach high
plasma levels, and some patients require a small amount of standard Sinemet
with each dose, particularly with the first dose of the day.
 
SELEGILINE (Eldepryl) -- The newest drug to become widely used used for
treatment of Parkinson's disease is selegiline, an inhibitor of monoamine
oxidase type B (MAO-B) also known as deprenyl (Medical Letter, 31:81, 1989).
Most monoamine oxidases found in the brain are type B; most found in the
gastrointestinal tract are type A. Three randomized placebo-controlled trials
in patients with early Parkinson's disease have found that treatment with
selegiline postponed the need for levodopa for six to nine months (JW Tetrud
and JW Langston, Science, 245:519, 1989; VV Myllyla et al, Neurology, 42:339,
1992; Parkinson Study Group, N Engl J Med, 328:176, Jan 21, 1993). Whether
this effect occurred only because selegiline decreased symptoms, or whether
it was due at least partly to slowing the progression of Parkinson's disease
remains to be established (CW Olanow and D Calne, Neurology, 42 suppl 4:13,
1992). Some clinicians now begin treatment with selegiline as soon as the
diagnosis of Parkinson's disease has been made, reserving levodopa until
symptoms become disabling. The usual dosage of selegiline is 5 mg with
breakfast and at lunch; to decrease the possibility of insomnia, the drug
should not be taken later in the day.
 
The cost of one month's treatment with Eldepryl, 5 mg b.i.d., is $123.26,
according to Drugs Topics Red Book April 1993 Update. Nausea and orthostatic
hypotension may occur. Selegiline in recommended doses, unlike MAO-A
inhibitors used for treatment of depression, does not cause hypertension
after ingestion of tyramine-rich foods or with concomitant levodopa therapy.
The drug has, however, caused toxic interactions with fluoxetine (Prozac) and
meperidine (Demerol, and others) (O Suchowersky and JD deVries, Can J
Psychiatry, 35:571, 1990; GL Zornberg et al, Lancet, 337:246, 1991; JL
Montastruc et al, Lancet, 341:555, Feb 27, 1993); both fluoxetine and
meperidine have been associated with fatal reactions when taken with MAO-A
inhibitors.
 
Since selegiline inhibits catabolism of dopamine in the brain, it can also be
given to patients whose response to levodopa is deteriorating. To avoid
increasing the toxicity of levodopa, selegiline should first be added in a
dosage of 2.5 mg once daily, increasing gradually to a a maximum of 5 mg
twice a day. It may be necessary to decrease the dosage of levodopa if
dyskinesias or other signs of excess dopaminergic stimulation appear.
 
VITAMIN E -- A multicenter controlled trial found that vitamin E
(tocopherol), which has been used in the hope that its antioxidant effect
would delay progression of Parkinson's disease, was not effective (Parkinson
Study Group, N Engl J Med, 378:176, Jan 21, 1993).
 
DOPAMINE AGONISTS -- Two ergot-derivative dopamine agonists, bromocriptine
(Parlodel) and pergolide (Permax - Medical Letter, 31:81, 1989), are
currently marketed in the USA mainly for adjunctive (with levodopa) treatment
of Parkinson's disease; lisuride is available in some other countries. These
drugs have less antiparkinson effect than levodopa used alone, but they are
less likely to cause dyskinesias and have a longer duration of action. A
double-blind trial in 22 patients never before treated with dopaminergic
drugs found that starting patients on bromocriptine and levodopa together was
no more effective than levodopa alone (WJ Weiner et al, Neurology, 43:21, Jan
1993).
 
Dopamine agonists can cause postural hypotension, which may limit their use.
Medical Letter consultants recommend starting with 1.25 mg of bromocriptine
daily for the first three days, then increasing slowly to 15 to 30 mg per
day, divided b.i.d. with meals. The recommended dosage of pergolide is 0.05
mg per day for the first three days, then increasing slowly to 1.5 to 3 mg
per day, divided t.i.d. Dopamine agonists can potentiate dyskinesias or toxic
psychosis caused by levodopa. As the dose of the dopamine agonist increases,
levodopa dosage may have to be decreased to avoid such effects. Even when
used alone, the dopamine agonists can cause confusion and psychosis.
 
Peripheral dopaminergic effects, such as cardiac arrhythmias and nausea, can
also occur; these can be blocked by the dopamine antagonist domperidone
(Motilium), which is available in Canada but not the USA. Ergot-related
adverse effects such as erythema, edema, pain, and digital spasms in the
extremities occur rarely. Retroperitoneal fibrosis has also rarely been
associated with use of these drugs.
 
ANTICHOLINERGICS -- In Parkinson's disease, the decreased activity of
dopamine makes the excitatory effects of acetylcholine more prominent. Before
levodopa, anticholinergic agents were the only drugs available to treat
Parkinson's disease, and they are still useful in some patients, especially
for treatment of tremor and drooling. Although not as effective as levodopa
or dopamine agonists, they may have an additive therapeutic effect at any
stage of the disease. Adverse effects of anticholinergic drugs include dry
mouth, constipation, urinary retention, aggravation of glaucoma, impaired
memory, confusion, and hallucinations; these may be more prominent in elderly
patients. Anticholinergics available in the USA include trihexyphenidyl
(Artane; and others), benztropine (Cogentin, and others), procyclidine
(Kemadrin), and biperiden (Akineton). Antihistamines such as diphenhydramine
(Benadryl, and others) also have anticholinergic effects and are occasionally
useful for patients who cannot tolerate the more potent anticholinergics.
Abrupt discontinuation of any of these drugs can cause severe exacerbation of
symptoms.
 
AMANTADINE -- Amantadine (Symmetrel, and others), mainly an antiviral drug,
in parkinsonism may increase release of dopamine in the brain. In a dosage of
100 mg b.i.d. or t.i.d., it has been used alone to treat early Parkinson's
disease, or as an adjunct in later stages. Some patients may not respond to
amantadine, but the drug should be taken for about two weeks before assuming
it is ineffective. Confusion and hallucinations, ankle edema, and livedo
reticularis can occur. Amantadine is not metabolized, but is excreted in
urine; dosage must be decreased for patients with renal dysfunction.
Amantadine and anticholinergics may have additive adverse effects on mental
function. As with anticholinergics, sudden withdrawal of amantadine can cause
severe exacerbation of parkinsonism symptoms.
 
ANTIDEPRESSANTS -- Depression commonly accompanies Parkinson's disease and
must be treated, if present, for the patient to benefit adequately from
antiparkinson drugs. A tricyclic antidepressant or trazodone (Desyrel) is
usually the drug of choice. Experience with fluoxetine (Prozac), other
selective serotonin reuptake inhibitors, or bupropion (Wellbutrin) is more
limited; worsening of Parkinson's symptoms has been reported with fluoxetine
(EN Steur, Neurology, 43:211, Jan 1993). MAO-A inhibitors should not be used
because they can cause marked swings in blood pressure in patients taking
levodopa.
 
CLOZAPINE -- Several reports indicate that psychosis associated with levodopa
or dopamine agonists responds to low doses of clozapine (Clozaril - Medical
Letter, 35:16, 1993), an antipsychotic drug with hematological toxicity but
few extrapyramidal effects (SI Wolk and CJ Douglas, J Clin Psychiatry,
53:373, 1992).
 
FETAL-TISSUE TRANSPLANTS -- The results of several recently published studies
indicate that transplantation of dopaminergic cells from human fetal brain
tissue may decrease the severity of Parkinson's disease and increase the
effectiveness of levodopa (S Fahn, N Engl J Med, 327:1589, Nov 26, 1992).
 
CONCLUSION -- Levodopa combined with carbidopa is still the most effective
symptomatic treatment for Parkinson's disease. Some clinicians believe it
should be started early in the disease when it is most effective; others wait
until symptoms become more severe. Many neurologists now attempt to slow the
progression of disability by prescribing selegiline as soon as the diagnosis
of Parkinson's disease has been established. Prior use of selegiline may
delay the need for levodopa, and concurrent use may permit use of lower
levodopa dosage. Dopamine agonists should be reserved for adjunctive use with
levodopa in the later stages of the disease.
 
 
CLOZAPINE FOR SCHIZOPHRENIA [32:809]
Vol. 32 (Issue 809) - January 12, 1990
 
Clozapine (Clozaril - Sandoz), a dibenzodiazepine antipsychotic drug that has
been available in Europe for many years, was recently approved for marketing
by the US Food and Drug Administration. Because of its toxicity, the labeling
for clozapine recommends using the drug only for schizophrenic patients who
have not responded adequately to standard antipsychotic drugs or have had
intolerable adverse effects.
 
ACTIVITY -- Like other antipsychotic drugs, clozapine is a dopamine-receptor
antagonist, but with some differences; unlike other antipsychotics, clozapine
causes only minimal elevation of serum prolactin concentrations and few
extrapyramidal effects. In addition to dopamine blockade, clozapine has
serotonergic, adrenergic, histaminergic (H1) and cholinergic blocking
activity (E Richelson, J Clin Psychiatry, 45:331, 1984).
 
PHARMACOKINETICS -- Clozapine is rapidly absorbed from the gastrointestinal
tract and reaches peak plasma concentrations in an average of 3.2 hours. It
is almost completely metabolized, and the metabolites are excreted in urine
and feces. The elimination half-life after multiple doses averages 12 hours,
but varies considerably.
 
ADVERSE EFFECTS -- The most serious adverse effect of clozapine is
agranulocytosis, which occurs in 1% to 2% of patients. Sixteen cases of
clozapine-induced agranulocytosis have been reported in the USA; all
recovered without sequelae within two to four weeks after the drug was
stopped. In earlier experience, however, more than one third of patients who
developed clozapine-related agranulocytosis died. Agranulocytosis has
generally occurred in the first six months of treatment, with the white blood
cell count usually decreasing gradually over a period of several weeks, but
sometimes falling precipitously within one week (JA Lieberman et al, J Clin
Psychiatry, 50:329, Sept 1989).
 
Seizures can also occur in patients taking clozapine; the risk appears to be
dose-related: 1% to 2% with less than 300 mg/day, 3% to 4% with 300 to 600
mg/day and 5% with 600 to 900 mg/day. Some patients who had seizures while
taking the drug have taken lower doses without recurrence, sometimes with the
addition of an anticonvulsant.
 
Other adverse effects of clozapine include sedation (which can be severe
during early treatment), tachycardia in about 25% of patients (which persists
in about 10%), sialorrhea, anticholinergic effects, transient hyperthermia,
and hypotension. Clozapine causes little or no sexual dysfunction, amenorrhea
or galactorrhea. It also has a low frequency of extrapyramidal effects and
apparently does not cause dystonic reactions or tardive dyskinesia. Some
patients with tardive dyskinesia have improved while taking the drug (JG
Small et al, J Clin Psychiatry, 48:263, 1987; JA Lieberman et al,
Psychopharmacol Bull, 25:57, 1989).
 
DOSAGE -- To minimize orthostatic hypotension, sedation and seizures,
clozapine treatment should begin with 25 mg once or twice daily, increasing
by 25 to 50 mg per day to 300-450 mg/day by the end of two weeks.
Subsequently, dosage should be increased no more often than once or twice
weekly, in increments of no more than 100 mg. Most patients respond to 300 to
600 mg/day in three divided doses, but some may require as much as the
maximum of 900 mg/day.
 
AVAILABILITY AND COST -- Because of concern about agranulocytosis, clozapine
is available only through the "Clozapine Patient Management System,"
administered by Caremark Homecare Corporation, which will send a health
worker to the patient each week to supply the tablets and take blood for
white cell counts. To obtain this service for outpatients, physicians have to
call a toll-free number (800-237-CPMS) or mail a patient enrollment form that
can be obtained from Sandoz representatives. Inpatients may have blood drawn
by local hospital personnel, and the drug may be delivered to the hospital
pharmacy. If the total white cell count falls below 3000/mm^3 or the
granulocyte count falls below 1500/mm^3, treatment will be interrupted. If
the total white cell count is less than 2000/mm^3 or granulocytes less than
1000/mm^3, the drug will be discontinued permanently.
 
The cost of the drug, the blood work, and the monitoring will be about $25
per patient per day, or about $9000 per year.
 
CONCLUSION -- Clozapine appears to be more effective than previously
available antipsychotic drugs for treatment of schizophrenia in patients who
have not responded to other agents or have had intolerable adverse effects.
The drug causes few extrapyramidal effects and may not cause tardive
dyskinesia, but it does cause agranulocytosis, which can be fatal.
 
UPDATE ON CLOZAPINE [35:890]
 
Vol. 35 (Issue 890) - February 19, 1993
 
Clozapine (Clozaril - Sandoz), an antipsychotic drug, was first marketed in
the USA three years ago (Medical Letter, 32:3, 1990). Because of its
hematological toxicity, the US Food and Drug Administration approved the drug
only for patients with schizophrenia who cannot tolerate or do not respond to
standard antipsychotic drugs.
 
ACTIVITY -- Clozapine differs from other antipsychotic drugs in its affinity
for various neurotransmitter receptors in the brain. It has the least
affinity of any antipsychotic drug for dopamine (D-2) receptors found in the
caudate nucleus, the highest affinity for muscarinic acetylcholine receptors
in the same area, and relatively little effect on gamma-aminobutyric acid
activity in the substantia nigra (E Richelson, J Clin Psychiatry, 46:8, 1985;
DM Coward et al, Psychopharmacology, 99:S6, 1989; HY Meltzer, Br J
Psychiatry, 160 suppl 17:22, 1992). Possibly as a result of this pattern of
activity, clozapine causes minimal elevation of serum prolactin
concentrations, has few extrapyramidal effects, and may not cause tardive
dyskinesia.
 
CLINICAL USE
Other Uses - The results of uncontrolled trials indicate that clozapine may
be useful in schizoaffective disorder and refractory bipolar disorder (RR
Owen, Jr et al, Psychopharmacol Bull, 25:253, 1989; SL McElroy et al, J Clin
Psychiatry, 52:411, 1991). Other reports indicate that low doses of clozapine
can be dramatically effective in levodopa-  or bromocriptine-induced
psychosis in patients with Parkinson's disease (EC Wolters et al, Clin
Neuropharmacol, 12:83, 1989; SI Wolk and CJ Douglas, J Clin Psychiatry,
53:373, Oct 1992).
 
AGRANULOCYTOSIS -- As of October 21, 1992, according to the manufacturer,
about 40,000 patients have taken the drug, and 171 developed agranulocytosis;
despite appropriate monitoring, seven of these patients died, mainly of
gram-negative septicemia. Most of the cases of agranulocytosis occurred
within the first six months of treatment. The mechanism of the drug's toxic
effect on granulocytes is unknown; both an immune reaction and a toxic
metabolite have been implicated (SL Gerson and H Meltzer, Drug Safety, 7
suppl 1:17, 1992; AV Pisciotta et al, Drug Safety, 7 suppl 1:33, 1992).
 
Monitoring - The manufacturer recommends that if the total white cell count
falls below 3000/mm3 or the granulocyte count falls below 1500/mm3 with
weekly monitoring, treatment should be interrupted, daily monitoring
instituted, and the drug resumed only if counts rise above these levels and
no infection is present. If the total white cell count is less than 2000/mm3
or the granulocyte count less than 1000/mm3, the drug should be discontinued
permanently. Rechallenge has been tried in a few patients who had developed
agranulocytosis; leukopenia or granulocytopenia recurred in all, with a more
rapid onset the second time (AZ Safferman et al, Lancet, 339:1296, 1992).
Some Medical Letter consultants suggest that the frequency of monitoring
could be curtailed over time, but guidelines are not available.
 
OTHER ADVERSE EFFECTS -- The most common adverse effects associated with
clozapine have been drowsiness or sedation (40%), sialorrhea (30%),
tachycardia (25%; persistent in 10%), dizziness (20%), and orthostatic
hypotension (9%). Weight gain and transient fever can occur. Generalized
tonic-clonic seizures occurred in about 3% of 1418 patients, with a higher
incidence in those taking 600 mg/day or more (O Devinsky et al, Neurology,
41:369, 1991). Myoclonic seizures can also occur (E Gouzoulis et al, Eur Arch
Psychiatry Clin Neurosci, 240:370, 1991). Acute pancreatitis has been
reported (JS Lamberti et al, Am J Psychiatry, 149:689, 1992; A Martin, Am J
Psychiatry, 149:714, 1992; FR Frankenburg and J Kando, Lancet, 340:251,
1992), and priapism has occurred in a few men taking clozapine (SI Rosen and
PM Hanno, J Urol, 148:876, Sept 1992; J Ziegler and D Behar, Am J Psychiatry,
149:272, 1992). Some patients who took clozapine after taking other
antipsychotic drugs have developed tardive dyskinesia.
 
INTERACTIONS -- Concurrent use of cimetidine (Tagamet) can increase serum
concentrations and adverse effects of clozapine (S Szymanski et al, J Clin
Psychiatry, 52:21, 1991). Central-nervous-system toxicity can occur with use
of lithium and clozapine (LM Blake et al, J Clin Psychopharmacol, 12:297, Aug
1992). Both the neuroleptic malignant syndrome and agranulocytosis with
pancytopenia have been reported when carbamazepine (Tegretol, and others) and
clozapine were taken together. Respiratory arrest has occurred with
concurrent use of benzodiazepines. Phenytoin (Dilantin, and others) can
decrease serum concentrations of clozapine and its effectiveness (Medical
Letter Handbook of Adverse Drug Interactions, 1993, page 90).
 
DOSAGE -- To minimize orthostatic hypotension, sedation, and seizures, the
manufacturer recommends starting clozapine treatment with a 12.5 mg dose
(although the smallest tablets available are 25 mg), followed by 25 mg once
or twice daily, and then increasing by 25 mg/day to 300 to 450 mg/day by the
end of two to three weeks. Subsequently, dosage should be increased no more
often than once or twice weekly, in increments of no more than 100 mg. If the
drug is stopped for any reason, treatment should start again at 12.5 mg/day.
Most patients respond to 300 to 600 mg/day in divided doses, but some may
benefit from higher doses, up to a maximum of 900 mg/day.
 
AVAILABILITY AND COST -- When originally marketed, clozapine was available
only with a monitoring arrangement controlled by the manufacturer at a cost
of about $9000 per year for both the drug and a weekly white blood cell count
(WBC). Currently, physicians and providers need only register with Sandoz to
assure that a system for weekly WBC monitoring is in place; no increase in
fatalities from agranulocytosis has been detected with the new approach. The
cost of the drug itself to the pharmacist is about $5,000 per year for a
dosage of 400 mg/day, according to Average Wholesale Price listings in Drug
Topics Red Book, February 1993 Update.
 
CONCLUSION -- Clozapine has continued to prove helpful to patients with
schizophrenia who have not responded to other drugs or have had intolerable
adverse effects. The risk of agranulocytosis appears to be low, but deaths
have occurred despite adequate monitoring. Whether clozapine is more
effective than other antipsychotic drugs remains to be established, but it
may not cause tardive dyskinesia and some Medical Letter consultants are
impressed with the quality of response in clozapine-treated patients.