CLOMIPRAMINE
DESCRIPTION:
Clofranil, clomipramine hydrochloride, is an antiobsessional drug that belongs
to the class (dibenzazepine) of pharmacologic agents known as tricyclic
antidepressants..
Clomipramine hydrochloride is 3-chloro- 5-(3-(dimethylamino)propyl)-10,11-
dihydro-5H- dibenz(b,f)azepine monohydrochloride.
Clomipramine hydrochloride is a white to off- white crystalline powder. It is
freely soluble in water, in methanol, and in methylene chloride, and insoluble
in ethyl ether and in hexane. Its molecular weight is 351.3.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACODYNAMICS
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors
through its effects on serotonergic neuronal transmission. The actual
neurochemical mechanism is unknown, but CMI's capacity to inhibit the reuptake
of serotonin (5-HT) is thought to be important.
PHARMACOKINETICS
ABSORPTION/BIOAVAILABILITY: CMI from Clofranil capsules is as bioavailable as
CMI from a solution. The bioavailability of CMI from capsules is not
significantly affected by food.
In a dose proportionality study involving multiple CMI doses, steady-state
plasma concentrations (CSS) and area-under-plasma- concentration-time curves
(AUC) of CMI and CMI's major active metabolite, desmethylclomipramine (DMI),
were not proportional to dose over the ranges evaluated, i.e., between 25-100
mg/day and between 25-150 mg/ day, although CSS and AUC are approximately
linearly related to dose between 100-150 mg/day. The relationship between dose
and CMI/DMI concentrations at higher daily doses has not been systematically
assessed, but if there is significant dose dependency at doses above 150 mg/day,
there is the potential for dramatically higher CSS and AUC even for patients
dosed within the recommended range. This may pose a potential risk to some
patients (see WARNINGS and PRECAUTIONS, Drug Interactions).
After a single 50-mg oral dose, maximum plasma concentrations of CMI occur
within 2-6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92
ng/mL). After multiple daily doses of 150 mg of Clofranil, steady-state maximum
plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI
and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. No pharmacokinetic
information is available for doses ranging from 150 mg/day to 250 mg/day, the
maximum recommended daily dose.
DISTRIBUTION: CMI distributes into cerebrospinal fluid (CSF) and brain and into
breast milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6.
The protein binding of CMI is approximately 97%, principally to albumin, and is
independent of CMI concentration. The interaction between CMI and other highly
protein-bound drugs has not been fully evaluated, but may be important (see
PRECAUTIONS, Drug Interactions).
METABOLISM: CMI is extensively biotransformed to DMI and other metabolites and
their glucuronide conjugates. DMI is pharmacologically active, but its effects
on OCD behaviors are unknown. These metabolites are excreted in urine and feces,
following biliary elimination. After a 25-mg radiolabeled dose of CMI in two
subjects, 60% and 51%, respectively, of the dose were recovered in the urine and
32% and 24%, respectively, in feces. In the same study, the combined urinary
recoveries of CMI and DMI were only about 0.8-1.3% of the dose administered. CMI
does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.
ELIMINATION: Evidence that the CSS and AUC for CMI and DMI may increase
disproportionately with increasing oral doses suggests that the metabolism of
CMI and DMI may be capacity limited. This fact must be considered in assessing
the estimates of the pharmacokinetic parameters presented below, as these were
obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of
CMI and DMI are nonlinear at doses above 150 mg, their elimination half-lives
may be considerably lengthened at doses near the upper end of the recommended
dosing range (i.e., 200 mg/day to 250mg/day). Consequently, CMI and DMI may
accumulate, and this accumulation may increase the incidence of any dose- or
plasma- concentration-dependent adverse reactions, in particular seizures (see
WARNINGS).
After a 150-mg dose, the half-life of CMI ranges from 19 hours to 37 hours
(mean, 32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr).
Steady-state levels after multiple dosing are typically reached within 7-14 days
for CMI. Plasma concentrations of the metabolite exceed the parent drug on
multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor
for CMI is approximately 2.5 and for DMI is 4.6. Importantly, it may take two
weeks or longer to achieve this extent of accumulation at constant dosing
because of the relatively long elimination half-lives of CMI and DMI (see DOSAGE
AND ADMINISTRATION). The effects of hepatic and renal impairment on the
disposition of Clofranil have not been determined.
INTERACTIONS: Co-administration of haloperidol with CMI increases plasma
concentrations of CMI. Coadministration of CMI with phenobarbital increases
plasma concentrations of phenobarbital (see PRECAUTIONS, Drug Interactions).
Younger subjects (18-40 years of age) tolerated CMI better and had significantly
lower steady-state plasma concentrations, compared with subjects over 65 years
of age. Children under 15 years of age had significantly lower plasma
concentration/dose ratios, compared with adults. Plasma concentrations of CMI
were significantly lower in smokers than in nonsmokers.
INDICATIONS AND USAGE:
Clofranil is indicated for the treatment of obsessions and compulsions in
patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions
must cause marked distress, be time-consuming, or significantly interfere with
social or occupational functioning, in order to meet the DSM-III-R (circa 1989)
diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that
are ego- dystonic. Compulsions are repetitive, purposeful, and intentional
behaviors performed in response to an obsession or in a stereotyped fashion, and
are recognized by the person as excessive or unreasonable.
The effectiveness of Clofranil for the treatment of OCD was demonstrated in
multicenter, placebo- controlled, parallel-group studies, including two 10-week
studies in adults and one 8-week study in children and adolescents 10-17 years
of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean
baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging
from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global
Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI experienced a mean
reduction of approximately 10 on the YBOCS, representing an average improvement
on this scale of 35% to 42% among adults and 37% among children and adolescents.
CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients
on placebo showed no important clinical response on either scale. The maximum
dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all
children and adolescents.
The effectiveness of Clofranil for long-term use (i.e., for more than 10 weeks)
has not been systematically evaluated in placebo-controlled trials. The
physician who elects to use Clofranil for extended periods should periodically
reevaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS:
Clofranil is contraindicated in patients with a history of hypersensitivity to
Clofranil or other tricyclic antidepressants.
Clofranil should not be given in combination, or within 14 days before or after
treatment, with a monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis,
seizures, coma, and death have been reported in patients receiving such
combinations.
Clofranil is contraindicated during the acute recovery period after a myocardial
infarction.
WARNINGS:
SEIZURES
During premarket evaluation, seizure was identified as the most significant risk
of Clofranil use.
The observed cumulative incidence of seizures among patients exposed to
Clofranil at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and
1.45% at 365 days. The cumulative rates correct the crude rate of 0.7% (25 of
3519 patients) for the variable duration of exposure in clinical trials.
Although dose appears to be a predictor of seizure, there is a confounding of
dose and duration of exposure, making it difficult to assess independently the
effect of either factor alone. The ability to predict the occurrence of seizures
in subjects exposed to doses of CMI greater than 250 mg is limited, given that
the plasma concentration of CMI may be dose-dependent and may vary among
subjects given the same dose. Nevertheless, prescribers are advised to limit the
daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children
and adolescents (see DOSAGE AND ADMINISTRATION).
Caution should be used in administering Clofranil to patients with a history of
seizures or other predisposing factors, e.g., brain damage of varying etiology,
alcoholism, and concomitant use with other drugs that lower the seizure
threshold.
Rare reports of fatalities in association with seizures have been reported by
foreign postmarketing surveillance, but not in U.S. clinical trials. In some of
these cases, Clofranil had been administered with other epileptogenic agents; in
others, the patients involved had possibly predisposing medical conditions. Thus
a causal association between Clofranil treatment and these fatalities has not
been established.
Physicians should discuss with patients the risk of taking Clofranil while
engaging in activities in which sudden loss of consciousness could result in
serious injury to the patient or others, e.g., the operation of complex
machinery, driving, swimming, climbing.
PRECAUTIONS:
GENERAL
SUICIDE: Since depression is a commonly associated feature of OCD, the risk of
suicide must be considered. Prescriptions for Clofranil should be written for
the smallest quantity of capsules consistent with good patient management, in
order to reduce the risk of overdose.
CARDIOVASCULAR EFFECTS: Modest orthostatic decreases in blood pressure and
modest tachycardia were each seen in approximately 20% of patients taking
Clofranil in clinical trials; but patients were frequently asymptomatic. Among
approximately 1400 patients treated with CMI in the premarketing experience who
had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of
patients receiving active control drugs and 0.7% of patients receiving placebo.
The most common ECG changes were PVCs, ST-T wave changes, and intraventricular
conduction abnormalities. These changes were rarely associated with significant
clinical symptoms. Nevertheless, caution is necessary in treating patients with
known cardiovascular disease, and gradual dose titration is recommended.
PSYCHOSIS, CONFUSION, AND OTHER NEUROPSYCHIATRIC PHENOMENA: Patients treated
with Clofranil have been reported to show a variety of neuropsychiatric signs
and symptoms including delusions, hallucinations, psychotic episodes, confusion,
and paranoia. Because of the uncontrolled nature of many of the studies, it is
impossible to provide a precise estimate of the extent of risk imposed by
treatment with Clofranil. As with tricyclic antidepressants to which it is
closely related, Clofranil may precipitate an acute psychotic episode in
patients with unrecognized schizophrenia.
MANIA/HYPOMANIA: During premarketing testing of Clofranil in patients with
affective disorder, hypomania or mania was precipitated in several patients.
Activation of mania or hypomania has also been reported in a small proportion of
patients with affective disorder treated with marketed tricyclic
antidepressants, which are closely related to Clofranil.
HEPATIC CHANGES: During premarketing testing, Clofranil was occasionally
associated with elevations in SGOT and SGPT (pooled incidence of approximately
1% and 3%, respectively) of potential clinical importance (i.e., values greater
than 3 times the upper limit of normal). In the vast majority of instances,
these enzyme increases were not associated with other clinical findings
suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of
more severe liver injury, some fatal, have been recorded in foreign
postmarketing experience. Caution is indicated in treating patients with known
liver disease, and periodic monitoring of hepatic enzyme levels is recommended
in such patients.
HEMATOLOGIC CHANGES: Although no instances of severe hematologic toxicity were
seen in the premarketing experience with Clofranil, there have been
postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia,
and pancytopenia in association with Clofranil use. As is the case with
tricyclic antidepressants to which Clofranil is closely related, leukocyte and
differential blood counts should be obtained in patients who develop fever and
sore throat during treatment with Clofranil.
CENTRAL NERVOUS SYSTEM: More than 30 cases of hyperthermia have been recorded by
nondomestic postmarketing surveillance systems. Most cases occurred when
Clofranil was used in combination with other drugs. When Clofranil and a
neuroleptic were used concomitantly, the cases were sometimes considered to be
examples of a neuroleptic malignant syndrome.
SEXUAL DYSFUNCTION: The rate of sexual dysfunction in male patients with OCD who
were treated with Clofranil in the premarketing experience was markedly
increased compared with placebo controls (i.e., 42% experienced ejaculatory
failure and 20% experienced impotence, compared with 2.0% and 2.6%,
respectively, in the placebo group). Approximately 85% of males with sexual
dysfunction chose to continue treatment.
WEIGHT CHANGES: In controlled studies of OCD, weight gain was reported in 18% of
patients receiving Clofranil, compared with 1% of patients receiving placebo. In
these studies, 28% of patients receiving Clofranil had a weight gain of at least
7% of their initial body weight, compared with 4% of patients receiving placebo.
Several patients had weight gains in excess of 25% of their initial body weight.
Conversely, 5% of patients receiving Clofranil and 1% receiving placebo had
weight losses of at least 7% of their initial body weight.
ELECTROCONVULSIVE THERAPY: As with closely related tricyclic antidepressants,
concurrent administration of Clofranil with electroconvulsive therapy may
increase the risks; such treatment should be limited to those patients for whom
it is essential, since there is limited clinical experience.
SURGERY: Prior to elective surgery with general anesthetics, therapy with
Clofranil should be discontinued for as long as is clinically feasible, and the
anesthetist should be advised.
USE IN CONCOMITANT ILLNESS: As with closely related tricyclic antidepressants,
Clofranil should be used with caution in the following:
(1) Hyperthyroid patients or patients receiving thyroid medication, because of
the possibility of cardiac toxicity;
(2) Patients with increased intraocular pressure, a history of narrow-angle
glaucoma, or urinary retention, because of the anticholinergic properties of the
drug;
(3) Patients with tumors of the adrenal medulla (e.g., pheochromocytoma,
neuroblastoma) in whom the drug may provoke hypertensive crises;
(4) Patients with significantly impaired renal function.
WITHDRAWAL SYMPTOMS: A variety of withdrawal symptoms have been reported in
association with abrupt discontinuation of Clofranil, including dizziness,
nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and
irritability. In addition, such patients may experience a worsening of
psychiatric status. While the withdrawal effects of Clofranil have not been
systematically evaluated in controlled trials, they are well known with closely
related tricyclic antidepressants, and it is recommended that the dosage be
tapered gradually and the patient monitored carefully during discontinuation
(see DRUG ABUSE AND DEPENDENCE).
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with patients for whom
they prescribe Clofranil:
(1) The risk of seizure (see WARNINGS);
(2) The relatively high incidence of sexual dysfunction among males (see Sexual
Dysfunction);
(3) Since Clofranil may impair the mental and/or physical abilities required for
the performance of complex tasks, and since Clofranil is associated with a risk
of seizures, patients should be cautioned about the performance of complex and
hazardous tasks (see WARNINGS);
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS
depressants concurrently, since Clofranil may exaggerate their response to these
drugs;
(5) Patients should notify their physician if they become pregnant or intend to
become pregnant during therapy;
(6) Patients should notify their physician if they are breast-feeding.
DRUG INTERACTIONS
The risks of using Clofranil in combination with other drugs have not been
systematically evaluated. Given the primary CNS effects of Clofranil, caution is
advised in using it concomitantly with other CNS-active drugs (see Information
for Patients). Clofranil should Not be used with MAO inhibitors (see
CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Clofranil
is administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic
effects of guanethidine, clonidine, or similar agents, and such an effect may be
anticipated with CMI because of its structural similarity to other tricyclic
antidepressants.
The plasma concentration of CMI has been reported to be increased by the
concomitant administration of haloperidol; plasma levels of several closely
related tricyclic antidepressants have been reported to be increased by the
concomitant administration of methylphenidate or hepatic enzyme inhibitors
(e.g., cimetidine, fluoxetine) and decreased by the concomitant administration
of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect
may be anticipated with CMI as well. Administration of CMI has been reported to
increase the plasma levels of phenobarbital, if given concomitantly (see
ACTIONS/CLINICAL PHARMACOLOGY, Interactions).
DRUGS METABOLIZED BY P450 2D6: The biochemical activity of the drug
metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in
a subset of the Caucasian population (about 7%-10% of Caucasians are so-called
"poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6
isozyme activity among Asian, African and other populations are not yet
available. Poor metabolizers have higher than expected plasma concentrations of
tricyclic antidepressants (TCAs) when given usual doses. Depending on the
fraction of drug metabolized by P450 2D6, the increase in plasma concentration
may be small, or quite large (8 fold increase in plasma AUC of the TCA). In
addition, certain drugs inhibit the activity of this isozyme and make normal
metabolizers resemble poor metabolizers. An individual who is stable on a given
dose of TCA may become abruptly toxic when given one of these inhibiting drugs
as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some
that are not metabolized by the enzyme (quinidine; cimetidine) and many that are
substrates for P450 2D6 (many other antidepressants, phenothiazines, and the
Type 1C antiarrhythmics propafenone and flecainide). While all the selective
serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and
paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The
extent to which SSRI-TCA interactions may pose clinical problems will depend on
the degree of inhibition and the pharmacokinetics of the SSRI involved.
Nevertheless, caution is indicated in the co-administration of TCAs with any of
the SSRIs and also in switching from one class to the other. Of particular
importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent
and active metabolite (at least 5 weeks may be necessary). Concomitant use of
tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may
require lower doses than usually prescribed for either the tricyclic
antidepressant or the other drug. Furthermore, whenever one of these drugs is
withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going
to be co-administered with another drug known to be an inhibitor of P450 2D6.
Because Clofranil is highly bound to serum protein, the administration of
Clofranil to patients taking other drugs that are highly bound to protein (e.g.,
warfarin, digoxin) may cause an increase in plasma concentrations of these
drugs, potentially resulting in adverse effects. Conversely, adverse effects may
result from displacement of protein-bound Clofranil by other highly bound drugs
(see ACTIONS/CLINICAL PHARMACOLOGY, Distribution).
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
In a 2-year bioassay, no clear evidence of carcinogenicity was found in rats
given doses 20 times the maximum daily human dose. Three out of 235 treated rats
had a rare tumor (hemangioendothelioma); it is unknown if these neoplasms are
compound related.
In reproduction studies, no effects on fertility were found in rats given doses
approximately 5 times the maximum daily human dose.
PREGNANCY CATEGORY C
No teratogenic effects were observed in studies performed in rats and mice at
doses up to 20 times the maximum daily human dose. Slight nonspecific fetotoxic
effects were seen in the offspring of pregnant mice given doses 10 times the
maximum daily human dose. Slight nonspecific embryotoxicity was observed in rats
given doses 5-10 times the maximum daily human dose.
There are no adequate or well-controlled studies in pregnant women. Withdrawal
symptoms, including jitteriness, tremor, and seizures, have been reported in
neonates whose mothers had taken Clofranil until delivery. Clofranil should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
NURSING MOTHERS
Clofranil has been found in human milk. Because of the potential for adverse
reactions, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
PEDIATRIC USE
In a controlled clinical trial in children and adolescents (10-17 years of age),
46 outpatients received Clofranil for up to 8 weeks. In addition, 150 adolescent
patients have received Clofranil in open-label protocols for periods of several
months to several years. Of the 196 adolescents studied, 50 were 13 years of age
or less and 146 were 14-17 years of age. While the adverse reaction profile in
this age group (see ADVERSE REACTIONS) is similar to that in adults, it is
unknown what, if any, effects long-term treatment with Clofranil may have on the
growth and development of children.
The safety and effectiveness in pediatric patients below the age of 10 have not
been established. Therefore, specific recommendations cannot be made for the use
of Clofranil in pediatric patients under the age of 10.
USE IN ELDERLY
Clofranil has not been systematically studied in older patients; but 152
patients at least 60 years of age participating in U.S. clinical trials received
Clofranil for periods of several months to several years. No unusual age-related
adverse events have been identified in this elderly population, but these data
are insufficient to rule out possible age-related differences, particularly in
elderly patients who have concomitant systemic illnesses or who are receiving
other drugs concomitantly.
DRUG INTERACTIONS:
The risks of using Clofranil in combination with other drugs have not been
systematically evaluated. Given the primary CNS effects of Clofranil, caution is
advised in using it concomitantly with other CNS-active drugs (see Information
for Patients). Clofranil should Not be used with MAO inhibitors (see
CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Clofranil
is administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic
effects of guanethidine, clonidine, or similar agents, and such an effect may be
anticipated with CMI because of its structural similarity to other tricyclic
antidepressants.
The plasma concentration of CMI has been reported to be increased by the
concomitant administration of haloperidol; plasma levels of several closely
related tricyclic antidepressants have been reported to be increased by the
concomitant administration of methylphenidate or hepatic enzyme inhibitors
(e.g., cimetidine, fluoxetine) and decreased by the concomitant administration
of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect
may be anticipated with CMI as well. Administration of CMI has been reported to
increase the plasma levels of phenobarbital, if given concomitantly (see
ACTIONS/CLINICAL PHARMACOLOGY, Interactions).
DRUGS METABOLIZED BY P450 2D6: The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of
the Caucasian population (about 7%-10% of Caucasians are so-called "poor
metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or
quite large (8 fold increase in plasma AUC of the TCA). In addition, certain
drugs inhibit the activity of this isozyme and make normal metabolizers resemble
poor metabolizers. An individual who is stable on a given dose of TCA may become
abruptly toxic when given one of these inhibiting drugs as concomitant therapy.
The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized
by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6
(many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics
propafenone and flecainide). While all the selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450
2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA
interactions may pose clinical problems will depend on the degree of inhibition
and the pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co-administration of TCAs with any of the SSRIs and also in
switching from one class to the other. Of particular importance, sufficient time
must elapse before initiating TCA treatment in a patient being withdrawn from
fluoxetine, given the long half-life of the parent and active metabolite (at
least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants
with drugs that can inhibit cytochrome P450 2D6 may require lower doses than
usually prescribed for either the tricyclic antidepressant or the other drug.
Furthermore, whenever one of these drugs is withdrawn from co-therapy, an
increased dose of tricyclic antidepressant may be required. It is desirable to
monitor TCA plasma levels whenever a TCA is going to be co-administered with
another drug known to be an inhibitor of P450 2D6.
Because Clofranil is highly bound to serum protein, the administration of
Clofranil to patients taking other drugs that are highly bound to protein (e.g.,
warfarin, digoxin) may cause an increase in plasma concentrations of these
drugs, potentially resulting in adverse effects. Conversely, adverse effects may
result from displacement of protein-bound Clofranil by other highly bound drugs
(see ACTIONS/CLINICAL PHARMACOLOGY, Distribution).
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
COMMONLY OBSERVED
The most commonly observed adverse events associated with the use of Clofranil
and not seen at an equivalent incidence among placebo-treated patients were
gastrointestinal complaints, including dry mouth, constipation, nausea,
dyspepsia, and anorexia; nervous system complaints, including somnolence,
tremor, dizziness, nervousness, and myoclonus; genitourinary complaints,
including changed libido, ejaculatory failure, impotence, and micturition
disorder; and other miscellaneous complaints, including fatigue, sweating,
increased appetite, weight gain, and visual changes.
LEADING TO DISCONTINUATION OF TREATMENT
Approximately 20% of 3616 patients who received Clofranil in U.S. premarketing
clinical trials discontinued treatment because of an adverse event.
Approximately one-half of the patients who discontinued (9% of the total) had
multiple complaints, none of which could be classified as primary. Where a
primary reason for discontinuation could be identified, most patients
discontinued because of nervous system complaints (5.4%), primarily somnolence.
The second-most-frequent reason for discontinuation was digestive system
complaints (1.3%), primarily vomiting and nausea.
INCIDENCE IN CONTROLLED CLINICAL TRIALS
The following table enumerates adverse events that occurred at an incidence of
1% or greater among patients with OCD who received Clofranil in adult or
pediatric placebo-controlled clinical trials. The frequencies were obtained from
pooled data of clinical trials involving either adults receiving Clofranil
(N=322) or placebo (N=319) or children treated with Clofranil (N=46) or placebo
(N=44). The prescriber should be aware that these figures cannot be used to
predict the incidence of side effects in the course of usual medical practice,
in which patient characteristics and other factors differ from those that
prevailed in the clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving
different treatments, uses, and investigators. The cited figures, however,
provide the physician with a basis for estimating the relative contribution of
drug and nondrug factors to the incidence of side effects in the populations
studied.
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EXPERIENCE
IN PLACEBO-CONTROLLED CLINICAL TRIALS
(PERCENTAGE OF PATIENTS REPORTING EVENT)
ADULTS CHILDREN AND
ADOLESCENTS
---------------------- --------------------------------------------------
BODY SYSTEM/ CLOFRANIL PLACEBO CLOFRANIL PLACEBO
ADVERSE EVENT* (N=322) (N=319) (N=46) (N=44)
----------------------------------------------------------------------------
NERVOUS SYSTEM
Somnolence 54 16 46 11
Tremor 54 2 33 2
Dizziness 54 14 41 14
Headache 52 41 28 34
Insomnia 25 15 11 7
Libido change 21 3 -- --
Nervousness 18 2 4 2
Myoclonus 13 -- 2 --
Increased appetite 11 2 -- 2
Paresthesia 9 3 2 2
Memory impairment 9 1 7 2
Anxiety 9 4 2 --
Twitching 7 1 4 5
Impaired concentration 5 2 -- --
Depression 5 1 -- --
Hypertonia 4 1 2 --
Sleep disorder 4 -- 9 5
Psychosomatic disorder 3 -- -- --
Yawning 3 -- -- --
Confusion 3 -- 2 --
Speech disorder 3 -- -- --
Abnormal dreaming 3 -- -- 2
Agitation 3 -- -- --
Migraine 3 -- -- --
Depersonalization 2 -- 2 --
Irritability 2 2 2 --
Emotional lability 2 -- -- 2
Panic reaction 1 -- 2 --
Aggressive reaction -- -- 2 --
Paresis -- -- 2 --
SKIN AND APPENDAGES
Increased sweating 29 3 9 --
Rash 8 1 4 2
Pruritis 6 -- 2 2
Dermatitis 2 -- -- 2
Acne 2 2 -- 5
Dry skin 2 -- -- 5
Urticaria 1 -- -- --
Abnormal skin odor -- -- 2 --
*Events reported by at least 1% of Clofranil patients are included.
CONTINUED
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EXPERIENCE
IN PLACEBO-CONTROLLED CLINICAL TRIALS
(PERCENTAGE OF PATIENTS REPORTING EVENT)
ADULTS CHILDREN AND
ADOLESCENTS
---------------------- -----------------------------------------------
BODY SYSTEM/ CLOFRANIL PLACEBO CLOFRANIL PLACEBO
ADVERSE EVENT* (N=322) (N=319) (N=46) (N=44)
-----------------------------------------------------------------------------------------------------------------------------------------
DIGESTIVE SYSTEM
Dry mouth 84 17 63 16
Constipation 47 11 22 9
Nausea 33 14 9 11
Dyspepsia 22 10 13 2
Diarrhea 13 9 7 5
Anorexia 12 -- 22 2
Abdominal pain 11 9 13 16
Vomiting 7 2 7 --
Flatulence 6 3 -- 2
Tooth disorder 5 -- -- --
Gastrointestinal disorder 2 -- -- 2
Dysphagia 2 -- -- --
Esophagitis 1 -- -- --
Eructation -- -- 2 2
Ulcerative stomatitis -- -- 2 --
BODY AS A WHOLE
Fatigue 39 18 35 9
Weight increase 18 1 2 --
Flushing 8 -- 7 --
Hot flushes 5 -- 2 --
Chest pain 4 4 7 --
Fever 4 -- 2 7
Allergy 3 3 7 5
Pain 3 2 4 2
Local edema 2 4 -- --
Chills 2 1 -- --
Weight decrease -- -- 7 --
Otitis media -- -- 4 5
Asthenia -- -- 2 --
Halitosis -- -- 2 --
CARDIOVASCULAR SYSTEM
Postural hypotension 6 -- 4 --
Palpitation 4 2 4 --
Tachycardia 4 -- 2 --
Syncope -- -- 2 --
RESPIRATORY SYSTEM
Pharyngitis 14 9 -- 5
Rhinitis 12 10 7 9
Sinusitis 6 4 2 5
Coughing 6 6 4 5
Bronchospasm 2 -- 7 2
Epistaxis 2 -- -- 2
Dyspnea -- -- 2 --
Laryngitis -- 1 2 --
*Events reported by at least 1% of Clofranil patients are included.
CONTINUED
INCIDENCE OF TREATMENT-EMERGENT ADVERSE EXPERIENCE
IN PLACEBO-CONTROLLED CLINICAL TRIALS
(PERCENTAGE OF PATIENTS REPORTING EVENT)
ADULTS CHILDREN AND
ADOLESCENTS
---------------------- ---------------------
BODY SYSTEM/ CLOFRANIL PLACEBO CLOFRANIL PLACEBO
ADVERSE EVENT* (N=322) (N=319) (N=46) (N=44)
-------------------------------------------------------------------------------------------------------------------------------------------------
UROGENITAL SYSTEM
MALE AND FEMALE PATIENTS COMBINED
Micturition disorder 14 2 4 2
Urinary tract infection 6 1 -- --
Micturition frequency 5 3 -- --
Urinary retention 2 -- 7 --
Dysuria 2 2 -- --
Cystitis 2 -- -- --
FEMALE PATIENTS ONLY (N=182) (N=167) (N=10) (N=21)
Dysmenorrhea 12 14 10 10
Lactation (nonpuerperal) 4 -- -- --
Menstrual disorder 4 2 -- --
Vaginitis 2 -- -- --
Leukorrhea 2 -- -- --
Breast enlargement 2 -- -- --
Breast pain 1 -- -- --
Amenorrhea 1 -- -- --
MALE PATIENTS ONLY (N=140) (N=152) (N=36) (N=23)
Ejaculation failure 42 2 6 --
Impotence 20 3 -- --
SPECIAL SENSES
Abnormal vision 18 4 7 2
Taste perversion 8 -- 4 --
Tinnitus 6 -- 4 --
Abnormal lacrimation 3 2 -- --
Mydriasis 2 -- -- --
Conjunctivitis 1 -- -- --
Anisocoria -- -- 2 --
Blepharospasm -- -- 2 --
Ocular allergy -- -- 2 --
Vestibular disorder -- -- 2 2
MUSCULOSKELETAL
Myalgia 13 9 -- --
Back pain 6 6 -- --
Arthralgia 3 5 -- --
Muscle weakness 1 -- 2 --
HEMIC AND LYMPHATIC
Purpura 3 -- -- --
Anemia -- -- 2 2
METABOLIC AND NUTRITIONAL
Thirst 2 2 -- 2
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Events reported by at least 1% of Clofranil patients are included.
OTHER EVENTS OBSERVED DURING THE PREMARKETING EVALUATION OF CLOFRANIL
During clinical testing in the U.S., multiple doses of Clofranil were
administered to approximately 3600 subjects. Untoward events associated with
this exposure were recorded by clinical investigators using terminology of their
own choosing. Consequently, it is not possible to provide a meaningful estimate
of the proportion of individuals experiencing adverse events without first
grouping similar types of untoward events into a smaller number of standardized
event categories.
In the tabulations that follow, a modified World Health Organization dictionary
of terminology has been used to classify reported adverse events. The
frequencies presented, therefore, represent the proportion of the 3525
individuals exposed to Clofranil who experienced an event of the type cited on
at least one occasion while receiving Clofranil. All events are included except
those already listed in the previous table, those reported in terms so general
as to be uninformative, and those in which an association with the drug was
remote. It is important to emphasize that although the events reported occurred
during treatment with Clofranil, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are
those occurring on one or more occasions in at least 1/100 patients; infrequent
adverse events are those occurring in 1/100 to 1/1000 patients; rare events are
those occurring in less than 1/1000 patients.
BODY AS A WHOLE: Infrequent--general edema, increased susceptibility to
infection, malaise. Rare--dependent edema, withdrawal syndrome.
CARDIOVASCULAR SYSTEM: Infrequent--abnormal ECG, arrhythmia, bradycardia,
cardiac arrest, extrasystoles, pallor. Rare--aneurysm, atrial flutter, bundle
branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial
infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis,
vasospasm, ventricular tachycardia.
DIGESTIVE SYSTEM: Infrequent--abnormal hepatic function, blood in stool,
colitis, duodenitis, gastric ulcer, gastritis, gastroesophageal reflux,
gingivitis, glossitis, hemorrhoids, hepatitis, increased saliva, irritable bowel
syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration, tooth caries.
Rare--cheilitis, chronic enteritis, discolored feces, gastric dilatation,
gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema,
paralytic ileus, salivary gland enlargement.
ENDOCRINE SYSTEM: Infrequent--hypothyroidism. Rare--goiter, gynecomastia,
hyperthyroidism.
HEMIC AND LYMPHATIC SYSTEM: Infrequent- -lymphadenopathy. Rare--leukemoid
reaction, lymphoma-like disorder, marrow depression.
METABOLIC AND NUTRITIONAL DISORDER: Infrequent- -dehydration, diabetes
mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia.
Rare--fat intolerance, glycosuria.
MUSCULOSKELETAL SYSTEM:Infrequent--arthrosis. Rare--dystonia, exostosis, lupus
erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa,
torticollis.
NERVOUS SYSTEM: Frequent--abnormal thinking, vertigo. Infrequent--abnormal
coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions,
delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria,
extrapyramidal disorder, hallucinations, hostility, hyperkinesia, hypnagogic
hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia, paranoia,
phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation,
suicidal ideation, suicide attempt, teeth-grinding. Rare--anticholinergic
syndrome, aphasia, apraxia, catalepsy, cholinergic syndrome, choreoathetosis,
generalized spasm, hemiparesis, hyperesthesia, hyperreflexia, hypoesthesia,
illusion, impaired impulse control, indecisiveness, mutism, neuropathy,
nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic
reaction, stupor, suicide.
RESPIRATORY SYSTEM: Infrequent--bronchitis, hyperventilation, increased sputum,
pneumonia. Rare--cyanosis, hemoptysis, hypoventilation, laryngismus.
SKIN AND APPENDAGES: Infrequent--alopecia, cellulitis, cyst, eczema,
erythematous rash, genital pruritus, maculopapular rash, photosensitivity
reaction, psoriasis, pustular rash, skin discoloration. Rare--chloasma,
folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin
ulceration.
SPECIAL SENSES: Infrequent--abnormal accommodation, deafness, diplopia, earache,
eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis,
taste loss. Rare--blepharitis, chromatopsia, conjunctival hemorrhage,
exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal
disorder, strabismus, visual field defect.
UROGENITAL SYSTEM: Infrequent--endometriosis, epididymitis, hematuria, nocturia,
oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal
calculus, renal pain, urethral disorder, urinary incontinence, uterine
hemorrhage, vaginal hemorrhage. Rare- -albuminuria, anorgasmy, breast
engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia,
premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation,
vulvar disorder.
DRUG ABUSE AND DEPENDENCE:
Clofranil has not been systematically studied in animals or humans for its
potential for abuse, tolerance, or physical dependence. While a variety of
withdrawal symptoms have been described in association with Clofranil
discontinuation (see PRECAUTIONS, Withdrawal Symptoms), there is no evidence for
drug-seeking behavior, except for a single report of potential Clofranil abuse
by a patient with a history of dependence on codeine, benzodiazepines, and
multiple psychoactive drugs. The patient received Clofranil for depression and
panic attacks and appeared to become dependent after hospital
discharge.
Despite the lack of evidence suggesting an abuse liability for Clofranil in
foreign marketing, it is not possible to predict the extent to which Clofranil
might be misused or abused once marketed in the U.S. Consequently, physicians
should carefully evaluate patients for a history of drug abuse and follow such
patients closely.
OVERDOSAGE:
Deaths may occur from overdosage with this class of drugs. Multiple drug
ingestion (including alcohol) is common in deliberate tricyclic overdose. As the
management is complex and changing, it is recommended that the physician contact
a poison control center for current information on treatment. Signs and symptoms
of toxicity develop rapidly after tricyclic overdose. Therefore, hospital
monitoring is required as soon as possible.
HUMAN EXPERIENCE
In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute
overdosage with Clofranil either alone or in combination with other drugs. One
death involved a patient suspected of ingesting a dose of 7000 mg. The second
death involved a patient suspected of ingesting a dose of 5750 mg. The 10
nonfatal cases involved doses of up to 5000 mg, accompanied by plasma levels of
up to 1010 ng/ml. All 10 patients completely recovered. Among reports from other
countries of Clofranil overdose, the lowest dose associated with a fatality was
750 mg. Based upon postmarketing reports in the United Kingdom, CMI's lethality
in overdose is considered to be similar to that reported for closely related
tricyclic compounds marketed as antidepressants.
MANIFESTATIONS
Signs and symptoms vary in severity depending upon factors such as the amount of
drug absorbed, the age of the patient, and the time elapsed since drug
ingestion. Critical manifestations of overdose include cardiac dysrhythmias,
severe hypotension, convulsions, and CNS depression including coma. Changes in
the electrocardiogram, particularly in QRS axis or width, are clinically
significant indicators of tricyclic toxicity. Other CNS manifestations may
include drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe
perspiration, hyperactive reflexes, muscle rigidity, and athetoid and choreiform
movements. Cardiac abnormalities may include tachycardia, signs of congestive
heart failure, and in very rare cases, cardiac arrest. Respiratory depression,
cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria may
also be present.
MANAGEMENT
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's
airway, establish an intravenous line, and initiate gastric decontamination. A
minimum of 6 hours of observation with cardiac monitoring and observation for
signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or
conduction blocks, and seizures is necessary. If signs of toxicity occur at any
time during this period, extended monitoring is required. There are case reports
of patients succumbing to fatal dysrhythmias late after overdose; these patients
had clinical evidence of significant poisoning prior to death and most received
inadequate gastrointestinal decontamination. Monitoring of plasma drug levels
should not guide management of the patient.
GASTROINTESTINAL DECONTAMINATION: All patients suspected of tricyclic overdose
should receive gastrointestinal decontamination. This should include large
volume gastric lavage followed by activated charcoal. If consciousness is
impaired, the airway should be secured prior to lavage. Emesis is
contraindicated.
CARDIOVASCULAR: A maximal limb-lead QRS duration of >/=0.10 seconds may be the
best indication of the severity of the overdose. Intravenous sodium bicarbonate
should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH
response is inadequate, hyperventilation may also be used. Concomitant use of
hyperventilation and sodium bicarbonate should be done with extreme caution with
frequent pH monitoring. A pH >7.60 or a Pco2 <20 mmHg is undesirable.
Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may
respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics
are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory
cardiovascular instability in patients with acute toxicity. However,
hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis
generally have been reported as ineffective in tricyclic poisoning.
CNS: In patients with CNS depression, early intubation is advised because of
the potential for abrupt deterioration. Seizures should be controlled with
benzodiazepines, or if these are ineffective, other anticonvulsants (e.g.,
phenobarbital, phenytoin). Physostigmine is not recommended except to treat
life-threatening symptoms that have been unresponsive to other therapies, and
then only in consultation with a poison control center.
PSYCHIATRIC FOLLOW-UP: Since overdosage is often deliberate, patients may
attempt suicide by other means during the recovery phase. Psychiatric referral
may be appropriate.
PEDIATRIC MANAGEMENT: The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact
the local poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION:
The treatment regimens described below are based on those used in controlled
clinical trials of Clofranil in 520 adults, and 91 children and adolescents with
OCD. During initial titration, Clofranil should be given in divided doses with
meals to reduce gastrointestinal side effects. The goal of this initial
titration phase is to minimize side effects by permitting tolerance to side
effects to develop or allowing the patient time to adapt if tolerance does not
develop.
Because both CMI and its active metabolite, DMI, have long elimination half-
lives, the prescriber should take into consideration the fact that steady-state
plasma levels may not be achieved until 2-3 weeks after dosage change (see
ACTIONS/CLINICAL PHARMACOLOGY). Therefore, after initial titration, it may be
appropriate to wait 2-3 weeks between further dosage adjustments.
INITIAL TREATMENT/DOSE ADJUSTMENT (ADULTS)
Treatment with Clofranil should be initiated at a dosage of 25 mg daily and
gradually increased, as tolerated, to approximately 100 mg during the first 2
weeks. During initial titration, Clofranil should be given in divided doses with
meals to reduce gastrointestinal side effects. Thereafter, the dosage may be
increased gradually over the next several weeks, up to a maximum of 250 mg
daily. After titration, the total daily dose may be given once daily at bedtime
to minimize daytime sedation.
INITIAL TREATMENT/DOSE ADJUSTMENT (CHILDREN AND ADOLESCENTS)
As with adults, the starting dose is 25 mg daily and should be gradually
increased (also given in divided doses with meals to reduce gastrointestinal
side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3
mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased
gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200
mg, whichever is smaller (see PRECAUTIONS, Pediatric Use). As with adults, after
titration, the total daily dose may be given once daily at bedtime to minimize
daytime sedation.
MAINTENANCE/CONTINUATION TREATMENT (ADULTS, CHILDREN, AND ADOLESCENTS)
While there are no systematic studies that answer the question of how long to
continue Clofranil, OCD is a chronic condition and it is reasonable to consider
continuation for a responding patient. Although the efficacy of Clofranil after
10 weeks has not been documented in controlled trials, patients have been
continued in therapy under double-blind conditions for up to 1 year without loss
of benefit. However, dosage adjustments should be made to maintain the patient
on the lowest effective dosage, and patients should be periodically reassessed
to determine the need for treatment. During maintenance, the total daily dose
may be given once daily at bedtime.
ANIMAL PHARMACOLOGY:
ANIMAL TOXICOLOGY
Testicular and lung changes commonly associated with tricyclic compounds have
been observed with Clofranil. In 1- and 2-year studies in rats, changes in the
testes (atrophy, aspermatogenesis, and calcification) and drug-induced
phospholipidosis in the lungs were observed at doses 4 times the maximum daily
human dose. Testicular atrophy was also observed in a 1-year oral toxicity study
in dogs at 10 times the maximum daily human dose.
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