SECOBARBITONE
DESCRIPTION:
The barbiturates are nonselective central nervous system (CNS) depressants that
are primarily used as sedative hypnotics. In subhypnotic doses, they are also
used as anticonvulsants. The barbiturates and their sodium salts are subject to
control under the Federal Controlled Substances Act.
Seconal(R) Sodium (Secobarbital Sodium Capsules, USP) is a barbituric acid
derivative and occurs as a white, odorless, bitter powder that is very soluble
in water, soluble in alcohol, and practically insoluble in ether. Chemically,
the drug is sodium 5-allyl- 5-(1-methylbutyl)barbiturate, with the empirical
formula C12H17N2NaO3. Its molecular weight is 260.27.
ACTIONS/CLINICAL PHARMACOLOGY:
Barbiturates are capable of producing all levels of CNS mood alteration, from
excitation to mild sedation, hypnosis, and deep coma. Overdosage can produce
death. In high enough therapeutic doses, barbiturates induce anesthesia.
Barbiturates depress the sensory cortex, decrease motor activity, alter
cerebellar function, and produce drowsiness, sedation, and hypnosis.
Barbiturate-induced sleep differs from physiologic sleep. Sleep laboratory
studies have demonstrated that barbiturates reduce the amount of time spent in
the rapid eye movement (REM) phase, or dreaming stage of sleep. Also, Stages III
and IV sleep are decreased. Following abrupt cessation of regularly used
barbiturates, patients may experience markedly increased dreaming, nightmares,
and/or insomnia. Therefore, withdrawal of a single therapeutic dose over 5 or 6
days has been recommended to lessen the REM rebound and disturbed sleep that
contribute to drug withdrawal syndrome (for example, decreasing the dose from 3
to 2 doses a day for 1 week).
In studies, secobarbital sodium and pentobarbital sodium have been found to lose
most of their effectiveness for both inducing and maintaining sleep by the end
of 2 weeks of continued drug administration, even with the use of multiple
doses. As with secobarbital sodium and pentobarbital sodium, other barbiturates
(including amobarbital) might be expected to lose their effectiveness for
inducing and maintaining sleep after about 2 weeks. The short-, intermediate-,
and to a lesser degree, long- acting barbiturates have been widely prescribed
for treating insomnia. Although the clinical literature abounds with claims that
the short- acting barbiturates are superior for producing sleep whereas the
intermediate-acting compounds are more effective in maintaining sleep,
controlled studies have failed to demonstrate these differential effects.
Therefore, as sleep medications, the barbiturates are of limited value beyond
short-term use.
Barbiturates have little analgesic action at subanesthetic doses. Rather, in
subanesthetic doses, these drugs may increase the reaction to painful stimuli.
All barbiturates exhibit anticonvulsant activity in anesthetic doses. However,
of the drugs in this class, only phenobarbital, mephobarbital, and metharbital
are effective as oral anticonvulsants in subhypnotic doses.
Barbiturates are respiratory depressants, and the degree of depression is
dependent on the dose. With hypnotic doses, respiratory depression is similar to
that which occurs during physiologic sleep accompanied by a slight decrease in
blood pressure and heart rate.
Studies in laboratory animals have shown that barbiturates cause reduction in
the tone and contractility of the uterus, ureters, and urinary bladder. However,
concentrations of the drugs required to produce this effect in humans are not
reached with sedative-hypnotic doses.
Barbiturates do not impair normal hepatic function, but have been shown to
induce liver microsomal enzymes, thus increasing and/or altering the metabolism
of barbiturates and other drugs (See Drug Interactions Under Precautions).
Pharmacokinetics--Barbiturates are absorbed in varying degrees following oral or
parenteral administration. The salts are more rapidly absorbed than are the
acids. The rate of absorption is increased if the sodium salt is ingested as a
dilute solution or taken on an empty stomach.
Duration of action, which is related to the rate at which the barbiturates are
redistributed throughout the body, varies among persons and in the same person
from time to time.
Seconal Sodium is classified as a short-acting barbiturate when taken orally.
Its onset of action is 10 to 15 minutes and its duration of action ranges from 3
to 4 hours.
Barbiturates are weak acids that are absorbed and rapidly distributed to all
tissues and fluids, with high concentrations in the brain, liver, and kidneys.
Lipid solubility of the barbiturates is the dominant factor in their
distribution within the body. The more lipid soluble the barbiturate, the more
rapidly it penetrates all tissues of the body. Barbiturates are bound to plasma
and tissue proteins to a varying degree, with the degree of binding increasing
directly as a function of lipid solubility.
Phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest
brain protein binding, the longest delay in onset of activity, and the longest
duration of action. At the opposite extreme is secobarbital, which has the
highest lipid solubility, highest plasma protein binding, highest brain protein
binding, the shortest delay in onset of activity, and the shortest duration of
action. The plasma half-life for secobarbital sodium in adults ranges between 15
to 40 hours, with a mean of 28 hours. No data are available for pediatric
patients and newborns.
Barbiturates are metabolized primarily by the hepatic microsomal enzyme system,
and the metabolic products are excreted in the urine and, less commonly, in the
feces. The excretion of unmetabolized barbiturate is 1 feature that
distinguishes the long-acting category from those belonging to other categories,
which are almost entirely metabolized. The inactive metabolites of the
barbiturates are excreted as conjugates of glucuronic acid.
INDICATIONS AND USAGE:
A. Hypnotic, for the short-term treatment of insomnia, since it appears to lose
its effectiveness for sleep induction and sleep maintenance after 2 weeks (See
Actions/Clinical Pharmacology).
B. Preanesthetic
CONTRAINDICATIONS:
Seconal Sodium is contraindicated in patients who are hypersensitive to
barbiturates. It is also contraindicated in patients with a history of manifest
or latent porphyria, marked impairment of liver function, or respiratory disease
in which dyspnea or obstruction is evident.
WARNINGS:
1. Habit-Forming--Seconal Sodium may be habit- forming. Tolerance and
psychological and physical dependence may occur with continued use (See Drug
Abuse and Dependence And Pharmacokinetics Under Actions/Clinical Pharmacology).
Patients who have psychological dependence on barbiturates may increase the
dosage or decrease the dosage interval without consulting a physician and
subsequently may develop a physical dependence on barbiturates. To minimize the
possibility of overdosage or development of dependence, the prescribing and
dispensing of sedative-hypnotic barbiturates should be limited to the amount
required for the interval until the next appointment. The abrupt cessation after
prolonged use in a person who is dependent on the drug may result in withdrawal
symptoms, including delirium, convulsions, and possibly death. Barbiturates
should be withdrawn gradually from any patient known to be taking excessive
doses over long periods of time (See Drug Abuse and Dependence).
2. Acute Or Chronic Pain--Caution should be exercised when barbiturates are
administered to patients with acute or chronic pain, because paradoxical
excitement could be induced or important symptoms could be masked.
3. Usage In Pregnancy--Barbiturates can cause fetal harm when administered to a
pregnant woman. Retrospective, case-controlled studies have suggested that there
may be a connection between the maternal consumption of barbiturates and a
higher than expected incidence of fetal abnormalities. Barbiturates readily
cross the placental barrier and are distributed throughout fetal tissues; the
highest concentrations are found in the placenta, fetal liver, and brain. Fetal
blood levels approach maternal blood levels following parenteral administration.
Withdrawal symptoms occur in infants born to women who receive barbiturates
throughout the last trimester of pregnancy (See Drug Abuse and Dependence). If
Seconal Sodium is used during pregnancy or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the
fetus.
4. Synergistic Effects--The concomitant use of alcohol or other CNS depressants
may produce additive CNS-depressant effects.
PRECAUTIONS:
General--Barbiturates may be habit-forming. Tolerance and psychological and
physical dependence may occur with continuing use (See Drug Abuse and
Dependence). Barbiturates should be administered with caution, if at all, to
patients who are mentally depressed, have suicidal tendencies, or have a history
of drug abuse.
Elderly or debilitated patients may react to barbiturates with marked
excitement, depression, or confusion. In some persons, especially pediatric
patients, barbiturates repeatedly produce excitement rather than depression.
In patients with hepatic damage, barbiturates should be administered with
caution and initially in reduced doses. Barbiturates should not be administered
to patients showing the premonitory signs of hepatic coma.
Information For Patients--The following information should be given to patients
receiving Seconal Sodium:
1. The use of Seconal Sodium carries with it an associated risk of psychological
and/or physical dependence. The patient should be warned against increasing the
dose of the drug without consulting a physician.
2. Seconal Sodium may impair the mental and/or physical abilities required for
the performance of potentially hazardous tasks, such as driving a car or
operating machinery. The patient should be cautioned accordingly.
3. Alcohol should not be consumed while taking Seconal Sodium. The concurrent
use of Seconal Sodium with other CNS depressants (eg, alcohol, narcotics,
tranquilizers, and antihistamines) may result in additional CNS-depressant
effects.
Laboratory Tests--Prolonged therapy with barbiturates should be accompanied by
periodic laboratory evaluation of organic systems, including hematopoietic,
renal, and hepatic systems (See General Under Precautions And Adverse
Reactions).
Drug Interactions--Most reports of clinically significant drug interactions
occurring with the barbiturates have involved phenobarbital. However, the
application of these data to other barbiturates appears valid and warrants
serial blood level determinations of the relevant drugs when there are multiple
therapies.
1. Anticoagulants--Phenobarbital lowers the plasma levels of dicumarol and
causes a decrease in anticoagulant activity as measured by the prothrombin time.
Barbiturates can induce hepatic microsomal enzymes, resulting in increased
metabolism and decreased anticoagulant response of oral anticoagulants (eg,
warfarin, acenocoumarol, dicumarol, and phenprocoumon). Patients stabilized on
anticoagulant therapy may require dosage adjustments if barbiturates are added
to or withdrawn from their dosage regimen.
2. Corticosteroids--Barbiturates appear to enhance the metabolism of exogenous
corticosteroids, probably through the induction of hepatic microsomal enzymes.
Patients stabilized on corticosteroid therapy may require dosage adjustments if
barbiturates are added to or withdrawn from their dosage regimen.
3. Griseofulvin--Phenobarbital appears to interfere with the absorption of
orally administered griseofulvin, thus decreasing its blood level. The effect of
the resultant decreased blood levels of griseofulvin on therapeutic response has
not been established. However, it would be preferable to avoid concomitant
administration of these drugs.
4. Doxycycline--Phenobarbital has been shown to shorten the half-life of
doxycycline for as long as 2 weeks after barbiturate therapy is discontinued.
This mechanism is probably through the induction of hepatic microsomal enzymes
that metabolize the antibiotic. If barbiturates and doxycycline are administered
concurrently, the clinical response to doxycycline should be monitored closely.
5. Phenytoin, Sodium Valproate, Valproic Acid- -The effect of barbiturates on
the metabolism of phenytoin appears to be variable. Some investigators report an
accelerating effect, whereas others report no effect. Because the effect of
barbiturates on the metabolism of phenytoin is not predictable, phenytoin and
barbiturate blood levels should be monitored more frequently if these drugs are
given concurrently. Sodium valproate and valproic acid increase the secobarbital
sodium serum levels; therefore, secobarbital sodium blood levels should be
monitored closely and appropriate dosage adjustment made as clinically
indicated.
6. CNS Depressants--The concomitant use of other CNS depressants, including
other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may
produce additive depressant effects.
7. Monoamine Oxidase Inhibitors (MAOIs)--MAOIs prolong the effects of
barbiturates, probably because metabolism of the barbiturate is inhibited.
8. Estradiol, Estrone, Progesterone, And Other Steroidal Hormones--Pretreatment
with or concurrent administration of phenobarbital may decrease the effect of
estradiol by increasing its metabolism. There have been reports of patients
treated with antiepileptic drugs (eg, phenobarbital) who become pregnant while
taking oral contraceptives. An alternate contraceptive method might be suggested
to women taking barbiturates.
Carcinogenesis--1. Animal Data. Phenobarbital sodium is carcinogenic in mice and
rats after lifetime administration. In mice, it produced benign and malignant
liver cell tumors. In rats, benign liver cell tumors were observed very late in
life.
2. Human Data--In a 29-year epidemiologic study of 9,136 patients who were
treated on an anticonvulsant protocol that included phenobarbital, results
indicated a higher than normal incidence of hepatic carcinoma. Previously, some
of these patients had been treated with thorotrast, a drug that is known to
produce hepatic carcinomas. Thus, this study did not provide sufficient evidence
that phenobarbital sodium is carcinogenic in humans.
A retrospective study of 84 pediatric patients with brain tumors matched to 73
normal controls and 78 cancer controls (malignant disease other than brain
tumors) suggested an association between exposure to barbiturates prenatally and
an increased incidence of brain tumors.
Usage In Pregnancy--1. Teratogenic Effects. Pregnancy Category D. See Usage in
Pregnancy Under Warnings.
2. Nonteratogenic Effects. Reports of infants suffering from long-term
barbiturate exposure in utero included the acute withdrawal syndrome of seizures
and hyperirritability from birth to a delayed onset of up to 14 days (See Drug
Abuse and Dependence).
Labor And Delivery--Hypnotic doses of barbiturates do not appear to impair
uterine activity significantly during labor. Full anesthetic doses of
barbiturates decrease the force and frequency of uterine contractions.
Administration of sedative-hypnotic barbiturates to the mother during labor may
result in respiratory depression in the newborn. Premature infants are
particularly susceptible to the depressant effects of barbiturates. If
barbiturates are used during labor and delivery, resuscitation equipment should
be available.
Data are not available to evaluate the effect of barbiturates when forceps
delivery or other intervention is necessary or to determine the effect of
barbiturates on the later growth, development, and functional maturity of the
pediatric patient.
Nursing Mothers--Caution should be exercised when Seconal Sodium is administered
to a nursing woman, because small amounts of barbiturates are excreted in the
milk.
Usage In Pediatric Patients--See Dosage and Administration.
DRUG INTERACTIONS:
Most reports of clinically significant drug interactions occurring with the
barbiturates have involved phenobarbital. However, the application of these data
to other barbiturates appears valid and warrants serial blood level
determinations of the relevant drugs when there are multiple therapies.
1. Anticoagulants--Phenobarbital lowers the plasma levels of dicumarol and
causes a decrease in anticoagulant activity as measured by the prothrombin time.
Barbiturates can induce hepatic microsomal enyzmes, resulting in increased
metabolism and decreased anticoagulant response of oral anticoagulants (eg,
warfarin, acenocoumarol, dicumarol, and phenprocoumon). Patients stabilized on
anticoagulant therapy may require dosage adjustments if barbiturates are added
to or withdrawn from their dosage regimen.
2. Corticosteroids--Barbiturates appear to enhance the metabolism of exogenous
corticosteroids, probably through the induction of hepatic microsomal enzymes.
Patients stabilized on corticosteroid therapy may require dosage adjustments if
barbiturates are added to or withdrawn from their dosage regimen.
3. Griseofulvin--Phenobarbital appears to interfere with the absorption of
orally administered griseofulvin, thus decreasing its blood level. The effect of
the resultant decreased blood levels of griseofulvin on therapeutic response has
not been established. However, it would be preferable to avoid concomitant
administration of these drugs.
4. Doxycycline--Phenobarbital has been shown to shorten the half-life of
doxycycline for as long as 2 weeks after barbiturate therapy is discontinued.
This mechanism is probably through the induction of hepatic microsomal enzymes
that metabolize the antibiotic. If barbiturates and doxycycline are administered
concurrently, the clinical response to doxycycline should be monitored closely.
5. Phenytoin, Sodium Valproate, Valproic Acid- -The effect of barbiturates on
the metabolism of phenytoin appears to be variable. Some investigators report an
accelerating effect, whereas others report no effect. Because the effect of
barbiturates on the metabolism of phenytoin is not predictable, phenytoin and
barbiturate blood levels should be monitored more frequently if these drugs are
given concurrently. Sodium valproate and valproic acid increase secobarbital
sodium serum levels; therefore, secobarbital sodium blood levels should be
monitored closely and appropriate dosage adjustment made as clinically
indicated.
6. CNS Depressants--The concomitant use of other CNS depressants, including
other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may
produce additive depressant effects.
7. Monoamine Oxidase Inhibitors (MAOIs)--MAOIs prolong the effects of
barbiturates, probably because metabolism of the barbiturate is inhibited.
8. Estradiol, Estrone, Progesterone, And Other Steroidal Hormones--Pretreatment
with or concurrent administration of phenobarbital may decrease the effect of
estradiol by increasing its metabolism. There have been reports of patients
treated with antiepileptic drugs (eg, phenobarbital) who become pregnant while
taking oral contraceptives. An alternate contraceptive method might be suggested
to women taking barbiturates.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions and their incidences were compiled from
surveillance of thousands of hospitalized patients who received barbiturates.
Because such patients may be less aware of some of the milder adverse effects of
barbiturates, the incidence of these reactions may be somewhat higher in fully
ambulatory patients.
MORE THAN 1 IN 100 PATIENTS
The most common adverse reaction estimated to occur at a rate of 1 to 3 patients
per 100 is the following:
Nervous System: Somnolence
LESS THAN 1 IN 100 PATIENTS
Adverse reactions estimated to occur at a rate of less than 1 in 100 patients
are listed below, grouped by organ system and by decreasing order of occurrence:
Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression,
nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia,
anxiety, dizziness, abnormality in thinking
Respiratory System: Hypoventilation, apnea
Cardiovascular System: Bradycardia, hypotension, syncope
Digestive System: Nausea, vomiting, constipation
Other Reported Reactions: Headache, injection site reactions, hypersensitivity
reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver
damage, megaloblastic anemia following chronic phenobarbital use
DRUG ABUSE AND DEPENDENCE:
Controlled Substance--Seconal Sodium Capsules are a Schedule II drug.
Dependence--Barbiturates may be habit-forming; tolerance, psychological
dependence, and physical dependence may occur, especially following prolonged
use of high doses of barbiturates. Daily administration in excess of 400 mg of
secobarbital for approximately 90 days is likely to produce some degree of
physical dependence. A dosage of 600 to 800 mg for at least 35 days is
sufficient to produce withdrawal seizures. The average daily dose for the
barbiturate addict is usually about 1.5 g. As tolerance to barbiturates
develops, the amount needed to maintain the same level of intoxication
increases; tolerance to a fatal dosage, however, does not increase more than
twofold. As this occurs, the margin between intoxicating dosage and fatal dosage
becomes smaller.
Symptoms of acute intoxication with barbiturates include unsteady gait, slurred
speech, and sustained nystagmus. Mental signs of chronic intoxication include
confusion, poor judgment, irritability, insomnia, and somatic complaints.
Symptoms of barbiturate dependence are similar to those of chronic alcoholism.
If an individual appears to be intoxicated with alcohol to a degree that is
radically disproportionate to the amount of alcohol in his or her blood, the use
of barbiturates should be suspected. The lethal dose of a barbiturate is far
less if alcohol is also ingested.
The symptoms of barbiturate withdrawal can be severe and may cause death. Minor
withdrawal symptoms may appear 8 to 12 hours after the last dose of a
barbiturate. These symptoms usually appear in the following order: anxiety,
muscle twitching, tremor of hands and fingers, progressive weakness, dizziness,
distortion in visual perception, nausea, vomiting, insomnia, and orthostatic
hypotension. Major withdrawal symptoms (convulsions and delirium) may occur
within 16 hours and last up to 5 days after abrupt cessation of barbiturates.
Intensity of withdrawal symptoms gradually declines over a period of
approximately 15 days. Individuals susceptible to barbiturate abuse and
dependence include alcoholics and opiate abusers, as well as other sedative-
hypnotic and amphetamine abusers.
Drug dependence on barbiturates arises from repeated administration on a
continuous basis, generally in amounts exceeding therapeutic dose levels. The
characteristics of drug dependence on barbiturates include the following: (a) a
strong desire or need to continue taking the drug; (b) a tendency to increase
the dose; (c) a psychic dependence on the effects of the drug related to
subjective and individual appreciation of those effects; and (d) a physical
dependence on the effects of the drug, requiring its presence for maintenance of
homeostasis and resulting in a definite, characteristic, and self-limited
abstinence syndrome when the drug is withdrawn.
Treatment of barbiturate dependence consists of cautious and gradual withdrawal
of the drug. Barbiturate-dependent patients can be withdrawn by using a number
of withdrawal regimens. In all cases, withdrawal takes an extended period. One
method involves substituting a 30-mg dose of phenobarbital for each 100- to 200-
mg dose of barbiturate that the patient has been taking. The total daily amount
of phenobarbital is then administered in 3 or 4 divided doses, not to exceed 600
mg daily. Should signs of withdrawal occur on the first day of treatment, a
loading dose of 100 to 200 mg of phenobarbital may be administered IM in
addition to the oral dose. After stabilization on phenobarbital, the total daily
dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. A
modification of this regimen involves initiating treatment at the patient's
regular dosage level and decreasing the daily dosage by 10% as tolerated by the
patient.
Infants that are physically dependent on barbiturates may be given
phenobarbital, 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity,
disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of
phenobarbital should be gradually decreased and completely withdrawn over a 2-
week period.
OVERDOSAGE:
The toxic dose of barbiturates varies considerably. In general, an oral dose of
1 g of most barbiturates produces serious poisoning in an adult. Death commonly
occurs after 2 to 10 g of ingested barbiturate. The sedated, therapeutic blood
levels of secobarbital range between 0.5 to 5 mcgm/mL; the usual lethal blood
level ranges from 15 to 40 mcgm/mL. Barbiturate intoxication may be confused
with alcoholism, bromide intoxication, and various neurologic disorders.
Potential tolerance must be considered when evaluating significance of dose and
plasma concentration.
Signs And Symptoms--Symptoms of oral overdose may occur within 15 minutes and
begin with central nervous system depression, underventilation, hypotension, and
hypothermia, which may progress to pulmonary edema and death. Hemorrhagic
blisters may develop, especially at pressure points.
In extreme overdose, all electrical activity in the brain may cease, in which
case a "flat" EEG normally equated with clinical death cannot be accepted as
indicative of brain death. This effect is fully reversible unless hypoxic damage
occurs. Consideration should be given to the possibility of barbiturate
intoxication even in situations that appear to involve trauma.
Complications such as pneumonia, pulmonary edema, cardiac arrhythmias,
congestive heart failure, and renal failure may occur. Uremia may increase CNS
sensitivity to barbiturates if renal function is impaired. Differential
diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents,
convulsive states, and diabetic coma.
Treatment--To obtain up-to-date information about the treatment of overdose, a
good resource is your certified Regional Poison Control Center. Telephone
numbers of certified poison control centers are listed in the Physicians' Desk
Reference (PDR). In managing overdosage, consider the possibility of multiple
drug overdoses, interaction among drugs, and unusual drug kinetics in your
patient.
Protect the patient's airway and support ventilation and perfusion. Meticulously
monitor and maintain, within acceptable limits, the patient's vital signs, blood
gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal
tract may be decreased by giving activated charcoal, which, in many cases, is
more effective than emesis or lavage; consider charcoal instead of or in
addition to gastric emptying. Repeated doses of charcoal over time may hasten
elimination of some drugs that have been absorbed. Safeguard the patient's
airway when employing gastric emptying or charcoal.
Diuresis and peritoneal dialysis are of little value; hemodialysis and
hemoperfusion enhance drug clearance and should be considered in serious
poisoning. If the patient has chronically abused sedatives, withdrawal reactions
may be manifest following acute overdose.
DOSAGE AND ADMINISTRATION:
Dosages of barbiturates must be individualized with full knowledge of their
particular characteristics. Factors of consideration are the patient's age,
weight, and condition.
Adults--As a hypnotic, 100 mg at bedtime. Preoperatively, 200 to 300 mg 1 to 2
hours before surgery.
Pediatric Patients--Preoperatively, 2 to 6 mg/kg, with a maximum dosage of 100
mg.
Special Patient Population--Dosage should be reduced in the elderly or
debilitated because these patients may be more sensitive to barbiturates. Dosage
should be reduced for patients with impaired renal function or hepatic disease.
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