Clinical Pharmacology

CLINICAL PHARMACOLOGY
Librium (chlordiazepoxide HCI) has antianxiety, sedative, appetite-stimulating and weak analgesic
actions. The precise mechanism of action is not known. The drug blocks EEG arousal from
stimulation of the brain stem reticular formation. It takes several hours for peak blood levels to be
reached and the half-life of the drug is between 24 and 48 hours. After the drug is discontinued
plasma levels decline slowly over a period of several days. Chlordiazepoxide is excreted in the urine,
with 1% to 2% unchanged and 3% to 6% as conjugate.

Animal Pharmacology: The drug has been studied extensively in many species of animals and these
studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is
involved in emotional responses.

Hostile monkeys were made tame by oral drug doses which did not cause sedation.
Chlordiazepoxide HCI revealed a "taming" action with the elimination of fear and aggression. The
taming effect of chlordiazepoxide HCI was further demonstrated in rats made vicious by lesions in
the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well
below the dose which caused sedation in these animals.

The LDM of parenterally administered chlordiazepoxide HCI was determined in mice (72 hours) and
rats (5 days), and calculated according to the method of Miller and Tainter, with the following
results: mice, IV, 123+12mg/kg; mice, IM, 3667mg/kg; rats, IV, 1207 mg/kg; rats, IM, > 160 mg/kg.

Effects on Reproduction: Reproduction studies in rats fed 10, 20 and 80 mg/kg daily and bred
through one or two matings showed no congenital anomalies, nor were there adverse effects on
lactation of the dams or growth of the newborn. However, in another study at 100 mg/kg daily there
was noted a significant decrease in the fertilization rate and a marked decrease in the viability and
body weight of off-spring which may be attributable to sedative activity, thus resulting in lack of
interest in mating and lessened

maternal nursing and care of the young. One neonate in each of the first and second matings in the
rat reproduction study at the 100 mg/kg dose exhibited major skeletal defects. Further studies are in
progress to determine the significance of these findings

Brand Names: Klonopin, Klonopin Wafer
Generic Name: clonazepam (Pronunciation: kloe NAZ e pam)
What is clonazepam (Klonopin)?
What are the possible side effects of clonazepam (Klonopin)?
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What should I discuss with my healthcare provider before taking clonazepam (Klonopin)?
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Where can I get more information?

What is clonazepam (Klonopin)?
Clonazepam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Clonazepam
affects chemicals in the brain that may become unbalanced and cause anxiety.

Clonazepam is used to treat seizure disorders or panic disorder.

Clonazepam may also be used for purposes not listed in this medication guide.

Clonazepam 0.5 mg832-TEV

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What are the possible side effects of clonazepam (Klonopin)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty
breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes,
depression, anxiety, or if you feel agitated, irritable, hostile, aggressive, restless, hyperactive
(mentally or physically), or have thoughts about suicide or hurting yourself.
Pharmacodynamics

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown,
although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid
(GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced
in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are
convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive
primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of
suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the
frequency, amplitude, duration and spread of discharge in minor motor seizures.

Pharmacokinetics

Clonazepam is rapidly and completely absorbed after oral administration. The absolute
bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are
reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to
plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being
excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-
amino derivative. This derivative can be acetylated, hydroxylated and glucuroni dated. Cytochrome
P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The
elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are
dose-independent throughout the dosing range. There is no evidence that clonazepam induces its
own metabolism or that of other drugs in humans.

Pharmacokinetics in Demographic Subpopulations and in Disease States

Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have
not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics
been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease
will impair clonazepam elimination. Thus, caution should be exercised when administering
clonazepam to these patients

Brand Names: Valium
Generic Name: diazepam (Pronunciation: dye AZ e pam)
What is diazepam (Valium)?
What are the possible side effects of diazepam (Valium)?
What is the most important information I should know about diazepam (Valium)?
What should I discuss with my healthcare provider before taking diazepam (Valium)?
How should I take diazepam (Valium)?
What happens if I miss a dose (Valium)?
What happens if I overdose (Valium)?
What should I avoid while taking diazepam (Valium)?
What other drugs will affect diazepam (Valium)?

What is diazepam (Valium)?
Diazepam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Diazepam

Diazepam is used to treat anxiety disorders, alcohol withdrawal symptoms, or muscle spasms.
Diazepam is sometimes used with other medications to treat seizures.

Diazepam may also be used for purposes not listed in this medication guide.

Diazepam 10 mg-IVA

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What are the possible side effects of diazepam (Valium)?
Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and
amnestic effects. Most of these effects are thought to result from a facilitation of the action of
gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system.

Pharmacokinetics

Absorption

After oral administration > 90% of diazepam is absorbed and the average time to achieve peak
plasma concentrations is 1 1.5 hours with a range of 0.25 to 2.5 hours. Absorption is delayed and
decreased when administered with a moderate fat meal. In the presence of food mean lag times are
approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in
the average time to achieve peak concentrations to about 2.5 hours in the presence of food as
compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in
addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and
its metabolites cross the blood-brain and placental barriers and are also found in breast milk in
concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In
young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The decline in the
plasma concentration-time profile after oral administration is biphasic. The initial distribution phase
has a half-life of approximately 1 hour, although it may range up to > 3 hours.

Metabolism

Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam,
and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and
temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely
eliminated by glucuronidation.

Elimination

The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48
hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100
hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their
glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam
accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life
is slightly prolonged.

Brand Names: Serax
Generic Name: oxazepam (Pronunciation: ox A ze pam)
What is oxazepam (Serax)?
What are the possible side effects of oxazepam (Serax)?
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What should I discuss with my healthcare provider before taking oxazepam (Serax)?
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What happens if I overdose (Serax)?
What should I avoid while taking oxazepam (Serax)?
What other drugs will affect oxazepam (Serax)?

What is oxazepam (Serax)?
Oxazepam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Oxazepam

Oxazepam is used to treat anxiety disorders or alcohol withdrawal symptoms.

Oxazepam may also be used for other purposes not listed in this medication guide.

Oxazepam 10 mg-ESI

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What are the possible side effects of oxazepam (Serax)?
breathing; swelling of your face, lips, tongue, or throat
Pharmacokinetic testing In twelve volunteers demonstrated that when given as a single 30 mg dose,
the capsule, tablet, and suspension were equivalent in extent of absorption. For the capsule and
tablet, peak plasma levels averaged 450 ng/mL and were observed to occur about 3 hours after
dosing. The mean elimination half-life for oxazepam was approximately 8.2 hours (range 5.7 to 10.9
hours). This product has a single, major inactive metabolite in man, a glucuronide excreted in the
urine.

Age (< 80 years old) does not appear to have a clinically significant effect on oxazepam kinetics. A
statistically significant increase in elimination half-life in the very elderly (> 80 years of age) as
compared to younger subjects has been reported, due to a 30% increase in volume of distribution,
as well as a 50% reduction in unbound clearance of oxazepam in the very elderly, (see
PRECAUTIONS, Geriatric Use).

Animal Pharmacology And Toxicology

In mice, Serax (oxazepam) exerts an anticonvulsant (anti-Metrazol) activity at 50-per-cent-effective
doses of about 0.6 mg/kg orally. (Such anticonvulsant activity of benzodiazepines correlates with
their tranquilizing properties.) To produce ataxia (rotabar test) and sedation (abolition of
spontaneous motor activity), the 50-percent-effective doses of this product are greater than 5 mg/kg
orally. Thus, about ten times the therapeutic (anticonvulsant) dose must be given before ataxia
ensues, indicating a wide separation of effective doses and doses inducing side effects.

In evaluation of anti anxiety activity of compounds, conflict behavioral tests in rats differentiate
continuous response for food in the presence of anxiety-provoking stress (shock) from drug-induced
motor in coordination. This product shows significant separation of doses required to relieve anxiety
and doses producing sedation or ataxia. Ataxia-producing doses exceed those of related CNS-acting
drugs.

Acute oral LDM in mice is greater than 5000 mg/kg, compared to 800 mg/kg for a related compound
(chlordiazepoxide). Subacute toxicity studies in dogs for four weeks at 480 mg/kg daily showed no
specific changes; at 960 mg/kg two out of eight died with evidence of circulatory collapse. This wide
margin of safety is significant compared to chlordiazepoxide HCL, which showed nonspecific changes
in six dogs at 80 mg/kg. On chlordiazepoxide, two out of six died with evidence of circulatory
collapse at 127 mg/kg, and six out of six died at 200 mg/kg daily. Chronic toxicity studies of Serax
(oxazepam) in dogs at 120 mg/kg/day for 52 weeks produced no toxic manifestation. Fatty
metamorphosis of the liver has been noted in six-week toxicity studies in rats given this product at
0.5% of the diet. Such accumulations of fat are considered reversible, as there is no liver necrosis or
fibrosis. Breeding studies in rats through two successive litters did not produce fetal abnormality.

Oxazepam has not been adequately evaluated for mutagenic activity. In a carcinogenicity study,
oxazepam was administered with diet to rats for two years. Male rats receiving 30 times the
maximum human dose showed a statistical increase, when compared to controls, in benign thyroid
follicular cell tumors, testicular interstitial cell adenomas, and prostatic adenomas. An earlier
published study reported that mice fed dietary dosages of 35 or 100 times the human daily dose of
oxazepam for 9 months developed a dose-related increase in liver adenomas.' In an independent
analysis of some of the microscopic slides from this mouse study, several of these tumors were
classified as liver carcinomas. At this time, there is no evidence that clinical use of oxazepam is
associated with tumors

Brand Names: BuSpar, BuSpar Dividose
Generic Name: buspirone (Pronunciation: byoo SPYE rone)
What is buspirone (Buspar)?
What are the possible side effects of buspirone (Buspar)?
What is the most important information I should know about buspirone (Buspar)?
What should I discuss with my healthcare provider before taking buspirone (Buspar)?
How should I take buspirone (Buspar)?
What happens if I miss a dose (Buspar)?
What happens if I overdose (Buspar)?
What should I avoid while taking buspirone (Buspar)?
What other drugs will affect buspirone (Buspar)?

What is buspirone (Buspar)?
Buspirone is an anti-anxiety medicine that affects chemicals in your brain that may become
unbalanced and cause anxiety.

Buspirone is used to treat symptoms of anxiety, such as fear, tension, irritability, dizziness, pounding
heartbeat, and other physical symptoms.

Buspirone may also be used for purposes not listed in this medication guide.

BuSpar 15 mg

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What are the possible side effects of buspirone (Buspar)?
What is the most important information I should know about buspirone (Buspar)?
Do not this medication if you are allergic to buspirone, or if you have used an MAO inhibitor such as
isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or
tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if
you take buspirone before the MAO inhibitor has cleared from your body.

Buspirone can cause side effects that may impair your thinking or reactions. Be careful if you drive or
do anything that requires you to be awake and alert.

Avoid drinking alcohol. It may increase some of the side effects caused by buspirone.

Grapefruit and grapefruit juice may interact with buspirone and lead to potentially dangerous
effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the
amount of grapefruit products in your diet without first talking to your doctor.

Buspirone is usually taken for only a short time. Do not take this medication for longer than 4 weeks
without your doctor's advice.

The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine
anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the
prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies
have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Buspirone has no
significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo
when tested in preclinical models.

Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that
buspirone may have indirect effects on other neurotransmitter systems.

BuSpar (buspirone) is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a
radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the
radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged
buspirone are very low and variable between subjects. Peak plasma levels of 1 ng/mL to 6 ng/mL
have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability
of unchanged buspirone when taken as a tablet is on the average about 90% of an equivalent dose
of solution, but there is large variability.

The effects of food upon the bioavailability of BuSpar (buspirone) have been studied in eight
subjects. They were given a 20 mg dose with and without food; the area under the plasma
concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone
increased by 84% and 116%, respectively, but the total amount of buspirone immunoreactive
material did not change. This suggests that food may decrease the extent of presystemic clearance
of buspirone (see DOSAGE AND ADMINISTRATION).

A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear
pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood
levels of unchanged buspirone than would be predicted from results of single-dose studies.

An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma
proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%,
while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known
whether these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such
changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro
study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin,
warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin.

Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by
cytochrome P450 3A4 (CYP3A4). (See PRECAUTIONS : DRUG INTERACTIONS.) Several hydroxylated
derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced.
In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of
buspirone, but is present in up to 20-fold greater amounts. However, this is probably not important
in humans: blood samples from humans chronically exposed to BuSpar (buspirone hydrochloride) do
not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood
level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels
found in animals given large doses of buspirone without signs of toxicity.

In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the
urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the
dose. The average elimination half-life of unchanged buspirone after single doses of 10 mg to 40 mg
is about 2 to 3 hours.

General
Brand Names: Inderal, Inderal LA, InnoPran XL
Generic Name: propranolol (Pronunciation: pro PRAN oh lol)
What is propranolol (Inderal)?
What are the possible side effects of propranolol (Inderal)?
What is the most important information I should know about propranolol (Inderal)?
What should I discuss with my healthcare provider before taking propranolol (Inderal)?
How should I take propranolol (Inderal)?
What happens if I miss a dose (Inderal)?
What happens if I overdose (Inderal)?
What should I avoid while taking propranolol (Inderal)?
What other drugs will affect propranolol (Inderal)?

What is propranolol (Inderal)?
Propranolol is a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through
arteries and veins).

Propranolol is used to treat tremors, angina (chest pain), hypertension (high blood pressure), heart
rhythm disorders, and other heart or circulatory conditions. It is also used to treat or prevent heart
attack, and to reduce the severity and frequency of migraine headaches.

Propranolol may also be used for purposes not listed in this medication guide.

Inderal 20 mg

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What are the possible side effects of propranolol (Inderal)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult
Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other
autonomic nervous system activity. It specifically competes with beta-adrenergic receptor agonist
agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the
chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased
proportionately. At dosages greater than required for beta blockade, propranolol also exerts a
quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The
significance of the membrane action in the treatment of arrhythmias is uncertain.

Mechanism of Action

The mechanism of the antihypertensive effect of propranolol has not been established. Factors that
may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of
renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor
centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or
below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma
volume appear to be minor and somewhat variable.

In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given
level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood
pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen
requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection
period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is
manifested during exercise by delayed onset of pain and increased work capacity.

Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic
blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages
greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like
membrane action, which affects the cardiac action potential. The significance of the membrane
action in the treatment of arrhythmias is uncertain.

The mechanism of the antimigraine effect of propranolol has not been established. Beta-adrenergic
receptors have been demonstrated in the pial vessels of the brain.

The specific mechanism of propranolol's antitremor effects has not been established, but beta-2
(noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have
demonstrated that Inderal (propranolol) is of benefit in exaggerated physiological and essential
(familial) tremor.

Pharmacokinetics And Drug Metabolism

Absorption

Propranolol is highly lipophilic and almost completely absorbed after oral administration. However,
it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol
reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral
dose.

Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no
change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in
the urine.

Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alphai acid
glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to
alpha1 glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of
distribution of propranolol is approximately 4 liters/kg.

Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.

Metabolism and Elimination

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is
metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-
dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been
estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and
17%, respectively, but with considerable variability between individuals. The four major metabolites
are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-
hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by
polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by
CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-
glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption
of propranolol in the usual therapeutic dose range.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and
poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-
hydroxy propranolol was significantly higher and of naphthyloxyactic acid significantly lower in EMs
than PMs.

The plasma half-life of propranolol is from 3 to 6 hours.

Brand Names: Prosom
Generic Name: estazolam (Pronunciation: es TA zoe lam)
What is estazolam (Prosom)?
What are the possible side effects of estazolam (Prosom)?
What is the most important information I should know about estazolam (Prosom)?
What should I discuss with my healthcare provider before taking estazolam (Prosom)?
How should I take estazolam (Prosom)?
What happens if I miss a dose (Prosom)?
What happens if I overdose (Prosom)?
What should I avoid while taking estazolam (Prosom)?
What other drugs will affect estazolam (Prosom)?

What is estazolam (Prosom)?
Estazolam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Estazolam
affects chemicals in the brain that may become unbalanced and cause sleep problems (insomnia).

Estazolam is used to treat insomnia symptoms, such as trouble falling or staying asleep.

Estazolam may also be used for purposes other than those listed in this medication guide.

Estazolam 1 mg-IVA

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What are the possible side effects of estazolam (Prosom)?
Stop using estazolam and call your doctor at once if you have any of these serious side effects:

weak or shallow breathing;
fast or pounding heartbeats;
confusion, slurred speech, unusual thoughts or behavior;
hallucinations, agitation, aggression;
thoughts of suicide or hurting yourself;
restless muscle movements in your eyes, tongue, jaw, or neck;
pale skin, easy bruising or bleeding, unusual weakness;
fever, chills, body aches, flu symptoms;
problems with urination; or
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing
of the skin or eyes).
Pharmacokinetics

Absorption

ProSom (estazolam) tablets have been found to be equivalent in absorption to an orally
administered solution of estazolam. In healthy subjects who received up to three times the
recommended dose of ProSom, peak estazolam plasma concentrations occurred within two hours
after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting
linear pharmacokinetics over the dosage range tested.

Distribution

Independent of concentration, estazolam in plasma is 93% protein bound.

Metabolism

Estazolam is extensively metabolized. Only two metabolites (1-oxo-estazolam & 4-hydroxy-
estazolam) were detected in human plasma up to 18 hrs.

The pharmacologic activity of estazolam is primarily from the parent drug. The elimination of the
parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites
that are eliminated largely in the urine both free and conjugated. In humans, greater than 70% of a
single dose of estazolam was recovered in the urine as metabolites. Less than 5% of a 2 mg dose of
estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces.
The principal urinary excretion product is an unidentified metabolite, presumed to be a metabolic
product of 4-hydroxyestazolam, accounting for at least 27% of the administered dose. 4-hydroxy-
estazolam is the major metabolite in plasma, with concentrations approaching 12% of those of the
parent eight hours after administration. Urinary 4-hydroxy-estazolam and 1-oxo-estazolam account
for 11.9% and 4.4% of the dose respectively. In vitro studies with human liver microsomes indicate
that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is
mediated by cytochrome P450 3A (CYP3A). While 4-hydroxy-estazolam and the lesser metabolite, 1-
oxo-estazolam, have some pharmacologic activity, their low potencies and low concentrations
preclude any significant contribution to the hypnotic effect of ProSom (estazolam) .

Elimination

The range of estimates for the mean elimination half-life of estazolam varied from 10 to 24 hours.
Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5
days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose
was excreted unchanged. Eleven metabolites were found in urine. Four metabolites were identified
as 1 -oxo-estazolam, 4'-hydroxy-estazolam, 4-hydroxy-estazolam, and benzophenone, as free
metabolites and glucuronides. The predominant metabolite in urine (17% of the administered dose)
has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam.

Brand Names: Halcion
Generic Name: triazolam (Pronunciation: trye AY zoe lam)
What is triazolam (Halcion)?
What are the possible side effects of triazolam (Halcion)?
What is the most important information I should know about triazolam (Halcion)?
What should I discuss with my healthcare provider before taking triazolam (Halcion)?
How should I take triazolam (Halcion)?
What happens if I miss a dose (Halcion)?
What happens if I overdose (Halcion)?
What should I avoid while taking triazolam (Halcion)?
What other drugs will affect triazolam (Halcion)?

What is triazolam (Halcion)?
Triazolam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Triazolam

Triazolam is used to treat insomnia symptoms, such as trouble falling or staying asleep.

Triazolam may also be used for other purposes not listed in this medication guide.

Triazolam 0.125 mg-PAR

oblong, white, imprinted with G, TR 125
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What are the possible side effects of triazolam (Halcion)?
Stop using triazolam and call your doctor at once if you have any of these serious side effects:

confusion, slurred speech, unusual thoughts or behavior;
thoughts of suicide or hurting yourself;
restless muscle movements in your eyes, tongue, jaw, or neck;
pale skin, easy bruising or bleeding, unusual weakness;
fever, chills, body aches, flu symptoms;
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing
of the skin or eyes).
Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of 1.5 to 5.5
hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no
evidence of altered systemic bioavailability, rate of elimination, or accumulation. Peak plasma levels
are reached within 2 hours following oral administration. Following recommended doses of
HALCION, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels
achieved are proportional to the dose given.

Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably
inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear
in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary
excretion appeared to be biphasic in its time course.

HALCION (triazolam) Tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or
plasma warfarin levels in male volunteers administered sodium warfarin orally.

Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin
in vitro.

Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly
distributed in the fetus with 14C concentrations approximately the same as in the brain of the
mother.

In sleep laboratory studies, HALCION (triazolam) Tablets significantly decreased sleep latency,
increased the duration of sleep, and decreased the number of nocturnal awakenings. After 2 weeks
of consecutive nightly administration, the drug's effect on total wake time is decreased, and the
values recorded in the last third of the night approach baseline levels. On the first and/or second
night after drug discontinuance (first or second post-drug night), total time asleep, percentage of
time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline
(predrug) nights. This effect is often called "rebound" insomnia.

The type and duration of hypnotic effects and the profile of unwanted effects during administration
of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any
active metabolites formed. When half-lives are long, the drug or metabolites may accumulate during
periods of nightly administration and be associated with impairments of cognitive and motor
performance during waking hours; the possibility of interaction with other psychoactive drugs or
alcohol will be enhanced. In contrast, if half-lives are short, the drug and metabolites will be cleared
before the next dose is ingested, and carry-over effects related to excessive sedation or CNS
depression should be minimal or absent. However, during nightly use for an extended period
pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may
develop. If the drug has a short half-life of elimination, it is possible that a relative deficiency of the
drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the
interval between each night's use. This sequence of events may account for two clinical findings
reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics:
1) increased wakefulness during the last third of the night and 2) the appearance of increased
daytime anxiety after 10 days of continuous treatment.

In a study of elderly (62-83 years old) versus younger subjects (21-41 years old) who received
HALCION (triazolam) at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both
greater sedation and impairment of psychomotor performance. These effects resulted largely from
higher plasma concentrations of triazolam in the elderly.

Brand Names: Doral
Generic Name: quazepam (Pronunciation: KWAY ze pam)
What is quazepam (Doral)?
What are the possible side effects of quazepam (Doral)?
What is the most important information I should know about quazepam (Doral)?
What should I discuss with my healthcare provider before taking quazepam (Doral)?
How should I take quazepam (Doral)?
What happens if I miss a dose (Doral)?
What happens if I overdose (Doral)?
What should I avoid while taking quazepam (Doral)?
What other drugs will affect quazepam (Doral)?

What is quazepam (Doral)?
Quazepam is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Quazepam

Quazepam is used to treat insomnia symptoms, such as trouble falling or staying asleep.

Quazepam may also be used for other purposes not listed in this medication guide.

Doral 7.5 mg

oblong, orange, imprinted with DORAL, 7.5
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What are the possible side effects of quazepam (Doral)?
Stop using quazepam and call your doctor at once if you have a serious side effect such as:

worsening insomnia;
confusion, anxiety, slurred speech, unusual thoughts or behavior;
muscle stiffness in your tongue, jaw, or neck;
jaundice (yellowing of the skin or eyes).
Mechanism of Action

Quazepam, like other central nervous system agents of the 1,4-benzodiazepine class, presumably
exerts its effects by binding to stereo-specific receptors at several sites within the central nervous
system (CNS). The exact mechanism of action is unknown.

Pharmacokinetics

Absorption

Quazepam is rapidly (absorption half-life of about 30 minutes) and well absorbed from the
gastrointestinal tract. The peak plasma concentration of quazepam is approximately 20 ng/mL after
a 15 mg dose and occurs at about 2 hours.

Metabolism

Quazepam, the active parent compound, is extensively metabolized in the liver; two of the plasma
metabolites are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. All three compounds show CNS
depressant activity.

Distribution

The degree of plasma protein binding for quazepam and its two major metabolites is greater than
95%.

Elimination

Following administration of 14C-quazepam, 31% of the dose appeared in the urine and 23% in the
feces over five days; only trace amounts of unchanged drug were present in the urine.

The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of Ndesalkyl-2-
oxoquazepam is 73 hours. Steady-state levels of quazepam and 2-oxoquazepam are attained by the
seventh daily dose and that of N-desalkyl-2-oxoquazepam by the thirteenth daily dose.

Brand Names: Rozerem
Generic Name: ramelteon (Pronunciation: ram EL tee on)
What is ramelteon (Rozerem)?
What are the possible side effects of ramelteon (Rozerem)?
What is the most important information I should know about ramelteon (Rozerem)?
What should I discuss with my healthcare provider before taking ramelteon (Rozerem)?
How should I take ramelteon (Rozerem)?
What happens if I miss a dose (Rozerem)?
What happens if I overdose (Rozerem)?
What should I avoid while taking ramelteon (Rozerem)?
What other drugs will affect ramelteon (Rozerem)?

What is ramelteon (Rozerem)?
Ramelteon is a sedative, also called a hypnotic. It works by affecting certain substances in your body
that help regulate your "sleep-wake cycle."

Ramelteon is used to treat insomnia that is associated with having trouble falling asleep.

Unlike some other sleep medications, ramelteon is not known to be habit-forming.

Ramelteon may also be used for purposes not listed in this medication guide.

Rozerem 8 mg

round, yellow, imprinted with TAK RAM-8
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What are the possible side effects of ramelteon (Rozerem)?
Mechanism of Action

ROZEREM (ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and
MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity
in vitro in cells expressing human MT1 or MT2 receptors.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-
promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be
involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle.

Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind
neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates.
Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard
panel.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the
binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is
17- to 25fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at
MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than
the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon.
M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other
receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of
endogenous enzymes.

All other known metabolites of ramelteon are inactive.

Pharmacokinetics

The pharmacokinetic profile of ROZEREM (ramelteon) has been evaluated in healthy subjects as well
as in subjects with hepatic or renal impairment. When administered orally to humans in doses
ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear
pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time
curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect;
the coefficient of variation for these values is approximately 100%. Several metabolites have been
identified in human serum and urine.

Absorption

Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75
hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of
ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass
metabolism.

Distribution

In vitro protein binding of ramelteon is approximately 82% in human serum, independent of
concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound
in human serum albumin. Ramelteon is not distributed selectively to red blood cells.

Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting
substantial tissue distribution.

Metabolism

Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with
secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in
the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved
to a minor degree.

The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-
III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination.
The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent
drug.

Elimination

Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in
urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the
dose was excreted in urine and feces as the parent compound. Elimination was essentially complete
by 96 hours post-dose.

Repeated once daily dosing with ROZEREM (ramelteon) does not result in significant accumulation
owing to the short elimination half-life of ramelteon (on average, approximately 1 to 2.6 hours).

Brand Names: Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist
Generic Name: zolpidem (Pronunciation: zole PI dem)
What is zolpidem (Ambien)?
What are the possible side effects of zolpidem (Ambien)?
What is the most important information I should know about zolpidem (Ambien)?
What should I discuss with my healthcare provider before taking zolpidem (Ambien)?
How should I take zolpidem (Ambien)?
What happens if I miss a dose (Ambien)?
What happens if I overdose (Ambien)?
What should I avoid while taking zolpidem (Ambien)?
What other drugs will affect zolpidem (Ambien)?

What is zolpidem (Ambien)?
Zolpidem is a sedative, also called a hypnotic. It affects chemicals in your brain that may become
unbalanced and cause sleep problems (insomnia).

Zolpidem is used to treat insomnia. The immediate-release forms of zolpidem are Ambien,
Intermezzo,Edluar, and Zolpimist, which are used to help you fall asleep. The extended-release form
of zolpidem is Ambien CR, which has a first layer that dissolves quickly to help you fall asleep, and a
second layer that dissolves slowly to help you stay asleep.

Ambien, Edluar, and Zolpimist are used to help you fall asleep when you first go to bed. Intermezzo,
is used to help you fall back to sleep if you wake up in the middle of the night and then have trouble
sleeping.

Your doctor will determine which form of zolpidem is best for you.

Zolpidem may also be used for purposes not listed in this medication guide.

Ambien 10 mg

oblong, white, imprinted with AMB 10, 5421
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What are the possible side effects of zolpidem (Ambien)?
Report any new or worsening symptoms to your doctor, such as: depression, anxiety, aggression,
agitation, confusion, unusual thoughts, hallucinations, memory problems, changes in personality,
risk-taking behavior, decreased inhibitions, no fear of danger, or thoughts of suicide or hurting
yourself.
Mechanism of Action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure
unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It
interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of
the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate
all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity
ratio of the 1/5 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute,
but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies
as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at
hypnotic doses.

Pharmacokinetics

The pharmacokinetic profile of Ambien is characterized by rapid absorption from the gastrointestinal
tract and a short elimination half-life (T1/2) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate
tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272)
ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean Ambien
elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg
tablets, respectively. Ambien is converted to inactive metabolites that are eliminated primarily by
renal excretion. Ambien demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein
binding was found to be 92.5 0.1% and remained constant, independent of concentration between
40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg
zolpidem tartrate tablets for 2 weeks.

A food-effect study in 30 healthy male subjects compared the pharmacokinetics of Ambien 10 mg
when administered while fasting or 20 minutes after a meal. Results demonstrated that with food,
mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was
prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that,
for faster sleep onset, Ambien should not be administered with or immediately after a meal.

Brand Names: Romazicon
Generic Name: flumazenil (Pronunciation: floo MAZ e nil)
What is flumazenil (Romazicon)?
What are the possible side effects of flumazenil (Romazicon)?
What is the most important information I should know about flumazenil (Romazicon)?
What should I discuss with my health care provider before receiving flumazenil (Romazicon)?
How is flumazenil given (Romazicon)?
What happens if I miss a dose (Romazicon)?
What happens if I overdose (Romazicon)?
What should I avoid while receiving flumazenil (Romazicon)?
What other drugs will affect flumazenil (Romazicon)?

What is flumazenil (Romazicon)?
Flumazenil reverses the effects of certain types of sedatives from the benzodiazepine (ben-zo-dye-
AYZ-e-peen) group of drugs. This includes Valium, Xanax, Tranxene, Librium, ProSom, Dalmane,
Ativan, Restoril, Halcion, and others.

Flumazenil is used to reverse the sedative effects of a benzodiazepine when used during surgery or
other medical procedure. Flumazenil is also used to treat benzodiazepine overdose.

Flumazenil may also be used for purposes other than those listed in this medication guide.

What are the possible side effects of flumazenil (Romazicon)?

Call your doctor at once if you have any of these serious side effects:

seizures (convulsions);
continued drowsiness for longer than 2 hours after receiving flumazenil;
confusion, fear, panic attack; or
fast or uneven heart rate.
Less serious side effects include:

pain or irritation where the medicine was injected;
agitation or tremors (shaking);
warmth, redness, or tingly feeling under your skin;
dizziness;
sweating or shivering;
headache;
blurred vision; or
ringing in your ears.
Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the
central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine
recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist
in some animal models of activity, but has little or no agonist activity in man.

Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic
neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or
general anesthetics) and does not reverse the effects of opioids.

In animals pretreated with high doses of benzodiazepines over several weeks, ROMAZICON
(flumazenil) elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was
seen in adult human subjects.

Pharmacodynamics

Intravenous ROMAZICON (flumazenil) has been shown to antagonize sedation, impairment of recall,
psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy
human volunteers. The duration and degree of reversal of sedative benzodiazepine effects are
related to the dose and plasma concentrations of flumazenil as shown in the following data from a
study in normal volunteers.

Magnitude and Duration of Reversal of Sedation as a function of flumazenil Dose - illustration
Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6
ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12
to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating
doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the
injection is completed. Eighty percent response will be reached within 3 minutes, with the peak
effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma
concentration of the sedating benzodiazepine as well as the dose of ROMAZICON (flumazenil) given.

In healthy volunteers, ROMAZICON (flumazenil) did not alter intraocular pressure when given alone
and reversed the decrease in intraocular pressure seen after administration of midazolam.

Pharmacokinetics

After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model.
The pharmacokinetics of flumazenil are dose-proportional up to 100 mg.

Distribution

Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of
4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are
proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. The volume of
distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is
approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin
accounts for two thirds of plasma protein binding.

Metabolism

Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil ( < 1%) is found in the
urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its
glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity
exhibited by the de-ethylated free acid.

Elimination

Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the
radioactivity appearing in urine and 5% to 10% in the feces. Clearance of flumazenil occurs primarily
by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of
normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg.

The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent
drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours

Clinical Pharmacology

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