Waylis Therapeutics LLC
R
x
Only
VALIUM
®
brand of
diazepam
TABLETS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS;
ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND
WITHDRAWAL REACTIONS
• Concomitant use of benzodiazepines and opioids may result in profound
sedation, respiratory depression, coma, and death. Reserve concomitant
prescribing of these drugs in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients for signs and symptoms of respiratory
depression and sedation (see WARNINGS and PRECAUTIONS).
• The use of benzodiazepines, including VALIUM, exposes users to risks of
abuse, misuse, and addiction, which can lead to overdose or death. Abuse
and misuse of benzodiazepines commonly involve concomitant use of other
medications, alcohol, and/or illicit substances, which is associated with an
increased frequency of serious adverse outcomes. Before prescribing
VALIUM and throughout treatment, assess each patient’s risk for abuse,
misuse, and addiction (see WARNINGS).
• The continued use of benzodiazepines, including VALIUM, may lead to
clinically significant physical dependence. The risks of dependence and
withdrawal increase with longer treatment duration and higher daily dose.
Abrupt discontinuation or rapid dosage reduction of VALIUM after
continued use may precipitate acute withdrawal reactions, which can be
life-threatening. To reduce the risk of withdrawal reactions, use a gradual
taper to discontinue VALIUM or reduce the dosage (see DOSAGE AND
ADMINISTRATION and WARNINGS).
DESCRIPTION
Valium (diazepam) is a benzodiazepine derivative. The chemical name of
diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-
2-one. It is a colorless to light yellow crystalline compound, insoluble in water.
The empirical formula is C
16
H
13
ClN
2
O, and the molecular weight is 284.75. The
structural formula is as follows:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Valium is available for oral administration as tablets containing 2 mg, 5 mg or
10 mg diazepam. In addition to the active ingredient diazepam, each tablet
contains the following inactive ingredients: anhydrous lactose, corn starch,
pregelatinized starch and calcium stearate with the following dyes: 5-mg tablets
contain FD&C Yellow No. 6 and D&C Yellow No. 10; 10-mg tablets contain
FD&C Blue No. 1. Valium 2-mg tablets contain no dye.
CLINICAL PHARMACOLOGY
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 C
max
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.
This label may not be the latest approved by FDA.
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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.
Pharmacokinetics in Special Populations
Children
In children 3 - 8 years old the mean half-life of diazepam has been reported to
be 18 hours.
Newborns
In full term infants, elimination half-lives around 30 hours have been reported,
with a longer average half-life of 54 hours reported in premature infants of 28
- 34 weeks gestational age and 8 - 81 days post-partum. In both premature and
full term infants the active metabolite desmethyldiazepam shows evidence of
continued accumulation compared to children. Longer half-lives in infants may
be due to incomplete maturation of metabolic pathways.
Geriatric
Elimination half-life increases by approximately 1 hour for each year of age
beginning with a half-life of 20 hours at 20 years of age. This appears to be due
to an increase in volume of distribution with age and a decrease in clearance.
Consequently, the elderly may have lower peak concentrations, and on multiple
dosing higher trough concentrations. It will also take longer to reach steady-
state. Conflicting information has been published on changes of plasma protein
binding in the elderly. Reported changes in free drug may be due to significant
decreases in plasma proteins due to causes other than simply aging.
Hepat
ic Insufficiency
In mild and moderate cirrhosis, average half-life is increased. The average
increase has been variously reported from 2-fold to 5-fold, with individual half-
lives over 500 hours reported. There is also an increase in volume of
distribution, and average clearance decreases by almost half. Mean half-life is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
receiving an opioid analgesic, prescribe a lower initial dose of Valium than
indicated in the absence of an opioid and titrate based on clinical response. If
an opioid is initiated in a patient already taking Valium, prescribe a lower initial
dose of the opioid and titrate based upon clinical response.
Advise both patients and caregivers about the risks of respiratory depression
and sedation when Valium is used with opioids. Advise patients not to drive or
operate heavy machinery until the effects of concomitant use with the opioid
have been determined (see PRECAUTIONS: Drug Interactions).
Abuse, Misuse, and Addiction
The use of benzodiazepines, including Valium, exposes users to the risks of
abuse, misuse, and addiction, which can lead to overdose or death. Abuse and
misuse of benzodiazepines often (but not always) involve the use of doses
greater than the maximum recommended dosage and commonly involve
concomitant use of other medications, alcohol, and/or illicit substances, which
is associated with an increased frequency of serious adverse outcomes,
including respiratory depression, overdose, or death (see DRUG ABUSE AND
DEPENDENCE: Abuse).
Before prescribing Valium and throughout treatment, assess each patient’s risk
for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use
of Valium, particularly in patients at elevated risk, necessitates counseling
about the risks and proper use of Valium along with monitoring for signs and
symptoms of abuse, misuse, and addiction. Prescribe the lowest effective
dosage; avoid or minimize concomitant use of CNS depressants and other
substances associated with abuse, misuse, and addiction (e.g., opioid
analgesics, stimulants); and advise patients on the proper disposal of unused
drug. If a substance use disorder is suspected, evaluate the patient and institute
(or refer them for) early treatment, as appropriate.
Dependence and Withdrawal Reactions
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue
Valium or reduce the dosage (a patient-specific plan should be used to taper the
dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage
Reduction of Valium).
Patients at an increased risk of withdrawal adverse reactions after
benzodiazepine discontinuation or rapid dosage reduction include those who
take higher dosages, and those who have had longer durations of use.
Acute Withdrawal Reactions
The continued use of benzodiazepines, including Valium, may lead to clinically
significant physical dependence. Abrupt discontinuation or rapid dosage
reduction of Valium after continued use, or administration of flumazenil (a
benzodiazepine antagonist) may precipitate acute withdrawal reactions, which
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
can be life-threatening (e.g., seizures) (see DRUG ABUSE AND
DEPENDENCE: Dependence).
Protracted Withdrawal Syndrome
In some cases, benzodiazepine users have developed a protracted withdrawal
syndrome with withdrawal symptoms lasting weeks to more than 12 months
(see DRUG ABUSE AND DEPENDENCE: Dependence).
Valium is not recommended in the treatment of psychotic patients and should
not be employed instead of appropriate treatment.
Since Valium has a central nervous system depressant effect, patients should be
advised against the simultaneous ingestion of alcohol and other CNS-
depressant drugs during Valium therapy.
As with other agents that have anticonvulsant activity, when Valium is used as
an adjunct in treating convulsive disorders, the possibility of an increase in the
frequency and/or severity of grand mal seizures may require an increase in the
dosage of standard anticonvulsant medication. Abrupt withdrawal of Valium in
such cases may also be associated with a temporary increase in the frequency
and/or severity of seizures.
Neonatal Sedation and Withdrawal Syndrome
Use of Valium late in pregnancy can result in sedation (respiratory depression,
lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability,
restlessness, tremors, inconsolable crying, and feeding difficulties) in the
neonate (see PRECAUTIONS: Pregnancy). Monitor neonates exposed to
Valium during pregnancy or labor for signs of sedation and monitor neonates
exposed to Valium during pregnancy for signs of withdrawal; manage these
neonates accordingly.
PRECAUTIONS
General
If Valium is to be combined with other psychotropic agents or anticonvulsant
drugs, careful consideration should be given to the pharmacology of the agents
to be employed - particularly with known compounds that may potentiate the
action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO
inhibitors and other antidepressants (see Drug Interactions).
The usual precautions are indicated for severely depressed patients or those in
whom there is any evidence of latent depression or anxiety associated with
depression, particularly the recognition that suicidal tendencies may be present
and protective measures may be necessary.
This label may not be the latest approved by FDA.
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Psychiatric and paradoxical reactions are known to occur when using
benzodiazepines (see ADVERSE REACTIONS). Should this occur, use of the
drug should be discontinued. These reactions are more likely to occur in
children and the elderly.
A lower dose is recommended for patients with chronic respiratory
insufficiency, due to the risk of respiratory depression.
Benzodiazepines should be used with extreme caution in patients with a history
of alcohol or drug abuse (see DRUG ABUSE AND DEPENDENCE).
In debilitated patients, it is recommended that the dosage be limited to the
smallest effective amount to preclude the development of ataxia or oversedation
(2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as
needed and tolerated). Some loss of response to the effects of benzodiazepines
may develop after repeated use of Valium for a prolonged time.
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Medication
Guide).
Risks from Concomitant Use with Opioids
Advise both patients and caregivers about the risks of potentially fatal
respiratory depression and sedation when Valium is used with opioids and not
to use such drugs concomitantly unless supervised by a health care provider.
Advise patients not to drive or operate heavy machinery until the effects of
concomitant use with the opioid have been determined (see WARNINGS: Risks
from Concomitant Use with Opioids and PRECAUTIONS: Drug Interactions).
Abuse, Misuse, and Addiction
Inform patients that the use of Valium, even at recommended dosages, exposes
users to risks of abuse, misuse, and addiction, which can lead to overdose and
death, especially when used in combination with other medications (e.g., opioid
analgesics), alcohol, and/or illicit substances. Inform patients about the signs
and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical
help if they develop these signs and/or symptoms; and on the proper disposal
of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG
ABUSE AND DEPENDENCE).
Withdrawal Reactions
Inform patients that the continued use of Valium may lead to clinically
significant physical dependence and that abrupt discontinuation or rapid dosage
reduction of Valium may precipitate acute withdrawal reactions, which can be
life-threatening. Inform patients that in some cases, patients taking
benzodiazepines have developed a protracted withdrawal syndrome with
withdrawal symptoms lasting weeks to more than 12 months. Instruct patients
that discontinuation or dosage reduction of Valium may require a slow taper
(see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE
AND DEPENDENCE).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be advised against the simultaneous ingestion of alcohol and
other CNS-depressant drugs during Valium therapy. As is true of most CNS-
acting drugs, patients receiving Valium should be cautioned against engaging
in hazardous occupations requiring complete mental alertness, such as
operating machinery or driving a motor vehicle.
Pregnancy
Advise pregnant females that use of Valium late in pregnancy can result in
sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal
symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying,
and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and
Withdrawal Syndrome and PRECAUTIONS: Pregnancy). Instruct patients to
inform their healthcare provider if they are pregnant.
Advise patients that there is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to Valium during pregnancy (see
Precautions, Pregnancy).
Nursing
Advise patients that breastfeeding is not recommended during treatment with
Valium (see PRECAUTIONS: Nursing Mothers).
Drug Interactions
Opioids
The concomitant use of benzodiazepines and opioids increases the risk of
respiratory depression because of actions at different receptor sites in the CNS
that control respiration. Benzodiazepines interact at GABA
A
sites and opioids
interact primarily at mu receptors. When benzodiazepines and opioids are
combined, the potential for benzodiazepines to significantly worsen opioid-
related respiratory depression exists. Limit dosage and duration of concomitant
use of benzodiazepines and opioids, and monitor patients closely for respiratory
depression and sedation.
Centrally Acting Agents
If Valium is to be combined with other centrally acting agents, careful
consideration should be given to the pharmacology of the agents employed
particularly with compounds that may potentiate or be potentiated by the action
of Valium, such as phenothiazines, antipsychotics, anxiolytics/sedatives,
hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative
antihistamines, narcotics, barbiturates, MAO inhibitors and other
antidepressants.
This label may not be the latest approved by FDA.
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Alcohol
Concomitant use with alcohol is not recommended due to enhancement of the
sedative effect.
Antacids
Diazepam peak concentrations are 30% lower when antacids are administered
concurrently. However, there is no effect on the extent of absorption. The lower
peak concentrations appear due to a slower rate of absorption, with the time
required to achieve peak concentrations on average 20 - 25 minutes greater in
the presence of antacids. However, this difference was not statistically
significant.
Compounds Which Inhibit Certain Hepatic Enzymes
There is a potentially relevant interaction between diazepam and compounds
which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and
2C19). Data indicate that these compounds influence the pharmacokinetics of
diazepam and may lead to increased and prolonged sedation. At present, this
reaction is known to occur with cimetidine, ketoconazole, fluvoxamine,
fluoxetine, and omeprazole.
Phenytoin
There have also been reports that the metabolic elimination of phenytoin is
decreased by diazepam.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In studies in which mice and rats were administered diazepam in the diet at a
dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the
maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m
2
basis)
for 80 and 104 weeks, respectively, an increased incidence of liver tumors was
observed in males of both species. The data currently available are inadequate
to determine the mutagenic potential of diazepam. Reproduction studies in rats
showed decreases in the number of pregnancies and in the number of surviving
offspring following administration of an oral dose of 100 mg/kg/day
(approximately 16 times the MRHD on a mg/m
2
basis) prior to and during
mating and throughout gestation and lactation. No adverse effects on fertility or
offspring viability were noted at a dose of 80 mg/kg/day (approximately 13
times the MRHD on a mg/m
2
basis).
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Pregnancy
Pregnancy Exposure Registry
There is a pregnancy registry that monitors pregnancy outcomes in women
exposed to psychiatric medications, including Valium, during pregnancy.
Healthcare providers are encouraged to register patients by calling the National
Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting
online at https://womensmentalhealth.org/pregnancyregistry/.
Risk Summary
Neonates born to mothers using benzodiazepines late in pregnancy have been
reported to experience symptoms of sedation and/or neonatal withdrawal (see
WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical
Considerations). Available data from published observational studies of
pregnant women exposed to benzodiazepines do not report a clear association
with benzodiazepines and major birth defects (see Data).
Diazepam has been shown to be teratogenic in mice and hamsters when given
orally at daily doses of 100 mg/kg or greater (approximately eight times the
maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a
mg/m
2
basis). Cleft palate and encephalopathy are the most common and
consistently reported malformations produced in these species by
administration of high, maternally toxic doses of diazepam during
organogenesis.
The background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. In the U.S. general population, the estimated
risk of major birth defects and of miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Benzodiazepines cross the placenta and may produce respiratory depression,
hypotonia and sedation in neonates. Monitor neonates exposed to Valium
during pregnancy and labor for signs of sedation, respiratory depression,
hypotonia, and feeding problems. Monitor neonates exposed to Valium during
pregnancy for signs of withdrawal. Manage these neonates accordingly (see
WARNINGS: Neonatal Sedation and Withdrawal Syndrome).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Labor or Delivery
Special care must be taken when Valium is used during labor and delivery, as
high single doses may produce irregularities in the fetal heart rate and
hypotonia, poor sucking, hypothermia, and moderate respiratory depression in
the neonates. With newborn infants it must be remembered that the enzyme
system involved in the breakdown of the drug is not yet fully developed
(especially in premature infants).
Data
Human Data
Published data from observational studies on the use of benzodiazepines
during pregnancy do not report a clear association with benzodiazepines and
major birth defects. Although early studies reported an increased risk of
congenital malformations with diazepam and chlordiazepoxide, there was no
consistent pattern noted. In addition, the majority of more recent case-control
and cohort studies of benzodiazepine use during pregnancy, which were
adjusted for confounding exposures to alcohol, tobacco and other medications,
have not confirmed these findings.
Animal Data
Diazepam has been shown to be teratogenic in mice and hamsters when given
orally at daily doses of 100 mg/kg or greater (approximately eight times the
maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a
mg/m
2
basis). Cleft palate and encephalopathy are the most common and
consistently reported malformations produced in these species by
administration of high, maternally toxic doses of diazepam during
organogenesis. Rodent studies have indicated that prenatal exposure to
diazepam doses similar to those used clinically can produce long-term changes
in cellular immune responses, brain neurochemistry, and behavior.
Nursing Mothers
Diazepam is present in breastmilk. There are reports of sedation, poor feeding,
and poor weight gain in infants exposed to benzodiazepines through breast
milk. Because of the potential for serious adverse reaction, including sedation
and withdrawal symptoms in breastfed infants, advise patient that
breastfeeding is not recommended during treatment with Valium.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 6 months have
not been established.
Geriatric Use
In elderly patients, it is recommended that the dosage be limited to the smallest
effective amount to preclude the development of ataxia or oversedation (2 mg
to 2.5 mg once or twice daily, initially to be increased gradually as needed and
tolerated).
Extensive accumulation of diazepam and its major metabolite,
desmethyldiazepam, has been noted following chronic administration of
diazepam in healthy elderly male subjects. Metabolites of this drug are known
to be substantially excreted by the kidney, and the risk of toxic reactions may
be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
Hepatic Insufficiency
Decreases in clearance and protein binding, and increases in volume of
distribution and half-life have been reported in patients with cirrhosis. In such
patients, a 2- to 5- fold increase in mean half-life has been reported. Delayed
elimination has also been reported for the active metabolite
desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic
encephalopathy. Increases in half-life have also been reported in hepatic fibrosis
and in both acute and chronic hepatitis (see CLINICAL PHARMACOLOGY:
Pharmacokinetics in Special Populations: Hepatic Insufficiency).
ADVERSE REACTIONS
Side effects most commonly reported were drowsiness, fatigue, muscle
weakness, and ataxia. The following have also been reported:
Central Nervous System: confusion, depression, dysarthria, headache, slurred
speech, tremor, vertigo
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Gastrointestinal System: constipation, nausea, gastrointestinal disturbances
Special Senses: blurred vision, diplopia, dizziness
Cardiovascular System: hypotension
Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute
hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage,
hallucinations, psychoses, delusions, increased muscle spasticity, insomnia,
sleep disturbances, and nightmares. Inappropriate behavior and other adverse
behavioral effects have been reported when using benzodiazepines. Should
these occur, use of the drug should be discontinued. They are more likely to
occur in children and in the elderly.
Urogenital System: incontinence, changes in libido, urinary retention
Skin and Appendages: skin reactions
Laboratories: elevated transaminases and alkaline phosphatase
Other: changes in salivation, including dry mouth, hypersalivation
Antegrade amnesia may occur using therapeutic dosages, the risk increasing at
higher dosages. Amnestic effects may be associated with inappropriate
behavior.
Minor changes in EEG patterns, usually low-voltage fast activity, have been
observed in patients during and after Valium therapy and are of no known
significance.
Because of isolated reports of neutropenia and jaundice, periodic blood counts
and liver function tests are advisable during long-term therapy.
Postmarketing Experience:
Injury, Poisoning and Procedural Complications: There have been reports of
falls and fractures in benzodiazepine users. The risk is increased in those taking
concomitant sedatives (including alcohol), and in the elderly.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Valium contains diazepam, a Schedule IV controlled substance.
Abuse
Valium is a benzodiazepine and a CNS depressant with a potential for abuse
and addiction. Abuse is the intentional, non-therapeutic use of a drug, even
once, for its desirable psychological or physiological effects. Misuse is the
intentional use, for therapeutic purposes, of a drug by an individual in a way
other than prescribed by a health care provider or for whom it was not
prescribed. Drug addiction is a cluster of behavioral, cognitive, and
physiological phenomena that may include a strong desire to take the drug,
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difficulties in controlling drug use (e.g., continuing drug use despite harmful
consequences, giving a higher priority to drug use than other activities and
obligations), and possible tolerance or physical dependence. Even taking
benzodiazepines as prescribed may put patients at risk for abuse and misuse of
their medication. Abuse and misuse of benzodiazepines may lead to addiction.
Abuse and misuse of benzodiazepines often (but not always) involve the use of
doses greater than the maximum recommended dosage and commonly involve
concomitant use of other medications, alcohol, and/or illicit substances, which
is associated with an increased frequency of serious adverse outcomes,
including respiratory depression, overdose, or death. Benzodiazepines are often
sought by individuals who abuse drugs and other substances, and by individuals
with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).
The following adverse reactions have occurred with benzodiazepine abuse
and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia,
blurred vision, confusion, depression, disinhibition, disorientation, dizziness,
euphoria, impaired concentration and memory, indigestion, irritability, muscle
pain, slurred speech, tremors, and vertigo.
The following severe adverse reactions have occurred with benzodiazepine
abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior,
seizures, coma, breathing difficulty, and death. Death is more often associated
with polysubstance use (especially benzodiazepines with other CNS
depressants such as opioids and alcohol).
Dependence
Physical Dependence
Valium may produce physical dependence from continued therapy. Physical
dependence is a state that develops as a result of physiological adaptation in
response to repeated drug use, manifested by withdrawal signs and symptoms
after abrupt discontinuation or a significant dose reduction of a drug. Abrupt
discontinuation or rapid dosage reduction of benzodiazepines or administration
of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal
reactions, including seizures, which can be life-threatening. Patients at an
increased risk of withdrawal adverse reactions after benzodiazepine
discontinuation or rapid dosage reduction include those who take higher
dosages (i.e., higher and/or more frequent doses), those who have had longer
durations of use (see WARNINGS: Dependence and Withdrawal Reactions).
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue
Valium or reduce the dosage (see DOSAGE and ADMINISTRATION:
Discontinuation or Dosage Reduction of Valium and WARNINGS:
Dependence and Withdrawal Reactions).
Acute Withdrawal Signs and Symptoms
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Acute withdrawal signs and symptoms associated with benzodiazepines have
included abnormal involuntary movements, anxiety, blurred vision,
depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal
adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased
appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory
impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness,
tachycardia, and tremor. More severe acute withdrawal signs and symptoms,
including life-threatening reactions, have included catatonia, convulsions,
delirium tremens, depression, hallucinations, mania, psychosis, seizures, and
suicidality.
Protracted Withdrawal Syndrome
Protracted withdrawal syndrome associated with benzodiazepines is
characterized by anxiety, cognitive impairment, depression, insomnia,
formication, motor symptoms (e.g., weakness, tremor, muscle twitches),
paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial
benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks
to more than 12 months. As a result, there may be difficulty in differentiating
withdrawal symptoms from potential re-emergence or continuation of
symptoms for which the benzodiazepine was being used; however, little
tolerance develops to the amnestic reactions and other cognitive impairments
caused by benzodiazepines.
Tolerance
Tolerance to Valium may develop from continued therapy. Tolerance is a
physiological state characterized by a reduced response to a drug after repeated
administration (i.e., a higher dose of a drug is required to produce the same
effect that was once obtained at a lower dose). Tolerance to the therapeutic
effect of Valium may develop; however, little tolerance develops to the
amnestic reactions and other cognitive impairments caused by benzodiazepines.
OVERDOSAGE
Overdosage of benzodiazepines is characterized by central nervous system
depression ranging from drowsiness to coma. In mild to moderate cases,
symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic
state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or
disinhibitory reactions (including agitation, irritability, impulsivity, violent
behavior, confusion, restlessness, excitement, and talkativeness) may occur. In
severe overdosage cases, patients may develop respiratory depression and
coma. Overdosage of benzodiazepines in combination with other CNS
depressants (including alcohol and opioids) may be fatal (see WARNINGS:
Dependence and Withdrawal Reactions). Markedly abnormal (lowered or
elevated) blood pressure, heart rate, or respiratory rate raise the concern that
additional drugs and/or alcohol are involved in the overdosage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In managing benzodiazepine overdosage, employ general supportive measures,
including intravenous fluids and airway management. Flumazenil, a specific
benzodiazepine receptor antagonist, is indicated for the complete or partial
reversal of the sedative effects of benzodiazepines in the management of
benzodiazepine overdosage, can lead to withdrawal and adverse reactions,
including seizures, particularly in the context of mixed overdosage with drugs
that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in
patients with long-term benzodiazepine use and physical dependency. The risk
of withdrawal seizures with flumazenil use may be increased in patients with
epilepsy. Flumazenil is contraindicated in patients who have received a
benzodiazepine for control of a potentially life-threatening condition (e.g.,
status epilepticus). If the decision is made to use flumazenil, it should be used
as an adjunct to, not as a substitute for, supportive management of
benzodiazepine overdosage. See the flumazenil injection Prescribing
Information.
Consider contacting the Poison Help line (1-800-222-1222) or a medical
toxicologist for additional overdosage management recommendations.
DOSAGE AND ADMINISTRATION
Dosage should be individualized for maximum beneficial effect. While the
usual daily dosages given below will meet the needs of most patients, there will
be some who may require higher doses. In such cases dosage should be
increased cautiously to avoid adverse effects.
ADULTS: USUAL DAILY DOSE:
Management of Anxiety Disorders and Relief of
Symptoms of Anxiety.
Symptomatic Relief in Acute Alcohol
Withdrawal.
Adjunctively for Relief of Skeletal Muscle
Spasm.
Depending upon severity of symptoms—2 mg
to 10 mg, 2 to 4 times daily
10 mg, 3 or 4 times during the first 24 hours,
reducing to 5 mg, 3 or 4 times daily as needed.
2 mg to 10 mg, 3 or 4 times daily
Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Patients, or in the presence of
debilitating disease.
PEDIATRIC PATIENTS:
Because of varied responses to CNS-acting
drugs, initiate therapy with lowest dose and
increase as required. Not for use in pediatric
patients under 6 months.
2 mg to 2.5 mg, 1 or 2 times daily initially;
increase gradually as needed and tolerated.
1 mg to 2.5 mg, 3 or 4 times daily initially;
increase gradually as needed and tolerated.
Discontinuation or Dosage Reduction of Valium
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue
Valium or reduce the dosage. If a patient develops withdrawal reactions,
consider pausing the taper or increasing the dosage to the previous tapered
dosage level. Subsequently decrease the dosage more slowly (see WARNINGS:
Dependence and Withdrawal Reactions and DRUG ABUSE AND
DEPENDENCE: Dependence).
HOW SUPPLIED
For oral administration, Valium is supplied as round, flat-faced scored tablets
with V-shaped perforation and beveled edges. Valium is available as follows:
2mg, white - bottles of 100 (NDC-80725-004-01)
5mg, yellow - bottles of 100 (NDC-80725-005-01)
10 mg, blue - bottles of 100 ( NDC-80725-006-01)
Engraved on tablets:
2 mg—2 and VALIUM® on the outside edge; vertically scored on reverse side
5 mg—5 and VALIUM® on the outside edge; vertically scored on reverse side
10 mg—10 and VALIUM® on the outside edge; vertically scored on reverse side
Storage
Store at room temperature 59º to 86ºF (15º to 30ºC). Dispense in tight, light-
resistant containers as defined in USP/NF.
Distributed by:
Waylis Therapeutics LLC
Wixom, MI 48393
248-313-9675
Revised: October 2023
© 2023 Waylis Therapeutics LLC. All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION
GUIDE VALIUM
(VAL-ee-um)
(diazepam) tablets, C-IV
What is the most important information I should know about VALIUM?
•
VALIUM is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or
other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness,
breathing problems (respiratory depression), coma and death. Get emergency help right away if any of
the following happens:
o
Shallow or slowed breathing,
o
Breathing stops (which may lead to the heart stopping),
o
Excessive sleepiness (sedation).
Do not drive or operate heavy machinery until you know how taking VALIUM with opioids affects
you.
•
Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with
benzodiazepines, including VALIUM, which can lead to overdose and serious side effects including coma
and death.
o
Serious side effects including coma and death have happened in people who have abused or
misused benzodiazepines, including VALIUM. These serious side effects may also include delirium,
paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider
or go to the nearest hospital emergency room right away if you get any of these serious side effects.
o
You can develop an addiction even if you take VALIUM exactly as prescribed by your healthcare
provider.
o
Take VALIUM exactly as your healthcare provider prescribed.
o
Do not share your VALIUM with other people.
o
Keep VALIUM in a safe place and away from children.
•
Physical dependence and withdrawal reactions. VALIUM can cause physical dependence and
withdrawal reactions.
o
Do not suddenly stop taking VALIUM. Stopping VALIUM suddenly can cause serious and life-
threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and
severe mental or nervous system changes, depression, seeing or hearing things that others do not see or
hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or
actions. Call your healthcare provider or go to the nearest hospital emergency room right away if
you get any of these symptoms.
o
Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to
more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression,
problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle
twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.
o
Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more
about the differences between physical dependence and drug addiction.
o
Do not take more VALIUM than prescribed or take VALIUM for longer than prescribed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is VALIUM?
•
VALIUM is a prescription medicine used:
o
to treat anxiety disorders
o
for the short-term relief of the symptoms of anxiety
o
to relieve the symptoms of alcohol withdrawal including agitation, shakiness (tremor), sudden and
severe mental or nervous system changes (delirium tremens) and seeing or hearing things that others do
not see or hear (hallucinations)
o
along with other medicines for the relief of muscle spasms
o
along with other medicines to treat seizure disorders.
•
VALIUM is a federal controlled substance (C-IV) because it contains diazepam that can be abused
or lead to dependence. Keep VALIUM in a safe place to prevent misuse and abuse. Selling or giving
away VALIUM may harm others, and is against the law. Tell your healthcare provider if you have abused
or been dependent on alcohol, prescription medicines or street drugs.
•
It is not known if VALIUM is safe and effective in children under 6 months of age.
•
It is not known if VALIUM is safe and effective for use longer than 4 months.
Do not take VALIUM if you:
•
are allergic to diazepam or any of the ingredients in VALIUM. See the end of this Medication Guide for
a complete list of ingredients in VALIUM.
•
have a disease that can cause muscle weakness called myasthenia gravis
•
have severe breathing problems (severe respiratory insufficiency)
•
have severe liver problems
•
have a sleep problem called sleep apnea syndrome
Before you take VALIUM, tell your healthcare provider about all of your medical conditions, including if
you:
•
have or have had depression, mood problems, or suicidal thoughts or behavior
•
have lung disease or breathing problems
•
have liver or kidney problems
•
are pregnant or plan to become pregnant.
o
Taking VALIUM late in pregnancy may cause your baby to have symptoms of sedation (breathing
problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability,
restlessness, shaking, excessive crying, feeding problems).
o
Tell your healthcare provider right away if you become pregnant or think you are pregnant during
treatment with VALIUM.
o
There is a pregnancy registry for women who take VALIUM during pregnancy. The purpose of the
registry is to collect information about the health of you and your baby. If you become pregnant during
treatment with VALIUM, talk to your healthcare provider about registering with the National Pregnancy
Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting
https://womensmentalhealth.org/pregnancyregistry/.
•
are breastfeeding or plan to breastfeed. VALIUM passes into your breast milk.
o
Talk to your healthcare provider about the best way to feed your baby if you take VALIUM.
o
Breastfeeding is not recommended during treatment with VALIUM.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements.
Taking VALIUM with certain other medicines can cause side effects or affect how well VALIUM or the other
medicines work. Do not start or stop other medicines without talking to your healthcare provider.
How should I take VALIUM?
•
Take VALIUM exactly as your healthcare provider tells you to take it. Your healthcare provider will tell
you how much VALIUM to take and when to take it.
•
Talk to your healthcare provider about slowly stopping VALIUM to avoid withdrawal symptoms.
•
If you take too much VALIUM, call your healthcare provider or go to the nearest hospital emergency
room right away.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of VALIUM? VALIUM may cause serious side effects, including:
•
See “What is the most important information I should know about VALIUM?”
•
Seizures. Taking VALIUM with other medicines used to treat epilepsy can cause an increase in the
number or severity of grand mal seizures.
•
VALIUM can make you sleepy or dizzy, and can slow your thinking and motor skills.
o
Do not drive, operate heavy machinery, or do other dangerous activities until you know how
VALIUM affects you.
o
Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking
VALIUM without first talking to your healthcare provider. When taken with alcohol or drugs
that cause sleepiness or dizziness, VALIUM may make your sleepiness or dizziness much worse.
•
Like other antiepileptic drugs, VALIUM may cause suicidal thoughts or actions in a very small
number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms, especially if they are
new,
worse, or worry you:
•
thoughts about suicide or dying
•
new or worse depression
•
feeling agitated or restless
•
trouble sleeping (insomnia)
•
acting aggressive, being angry or violent
•
other unusual changes in behavior or mood
•
attempts to commit suicide
•
new or worse anxiety or irritability
•
an extreme increase in activity and talking (mania)
•
new or worse panic attacks
•
acting on dangerous impulses
How can I watch for early symptoms of suicidal thoughts and actions?
•
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
•
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
The most common side effects of VALIUM include:
•
drowsiness
•
muscle weakness
•
loss of control of body movements (ataxia)
•
fatigue
These are not all the possible side effects of VALIUM. Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Waylis at 1-303-557-7642
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store VALIUM?
•
Store VALIUM in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C)
and out of the light.
•
Keep VALIUM and all medicines out of the reach of children.
General information about the safe and effective use of VALIUM.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
VALIUM for a condition for which it was not prescribed. Do not give VALIUM to other people, even if they
have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider
for information about VALIUM that is written for health professionals.
What are the ingredients in VALIUM?
Active ingredient: diazepam
Inactive ingredients: anhydrous lactose, corn starch, pregelatinized starch and calcium stearate
Distributed by: Waylis Therapeutics LLC., Wixom, MI 48393
For more information, call . 1-303-557-7642.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2023
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gurpreet
Gill Sangha
Digitally signed by Gurpreet Gill Sangha
Date: 10/11/2023 08:53:40AM
GUID: 5135f2ad000117842392c50c36c7f28a
(
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda