Included as part of the PRECAUTIONS section.
Risks From Concomitant Use With Opioids
Concomitant use of benzodiazepines, including DORAL, and
opioids may result in profound sedation, respiratory depression, coma, and
death. Because of these risks, reserve concomitant prescribing of these drugs
for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant
use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to use of opioids alone. If a decision is made to prescribe
DORAL concomitantly with opioids, prescribe the lowest effective dosages and
minimum durations of concomitant use, and follow patients closely for signs and
symptoms of respiratory depression and sedation. In patients already receiving
an opioid analgesic, prescribe a lower initial dose of DORAL than indicated in
the absence of an opioid and titrate based on clinical response. If an opioid is
initiated in a patient already taking DORAL, 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 DORAL 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 DRUG INTERACTIONS,
CNS-Depressant Effects And Daytime Impairment
DORAL is a central nervous system (CNS) depressant and
can impair daytime function in some patients even when used as prescribed.
Prescribers should monitor for excess depressant effects, but impairment can
occur in the absence of subjective symptoms, and may not be reliably detected
by ordinary clinical exam (i.e. less than formal psychomotor testing). While
pharmacodynamics tolerance or adaptation to some adverse depressant effects of
DORAL may develop, patients using DORAL should be cautioned against driving or
engaging in other hazardous activities or activities requiring complete mental
Additive effects occur with concomitant use of other CNS
depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants,
alcohol), including daytime use. Downward dose adjustment of DORAL and
concomitant CNS depressants should be considered. The potential for adverse
drug interactions continues for several days following discontinuation of
DORAL, until serum levels of both active parent drug and psychoactive
Use of DORAL with other sedative-hypnotics is not
recommended. Alcohol generally should not be used during treatment with DORAL.
The risk of next-day psychomotor impairment is increased if DORAL is taken with
less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended
dose is taken; if co-administered with other CNS depressants [see DOSAGE AND
Benzodiazepine Withdrawal Syndrome
A withdrawal syndrome similar to that from alcohol (e.g.,
convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating) can
occur following abrupt discontinuation of DORAL. The more severe withdrawal
effects are usually limited to patients taking higher than recommended doses
over an extended time. Abrupt discontinuation should be avoided in such
patients, and the dose gradually tapered. Prescribers should monitor patients
for tolerance, abuse, and dependence.
Milder withdrawal symptoms (e.g., dysphoria and insomnia)
can occur following abrupt discontinuation of benzodiazepines taken at
therapeutic levels for short periods [See Drug Abuse And Dependence].
Need To Evaluate For Co-morbid Diagnoses
Because sleep disturbances may be the presenting
manifestation of a physical and/or psychiatric disorder, symptomatic treatment
of insomnia should be initiated only after a careful evaluation of the patient.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate
the presence of a primary psychiatric and/or medical illness that should be
evaluated. Worsening of insomnia or the emergence of new thinking or behavior
abnormalities may be the consequence of an unrecognized psychiatric or physical
disorder. Such findings have emerged during the course of treatment with sedative-hypnotic
Severe Anaphylactic And Anaphylactoid Reactions
Rare cases of angioedema involving the tongue, glottis or
larynx have been reported in patients after taking the first or subsequent
doses of sedative-hypnotics, including DORAL. Some patients have had additional
symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest
Some patients have required medical therapy in the
emergency department. If angioedema involves the tongue, glottis or larynx,
airway obstruction may occur and be fatal. Patients who develop angioedema after
treatment with DORAL should not be rechallenged with the drug.
Abnormal Thinking and Behavior Changes
Abnormal thinking and behavior changes have been reported
in patients treated with sedative-hypnotics including DORAL. Some of these
changes include decreased inhibition (e.g., aggressiveness and extroversion
that seemed out of character), bizarre behavior, and depersonalization. Visual
and auditory hallucinations have also been reported. Amnesia, and other
neuro-psychiatric symptoms may occur.
Paradoxical reactions such as stimulation, agitation,
increased muscle spasticity, and sleep disturbances may occur unpredictably.
Complex behaviors such as “sleep-driving”
(i.e., driving while not fully awake, with amnesia for the event) have been
reported with use of sedative-hypnotics. These behaviors can occur with initial
treatment or in patients previously tolerant of DORAL or other sedative-hypnotics.
Although these behaviors can occur with use at therapeutic doses, risk is
increased by higher doses or concomitant use of alcohol or other CNS
depressants. Due to risk to the patient and community, DORAL should be discontinued
if “sleep-driving” occurs.
Other complex behaviors (e.g., preparing and eating food,
making phone calls, or having sex) have been reported in patients who are not
fully awake after taking a sedative-hypnotic. As with sleep-driving, patients
usually do not remember these events.
Worsening Of Depression
Benzodiazepines may worsen depression. Consequently,
appropriate precautions (e.g., limiting the total prescription size and
increased monitoring for suicidal ideation) should be considered.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Inform patients and caregivers that potentially fatal
additive effects may occur if DORAL is used with opioids and not to use such
drugs concomitantly unless supervised by a healthcare provider [see WARNINGS
AND PRECAUTIONS, DRUG INTERACTIONS]
Inform patients about the benefits and risks of DORAL,
stressing the importance of use as directed. Assist patients in understanding
the Medication Guide and instruct them to read it with each prescription refill.
CNS Depressant Effects And Next-Day Impairment
Tell patients that DORAL can cause next-day impairment,
even in the absence of symptoms. Caution patients against driving or engaging
in other hazardous activities or activities requiring complete mental alertness
when using DORAL. Tell patients that daytime impairment may persist for several
days following discontinuation of DORAL.
Instruct patients to contact you before stopping or
decreasing the dose of DORAL, because withdrawal symptoms can occur.
Abnormal Thinking And Behavior Change
Instruct patients that sedative hypnotics can cause
abnormal thinking and behavior change, including “sleep-driving” and other
complex behaviors while not being fully awake (preparing and eating food, making
phone calls, or having sex). Tell patients to call you immediately if they
develop any of these symptoms.
Severe Allergic Reactions
Inform patients that severe allergic reactions can occur
from DORAL. Describe the signs/symptoms of these reactions and advise patients
to see medical attention immediately if these occur.
Tell patients that DORAL can worsen depression, and to
immediately report any suicidal thoughts.
Alcohol And Other Drugs
Ask patients about alcohol consumption, medicines they
are taking now, and drugs they may be taking without a prescription. Advise
patients that alcohol generally should not be used during treatment with DORAL.
Instruct patients to inform you if they are nursing or
pregnant, or may become pregnant while taking DORAL.
Tolerance, Abuse, And Dependence
Tell patients not to increase the dose of DORAL on their
own, and to inform you if they believe the drug “does not work”.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
DORAL showed no evidence of carcinogenicity in oral
carcinogenicity studies in mice and hamsters.
DORAL was negative in the bacterial reverse mutation
(Ames) assay and equivocal in the mouse lymphoma tk assay.
Impairment Of Fertility
Reproduction studies in mice conducted with DORAL at
doses equal to 60 and
180 times the human dose of 15 mg produced slight
reductions in fertility rate. Similar reductions in fertility rate have been
reported in mice dosed with other benzodiazepines, and is believed to be
related to the sedative effects of these drugs at high doses
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. Administration of benzodiazepines immediately prior to or
during childbirth can result in a syndrome of hypothermia, hypotonia,
respiratory depression, and difficulty feeding. In addition, infants born to
mothers who have taken benzodiazepines during the later stages of pregnancy can
develop dependence, and subsequently withdrawal, during the postnatal period.
Although administration of DORAL to pregnant animals did not indicate a risk
for adverse effects on morphological development at clinically relevant doses,
data for other benzodiazepines suggest the possibility of adverse developmental
effects (long-term effects on neurobehavioral and immunological function) in
animals following prenatal exposure to benzodiazepines. DORAL should be used
during pregnancy only if the potential benefit justifies the potential risk.
Developmental toxicity studies of DORAL in mice at doses
up to 400 times the human dose (15 mg) revealed no major drug-related
malformations. Minor fetal skeletal variations that occurred were delayed
ossification of the sternum, vertebrae, distal phalanges and supraoccipital
bones, at doses approximately 70 and 400 times the human dose. A developmental
toxicity study of DORAL in New Zealand rabbits at doses up to approximately 130
times the human dose demonstrated no effect on fetal morphology or development
DORAL and its metabolites are excreted in human milk.
Caution should be exercised when administering DORAL to a nursing woman.
Safety and effectiveness in pediatric patients have not
DORAL may cause confusion and over-sedation in the
elderly. Elderly patients generally should be started on a low dose of DORAL
and observed closely. Elderly and debilitated patients may be more sensitive to
benzodiazepines, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy. A
double-blind controlled sleep laboratory study (N=30) compared the effects of
DORAL 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5
mg and 15 mg doses appeared to be well tolerated. Caution must be used in interpreting
this data due to the small size of the study.