RESTORIL (temazepam) capsule
SpecGx LLC
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 Restoril, 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 Restoril and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS).
-
The continued use of benzodiazepines, including Restoril, 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 Restoril 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 Restoril or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS).
DESCRIPTION
Restoril™ (temazepam) is a benzodiazepine hypnotic agent. The chemical name is 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and the structural formula is:
Temazepam is a white, crystalline substance, very slightly soluble in water and sparingly soluble in alcohol USP.
Restoril™ (temazepam) Capsules USP, 7.5 mg, 15 mg, 22.5 mg, and 30 mg, are for oral administration.
7.5 mg, 15 mg, 22.5 mg, and 30 mg Capsules
Active Ingredient: temazepam USP
7.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red iron oxide, titanium dioxide.
May also include: n-butyl alcohol, iron oxide red, shellac, shellac glaze, SD-35A alcohol.
15 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45 alcohol.
22.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45 alcohol.
30 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45 alcohol.
CLINICAL PHARMACOLOGY
Pharmacokinetics
In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using 3H labeled drug, Restoril was well absorbed and found to have minimal (8%) first pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4 to 0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the study population and method of determination. Metabolites were formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam. There is no accumulation of metabolites. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range.
Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).
Bioavailability, Induction, and Plasma Levels
Following ingestion of a 30 mg Restoril capsule, measurable plasma concentrations were achieved 10 to 20 minutes after dosing with peak plasma levels ranging from 666 to 982 ng/mL (mean 865 ng/mL) occurring approximately 1.2 to 1.6 hours (mean 1.5 hours) after dosing.
In a 7 day study, in which subjects were given a 30 mg Restoril capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2 to 7) were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable.
At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man.
Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward Effects
The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the administered drug and for some hypnotics, the half-life of any active metabolites formed. Benzodiazepine hypnotics have a spectrum of half-lives from short (<4 hours) to long (>20 hours). When half-lives are long, drug (and for some drugs their active metabolites) may accumulate during periods of nightly administration and be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug (and, where appropriate, its active 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 elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its active metabolites (i.e., 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 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night, and the appearance of increased signs of daytime anxiety.
Controlled Trials Supporting Efficacy
Restoril improved sleep parameters in clinical studies. Residual medication effects (“hangover”) were essentially absent. Early morning awakening, a particular problem in the geriatric patient, was significantly reduced.
Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time and sleep latency, with significant drug-placebo differences at 2 weeks occurring only for total sleep time at the 2 higher doses, and for sleep latency only at the highest dose.
In these sleep laboratory studies, REM sleep was essentially unchanged and slow wave sleep was decreased. No measurable effects on daytime alertness or performance occurred following Restoril treatment or during the withdrawal period, even though a transient sleep disturbance in some sleep parameters was observed following withdrawal of the higher doses. There was no evidence of tolerance development in the sleep laboratory parameters when patients were given Restoril nightly for at least 2 weeks.
In addition, normal subjects with transient insomnia associated with first night adaptation to the sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time, sleep latency and number of awakenings, with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep time at the 2 higher doses and for number of awakenings only at the 30 mg dose.
INDICATIONS AND USAGE
Restoril™ (temazepam) is indicated for the short-term treatment of insomnia (generally 7 to 10 days).
For patients with short-term insomnia, instructions in the prescription should indicate that Restoril™ (temazepam) should be used for short periods of time (7 to 10 days).
The clinical trials performed in support of efficacy were 2 weeks in duration with the final formal assessment of sleep latency performed at the end of treatment.
WARNINGS
Risks from Concomitant Use with Opioids
Concomitant use of benzodiazepines, including Restoril, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs 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 Restoril 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 Restoril than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Restoril, 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 Restoril 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 Restoril, 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 Restoril and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Restoril, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Restoril 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 Restoril or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION, Discontinuation or Dosage Reduction of Restoril ).
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 Restoril, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Restoril after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which 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 ).
Sleep disturbance may be the presenting manifestation of an underlying physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated. 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 may be the consequence of an unrecognized psychiatric or physical disorder as may the emergence of new abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in association with the use of drugs with central nervous system depressant activity, including those of the benzodiazepine class. Because some of the worrisome adverse effects of benzodiazepines, including Restoril, appear to be dose related (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ), it is important to use the lowest possible effective dose. Elderly patients are especially at risk.
Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem out of character, similar to that seen with alcohol. Other kinds of behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, and depersonalization. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with Restoril alone at therapeutic doses, the use of alcohol and other CNS depressants with Restoril appears to increase the risk of such behaviors, as does the use of Restoril at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Restoril should be strongly considered for patients who report a “sleep-driving” episode. 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. Amnesia and other neuro-psychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking has been reported in association with the use of sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Because Restoril can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.
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 Restoril. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. 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 Restoril should not be rechallenged with the drug.
Neonatal Sedation and Withdrawal Syndrome
Use of Restoril 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 Restoril during pregnancy or labor for signs of sedation and monitor neonates exposed to Restoril during pregnancy for signs of withdrawal; manage these neonates accordingly.
PRECAUTIONS
General
Since the risk of the development of oversedation, dizziness, confusion, and/or ataxia increases substantially with larger doses of benzodiazepines in elderly and debilitated patients, 7.5 mg of Restoril is recommended as the initial dosage for such patients.
Restoril should be administered with caution in severely depressed patients or those in whom there is any evidence of latent depression; it should be recognized that suicidal tendencies may be present and protective measures may be necessary.
The usual precautions should be observed in patients with impaired renal or hepatic function and in patients with chronic pulmonary insufficiency.
If Restoril is to be combined with other drugs having known hypnotic properties or CNS-depressant effects, consideration should be given to potential additive effects.
The possibility of a synergistic effect exists with the co-administration of Restoril and diphenhydramine. One case of stillbirth at term has been reported 8 hours after a pregnant patient received Restoril and diphenhydramine. A cause and effect relationship has not yet been determined (see CONTRAINDICATIONS ).
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 Restoril is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare 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 Restoril, 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 Restoril may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Restoril 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 Restoril may require a slow taper (see WARNINGS, Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ).
“Sleep-Driving” and Other Complex Behaviors
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Restoril is taken with alcohol or other central nervous system depressants (see WARNINGS ). 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.
Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients.
Pregnancy
Advise pregnant females that use of Restoril 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 Restoril during pregnancy (see PRECAUTIONS, Pregnancy ).
Nursing
Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using Restoril to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS, Nursing Mothers ).
Laboratory Tests
The usual precautions should be observed in patients with impaired renal or hepatic function and in patients with chronic pulmonary insufficiency. Abnormal liver function tests as well as blood dyscrasias have been reported with benzodiazepines.
Drug Interactions
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 GABAA 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.
The benzodiazepines, including temazepam, produce additive CNS-depressant effects when co-administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.
The pharmacokinetic profile of temazepam does not appear to be altered by orally administered cimetidine dosed according to labeling.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day for 24 months and in mice at dietary doses of 160 mg/kg/day for 18 months. No evidence of carcinogenicity was observed although hyperplastic liver nodules were observed in female mice exposed to the highest dose. The clinical significance of this finding is not known.
Fertility in male and female rats was not adversely affected by Restoril.
No mutagenicity tests have been done with temazepam.
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Restoril, 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).
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 Restoril during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Restoril during pregnancy for signs of withdrawal. Manage these neonates accordingly (see
WARNINGS, Neonatal Sedation and Withdrawal Syndrome
).
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
Reproduction studies in animals with temazepam were performed in rats and rabbits. In a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling mortality. Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and 120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered skeletal variants, in a second study at doses of 240 mg/kg or higher. In rabbits, occasional abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose relationship. Although these abnormalities were not found in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg or higher, there was an increased incidence of the 13th rib variant when compared to the incidence in concurrent and historical controls.
Nursing Mothers
Risk Summary
Temazepam is present in breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of temazepam on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Restoril and any potential adverse effects on the breastfed infant from Restoril or from the underlying maternal condition.
Clinical Considerations
Infants exposed to Restoril through breast milk should be monitored for sedation, poor feeding and poor weight gain.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Restoril did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy commonly observed in this population. Restoril 7.5 mg is recommended as the initial dosage for patients aged 65 and over since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls increases substantially with larger doses of benzodiazepines in elderly and debilitated patients.
ADVERSE REACTIONS
During controlled clinical studies in which 1076 patients received Restoril at bedtime, the drug was well tolerated. Side effects were usually mild and transient. Adverse reactions occurring in 1% or more of patients are presented in the following table:
| |
Restoril % Incidence (n=1076) |
Placebo % Incidence (n=783) |
| Drowsiness |
9.1 |
5.6 |
| Headache |
8.5 |
9.1 |
| Fatigue |
4.8 |
4.7 |
| Nervousness |
4.6 |
8.2 |
| Lethargy |
4.5 |
3.4 |
| Dizziness |
4.5 |
3.3 |
| Nausea |
3.1 |
3.8 |
| Hangover |
2.5 |
1.1 |
| Anxiety |
2.0 |
1.5 |
| Depression |
1.7 |
1.8 |
| Dry Mouth |
1.7 |
2.2 |
| Diarrhea |
1.7 |
1.1 |
| Abdominal Discomfort |
1.5 |
1.9 |
| Euphoria |
1.5 |
0.4 |
| Weakness |
1.4 |
0.9 |
| Confusion |
1.3 |
0.5 |
| Blurred Vision |
1.3 |
1.3 |
| Nightmares |
1.2 |
1.7 |
| Vertigo |
1.2 |
0.8 |
The following adverse events have been reported less frequently (0.5% to 0.9%):
Central Nervous System – anorexia, ataxia, equilibrium loss, tremor, increased dreaming
Cardiovascular – dyspnea, palpitations
Gastrointestinal – vomiting
Musculoskeletal – backache
Special Senses – hyperhidrosis, burning eyes
Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%).
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Restoril contains temazepam, a Schedule IV controlled substance.
Abuse
Restoril 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 healthcare 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, 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
Restoril 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) and 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 Restoril or reduce the dosage (see DOSAGE and ADMINISTRATION, Discontinuation or Dosage Reduction of Restoril and WARNINGS, Dependence and Withdrawal Reactions ).
Acute Withdrawal Signs and Symptoms
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 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.
Tolerance
Tolerance to Restoril 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 Restoril 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, Abuse, Misuse, and Addiction ). 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.
In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist 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 (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.
DOSAGE AND ADMINISTRATION
While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined.
Discontinuation or Dosage Reduction of Restoril
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Restoril 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
Restoril™ (temazepam) Capsules USP
7.5 mg
Blue and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and
Bottle of 30 . . . . . . . . . .NDC 0406-9915-03
Bottle of 100 . . . . . . . . .NDC 0406-9915-01
15 mg
Maroon and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and
Bottle of 100 . . . . . . . . .NDC 0406-9916-01
22.5 mg
Opaque blue capsules, with the opaque blue body imprinted “FOR SLEEP” on one side and
Bottle of 30 . . . . . . . . . .NDC 0406-9914-03
30 mg
Maroon and blue capsules, with the blue body imprinted “FOR SLEEP” on one side and
Bottle of 100 . . . . . . . . .NDC 0406-9917-01
Dispense in a well-closed, light-resistant container with a child-resistant closure.
Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo,
© 2023 Mallinckrodt.
Rev 01/2023
Mallinckrodt™
Pharmaceuticals
An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/L20R02.pdf or by calling 1-800-778-7898 for alternate delivery options.
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MEDICATION GUIDE |
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What is the most important information I should know about RESTORIL?
Do not drive or operate heavy machinery until you know how taking RESTORIL and opioids affects you.
Call your healthcare provider right away if you find out that you have done any of the above activities after taking RESTORIL. |
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What is RESTORIL?
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Do not take RESTORIL if you
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Before you take RESTORIL, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. |
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How should I take RESTORIL?
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What are the possible side effects of RESTORIL?
The most common side effects of RESTORIL include:
You may still feel drowsy the next day after taking RESTORIL. Do not drive or do other dangerous activities after taking RESTORIL until you feel fully awake.
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How should I store RESTORIL?
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General information about the safe and effective use of RESTORIL.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RESTORIL for a condition for which it was not prescribed. Do not give RESTORIL to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about RESTORIL that is written for healthcare professionals. |
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What are the ingredients in RESTORIL?
Active Ingredient: temazepam Inactive Ingredients: gelatin, lactose, magnesium stearate, red iron oxide, titanium dioxide Manufactured by SpecGx LLC Webster Groves, MO 63119 If you would like more information, call Mallinckrodt Inc. at 1-800-778-7898 or visit www.mallinckrodt.com. Mallinckrodt™ |
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This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: January 2023 L20R02 |
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 7.5 mg Bottle
NDC 0406-9915-01
100 Capsules
Restoril™
(temazepam) Capsules USP
CIV
7.5 mg
Rx only
Each capsule contains: Temazepam USP..............7.5 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Mallinckrodt™
L00R01
Rev 09/2017
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 15 mg Bottle
NDC 0406-9916-01
100 Capsules
Restoril™
(temazepam) Capsules USP
CIV
15 mg
Rx only
Each capsule contains: Temazepam USP..............15 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Mallinckrodt™
L00R07
Rev 09/2017
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 22.5 mg Bottle
NDC 0406-9914-03
30 Capsules
Restoril™
(temazepam) Capsules USP
CIV
22.5 mg
Rx only
Each capsule contains: Temazepam USP..............22.5 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Mallinckrodt™
L00R03
Rev 09/2017
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 30 mg Bottle
NDC 0406-9917-01
100 Capsules
Restoril™
(temazepam) Capsules USP
CIV
30 mg
Rx only
Each capsule contains: Temazepam USP..............30 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Mallinckrodt™
L00R02
Rev 09/2017
