Somese

Somese is indicated for the short-term treatment of insomnia (generally 7-10 days). Use for more than 2-3 weeks requires complete reevaluation of the patient (see WARNINGS).

Prescriptions for Somese should be written for short-term use (7-10 days) and it should not be prescribed in quantities exceeding a 1-month supply.

It is important to individualize the dosage of Somese Tablets for maximum beneficial effect and to help avoid significant adverse effects.

The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.

In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients.

As with all medications, the lowest effective dose should be used.

Somese Tablets are contraindicated in patients with known hypersensitivity to this drug or other benzodiazepines.

Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.

Somese is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant while receiving Somese, she should be warned of the potential risk to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.

Somese is contraindicated with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several HIV protease inhibitors, (see WARNINGS and DRUG INTERACTIONS).

WARNINGS

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines, including Somese, 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 Somese 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 Somese than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Somese, 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 Somese 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.

Persistent Or Worsening Insomnia

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 drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose related (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), it is important to use the smallest possible effective dose, especially in the elderly.

“Sleep-driving” And Other Complex Behaviors

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 sedativehypnotic- naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleepdriving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics 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.

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 Somese. 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 Somese should not be rechallenged with the drug.

Central Nervous System Manifestations

An increase in daytime anxiety has been reported for Somese after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal (see CLINICAL PHARMACOLOGY). If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including Somese. Some of these changes may be characterized by decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (eg, sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines.

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 of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with Somese Tablets.

As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of Somese. Data from several sources suggest that anterograde amnesia may occur at a higher rate with Somese than with other benzodiazepine hypnotics.

Triazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A

The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.

The following are examples of drugs known to inhibit the metabolism of triazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A.

Potent CYP 3A inhibitors

Potent inhibitors of CYP 3A that should not be used concomitantly with triazolam include ketoconazole, itraconazole, nefazodone and several HIV protease inhibitors including ritonavir, indinavir, nelfinavir, saquinavir and lopinavir. Although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not recommended (see CONTRAINDICATIONS).

Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam)

Macrolide Antibiotics

Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics.

Cimetidine

Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended.

Other drugs possibly affecting triazolam metabolism

Other drugs possibly affecting triazolam metabolism by inhibition of CYP 3A are discussed in the PRECAUTIONS section (see DRUG INTERACTIONS).

PRECAUTIONS

General

In elderly and/or debilitated patients it is recommended that treatment with Somese Tablets be initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired coordination.

Some side effects reported in association with the use of Somese appear to be dose related. These include drowsiness, dizziness, light-headedness, and amnesia.

The relationship between dose and what may be more serious behavioral phenomena is less certain. Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective dose (see DOSAGE AND ADMINISTRATION).

Cases of “traveler's amnesia” have been reported by individuals who have taken Somese to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases.

Caution should be exercised if Somese is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time.

The usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently.

Information For Patients

The text of a Medication Guide for patients is included at the end of this insert. To assure safe and effective use of Somese, the information and instructions provided in this Medication Guide should be discussed with patients.

Risks From Concomitant Use With Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Somese 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.

“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 sedative-hypnotics are 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.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of carcinogenic potential was observed in mice during a 24-month study with Somese in doses up to 4,000 times the human dose.

Pregnancy

Teratogenic effects

Pregnancy category X

(see CONTRAINDICATIONS).

Non-teratogenic Effects

It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines.

Nursing Mothers

Human studies have not been performed; however, studies in rats have indicated that Somese and its metabolites are secreted in milk. Therefore, administration of Somese to nursing mothers is not recommended.

Pediatric Use

Safety and effectiveness of Somese in individuals below 18 years of age have not been established.

Geriatric Use

The elderly are especially susceptible to the dose related adverse effects of Somese. They exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with younger subjects at the same dose. To minimize the possibility of development of oversedation, the smallest effective dose should be used (see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Tolerance/Withdrawal Phenomena

Some loss of effectiveness or adaptation to the sleep inducing effects of these medications may develop after nightly use for more than a few weeks and there may be a degree of dependence that develops. For the benzodiazepine sleeping pills that are eliminated quickly from the body, a relative deficiency of the drug may occur at some point in the interval between each night's use. This can lead to (1) increased wakefulness during the last third of the night, and (2) the appearance of increased signs of daytime anxiety or nervousness. These two events have been reported in particular for Somese.

There can be more severe 'withdrawal' effects when a benzodiazepine sleeping pill is stopped. Such effects can occur after discontinuing these drugs following use for only a week or two, but may be more common and more severe after longer periods of continuous use. One type of withdrawal phenomenon is the occurrence of what is known as 'rebound insomnia'. That is, on the first few nights after the drug is stopped, insomnia is actually worse than before the sleeping pill was given. Other withdrawal phenomena following abrupt stopping of benzodiazepine sleeping pills range from mild unpleasant feelings to a major withdrawal syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely, convulsions.

During placebo-controlled clinical studies in which 1,003 patients received Somese Tablets, the most troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness, dizziness, or light-headedness.

The figures cited below are estimates of untoward clinical event incidence among subjects who participated in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of Somese. The figures cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo, as each group of drug trials is conducted under a different set of conditions.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and nondrug factors to the untoward event incidence rate in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of anxiety] in some subjects but induce it [an untoward event] in others.)

In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.

Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs.

In addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of Somese and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc.

Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. Should these occur, use of the drug should be discontinued.

The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis.

Laboratory analyses were performed on all patients participating in the clinical program for Somese. The following incidences of abnormalities were observed in patients receiving Somese and the corresponding placebo group. None of these changes were considered to be of physiological significance.

When treatment with Somese is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable.

Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during therapy with Somese and are of no known significance.

Drug Abuse And Dependence

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

Controlled Substance

Triazolam is a controlled substance under the Controlled Substance Act, and Somese Tablets have been assigned to Schedule IV.

Abuse, Dependence And Withdrawal

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia), have occurred following abrupt discontinuance of benzodiazepines, including Somese. The more severe symptoms are usually associated with higher dosages and longer usage, although patients at therapeutic dosages given for as few as 1-2 weeks can also have withdrawal symptoms and in some patients there may be withdrawal symptoms (daytime anxiety, agitation) between nightly doses (see CLINICAL PHARMACOLOGY). Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks. The recommendation for tapering is particularly important in any patient with a history of seizure.

The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders. Such dependence-prone individuals should be under careful surveillance when receiving Somese. As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.

Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg).

Manifestations of overdosage with Somese Tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of Somese. Seizures have occasionally been reported after overdosages.

Death has been reported in association with overdoses of triazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including triazolam, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone.

As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including