Intermezzo

Overdose

In post-marketing experience of overdose with oral zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative-hypnotic effect was shown to be reduced by flumazenil and therefore flumazenil may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

As with management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage.

Contraindications

Intermezzo is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions with zolpidem include anaphylaxis and angioedema.

Undesirable effects

The following serious adverse reactions in zolpidem-treated patients are discussed in greater detail in other sections of the labeling:

• CNS-depressant effects and next-day impairment
• Serious anaphylactic and anaphylactoid reactions
• Abnormal thinking and behavioral changes, and complex behaviors
• Withdrawal effects

The safety data described below are based on two double-blind placebo-controlled trials of Intermezzo in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening. These two trials included 230 and 82 patients treated with 3.5 mg and 1.75 mg of Intermezzo, respectively. The first study was a 3way crossover sleep-laboratory study in 82 patients (58 female and 24 male; median age 47 years; 51% Caucasian, 44% African-American) of 1.75 mg and 3.5 mg of Intermezzo compared to placebo (Study 1). The second study was a 4-week, parallel-group at-home study in 295 patients (201 female and 94 male; median age 43 years) of 3.5 mg of Intermezzo compared to placebo, used on an as-needed basis after spontaneous middle-of-the-night awakenings (Study 2). In Study 2, patients took Intermezzo during the night on 62% of study nights.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice.

Table 1 shows the incidence of adverse reactions reported in Study 2 that occurred in 2% or more of Intermezzo-treated (3.5 mg) patients in which the incidence was greater than the incidence in placebo-treated patients. For women and other patients taking the 1.75 mg dose in Study 1, the incidence of adverse reactions was similar to the incidence seen with 3.5 mg of Intermezzo in Table 1.

The most commonly reported adverse reactions in all treatment groups were headache, nausea, and fatigue.

Table 1: Summary of Adverse Reactions ( ≥ 2%) in Outpatient, Double-Blind, Parallel-Group, Placebo-Controlled Study (Study 2)

The following adverse reactions have been identified during post-approval use of Intermezzo. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

• Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, and mucosal inflammation.

Therapeutic indications

Intermezzo® (zolpidem tartrate) sublingual tablet is indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep.

Intermezzo is not indicated for the treatment of middle-of-the-night insomnia when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking.

Pharmacokinetic properties

Women cleared zolpidem tartrate from the body after sublingual administration of a 3.5 mg dose of Intermezzo at a lower rate than men (2.7 mL/min/kg vs. 4.0 mL/min/kg). Cmax and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended dose of Intermezzo for women is 1.75 mg, and the recommended dose for adult men is 3.5 mg.

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Fertility, pregnancy and lactation

There are no adequate and well-controlled studies of zolpidem in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Intermezzo should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis.

Qualitative and quantitative composition

Intermezzo is available as 1.75 mg and 3.5 mg tablets for sublingual administration.

Intermezzo 1.75 mg tablets are yellow, round, uncoated, biconvex, debossed with ZZ on one side.

Intermezzo 3.5 mg tablets are beige, round, uncoated, biconvex, debossed with ZZ on one side.

Each sublingual tablet is individually packaged in a unit-dose pouch.

Intermezzo 1.75 mg tablets are yellow, round, uncoated, biconvex, debossed with ZZ on one side and supplied as:

NDC 59011-256-30: Carton of 30 unit-dose pouches

Intermezzo 3.5 mg tablets are beige, round, uncoated, biconvex, debossed with ZZ on one side and supplied as:

NDC 59011-255-30: Carton of 30 unit-dose pouches

Store between 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.

The patient should be instructed not to remove the sublingual tablet from the unit-dose pouch until the patient is ready to consume it.

Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 Manufactured by: Patheon Pharmaceuticals, Inc., Cincinnati, OH 45237. Revised: Sep 2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Intermezzo, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of Intermezzo and of other concomitant CNS depressants may be necessary when Intermezzo is administered with such agents because of the potentially additive effects. The use of Intermezzo with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

In a driving study, healthy subjects who received Intermezzo with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo. The risk of next-day driving impairment (and psychomotor impairment) is increased if Intermezzo is taken with less than 4 hours of bedtime remaining, if higher than recommended dose is taken, if co-administered with other CNS depressants, or coadministered with other drugs that increase the blood levels of zolpidem.

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, including zolpidem.

Cases of angioedema involving the tongue, glottis, or larynx have been reported in patients after taking the first or subsequent doses of zolpidem. 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 throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema or anaphylaxis after treatment with zolpidem should not be rechallenged with Intermezzo.

Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including zolpidem. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation, and depersonalization. Visual and auditory hallucinations have also been reported.

In controlled trials of zolpidem tartrate 10 mg taken at bedtime, < 1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime, reported hallucinations, versus 0% treated with placebo.

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 in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as “ sleep-driving” have occurred with zolpidem alone at therapeutic doses, the co-administration of zolpidem with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Intermezzo 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, anxiety and other neuro-psychiatric symptoms may also occur.

The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.

Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Intermezzo is prescribed to patients with compromised respiratory function. Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risks of respiratory depression should be considered prior to prescribing Intermezzo in patients with respiratory impairment including sleep apnea and myasthenia gravis.

There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence.

See FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with Intermezzo. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Intermezzo and with each prescription refill.

Review the Intermezzo Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Intermezzo should be taken only as prescribed.

Tell patients that Intermezzo has the potential to cause next-day impairment, and that this risk is increased if dosing instructions are not carefully followed. Tell patients to wait for at least 4 hours after dosing and until they feel fully awake before driving or engaging in other activities requiring full mental alertness.

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.

Instruct patients to inform their families that zolpidem has been associated with “ sleep-driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex), and tell patients and their families to call their healthcare providers immediately if they develop any of these symptoms.

Tell patients to immediately report any suicidal thoughts.

For detailed instructions on how to use Intermezzo, tell patients to refer to the Patient Instructions for Use.

Tell patients that Intermezzo is to be taken only once per night if needed if they wake in the middle of the night and have difficulty returning to sleep. Tell patients that Intermezzo should only be taken if they have 4 hours of bedtime remaining before the planned time of waking.

Instruct the patient to place the tablet under the tongue, allowing it to disintegrate completely before swallowing. Tell the patient that Intermezzo should not be swallowed whole. Tell patients that the effect of Intermezzo may be slowed if taken with or immediately after a meal.

Instruct patients to remove the tablet from the unit-dose pouch just prior to dosing. Advise patients NOT to take Intermezzo if they drank alcohol that day or before bed.

Healthcare professionals can telephone Purdue Pharma's Medical Services Department (1-888-726-7535) for information on this product.

Zolpidem was administered in the diet to rats and mice for 2 years at doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 7, 30, and 140 times, respectively, the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg zolpidem base) on a mg/m² basis. In rats, these doses are approximately 15, 60, and 280 times, respectively, the RHD on a mg/m² basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid-and high doses.

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg/day) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested. The no-effect dose for these findings is approximately 70 times the RHD on a mg/m² basis. There was no impairment of fertility at any dose tested.

There are no adequate and well-controlled studies of zolpidem in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Intermezzo should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis.

Zolpidem is excreted in human milk. The effect of zolpidem on the nursing infant is not known.

Intermezzo is not recommended for use in children. Safety and effectiveness of Intermezzo have not been established in pediatric patients below the age of 18.

In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations.

Intermezzo dosage adjustment is necessary in geriatric patients. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Intermezzo and observed closely.

Clinical trial experience with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime:

A total of 154 patients in U.S.-controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving oral zolpidem tartrate at doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (see Table 2).

Table 2: Adverse Reactions in Geriatric Patients in Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime

A total of 30/1,959 (2%) non-U.S. patients receiving other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem tartrate doses > 10 mg. A total of 24/1,959 (1%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem tartrate doses > 10 mg.

The dose of Intermezzo in elderly patients is 1.75 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative-hypnotic drugs.

Women cleared zolpidem tartrate from the body after sublingual administration of a 3.5 mg dose of Intermezzo at a lower rate than men (2.7 mL/min/kg vs. 4.0 mL/min/kg). Cmax and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended dose of Intermezzo for women is 1.75 mg, and the recommended dose for adult men is 3.5 mg.

Dosage (Posology) and method of administration

Intermezzo is to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. Intermezzo should only be taken if the patient has at least 4 hours of bedtime remaining before the planned time of waking.

Intermezzo should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. For optimal effect, Intermezzo should not be administered with or immediately after a meal. The tablet should be removed from the pouch just prior to dosing.

The recommended and maximum dose of Intermezzo is 1.75 mg for women and 3.5 mg for men, taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep. The recommended doses for women and men are different because women clear zolpidem from the body at a lower rate than men.

The recommended Intermezzo dose for men and women who are taking concomitant CNS depressants is 1.75 mg. Dose adjustment of concomitant CNS depressants may be necessary when co-administered with Intermezzo because of potentially additive effects. The use of Intermezzo with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

Geriatric patients may be especially sensitive to the effects of zolpidem. The recommended dose of Intermezzo in men and women over 65 years old is 1.75 mg, taken only once per night if needed.

The recommended dose of Intermezzo in patients with hepatic impairment is 1.75 mg, taken only once per night if needed.

Interaction with other medicinal products and other forms of interaction

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated.

Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC0-∞of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T½ (-36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem.

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30 %) along with an increase in the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.