Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam XR. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)]. Even after relatively short-term use at doses of ≤ 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.
In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.
Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval.
Alprazolam XR is contraindicated in patients receiving strong inhibitors of CYP3A such as azole antifungal agents [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.
Dosage adjustment is necessary when Alprazolam XR and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of Alprazolam XR [see Dosage and Administration (2.5), Drug Interactions (7.1)].
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of Alprazolam XR, as appropriate, during co-administration with these drugs.
Approximately 17% of the 531 patients who received Alprazolam XR in placebo-controlled clinical trials for panic disorder had at least 1 adverse event that led to discontinuation compared to 8% of 349 placebotreated patients. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with Alprazolam XR at a rate at least twice that of placebo) are shown in Table 1.
Table 2 shows the incidence of adverse reactions that occurred during 6- and 8-week placebo-controlled trials in 1% or more of patients treated with Alprazolam XR where the incidence in patients treated with Alprazolam XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with Alprazolam XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased.
Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with Alprazolam XR. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent); those occurring in less than 1/100 patients but at least 1/1000 patients (infrequent); those occurring in fewer than 1/1000 patients (rare).
- Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia
- Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain
- Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia
- Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion
- General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors
- Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching
- Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor
- Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation
- Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence
- Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea
- Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria
- Vascular disorders: Infrequent: hypotension
Discontinuation-Emergent Adverse Reactions Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam XR
Table 3 shows the incidence of discontinuation-emergent adverse reactions that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with Alprazolam XR where the incidence in patients treated with Alprazolam XR was 2 times greater than the incidence in placebo-treated patients.
Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam XR-treated Patients and at least twice the Rate of Placebo-treated Patients in Short-Term, Placebo-Controlled Trials | |
|---|
| Alprazolam XR
n=422 (%) | Placebo
n=261 (%) |
|---|
| Nervous system disorders | | |
| Tremor | 28.2 | 10.7 |
| Headache | 26.5 | 12.6 |
| Hypoesthesia | 7.8 | 2.3 |
| Paraesthesia | 7.1 | 2.7 |
| Psychiatric disorders | | |
| Insomnia | 24.2 | 9.6 |
| Nervousness | 21.8 | 8.8 |
| Depression | 10.9 | 5.0 |
| Derealization | 8.0 | 3.8 |
| Anxiety | 7.8 | 2.7 |
| Depersonalization | 5.7 | 1.9 |
| Gastrointestinal disorders | | |
| Diarrhea | 12.1 | 3.1 |
| Respiratory, thoracic and mediastinal disorders | | |
| Hyperventilation | 8.5 | 2.7 |
| Metabolism and nutrition disorders | | |
| Appetite decreased | 9.5 | 3.8 |
| Musculosketal and connective tissue disorders | | |
| Muscle twitching | 7.4 | 2.7 |
| Vascular disorders | | |
| Hot flushes | 5.9 | 2.7 |
There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2), Drug Abuse and Dependence (9.3)].
Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Alprazolam XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.
Risk Summary
Neonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).
The estimated 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 and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)].
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 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. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.
Risk Summary
Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with Alprazolam XR.
Physical Dependence
Alprazolam XR 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 and Precautions (5.3)].
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Alprazolam XR or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].
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 associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.
Tolerance
Tolerance to Alprazolam XR 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 Alprazolam XR may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Absorption
Following oral administration of Alprazolam XR in the morning, peak plasma concentration of alprazolam (Cmax) occurs in about 10 hours postdose. Compared to morning dosing, alprazolam Cmax increased by 30% and the Tmax decreased by an hour following dosing at night.
The mean absolute bioavailability of alprazolam following administration of Alprazolam XR is approximately 90%, and the relative bioavailability compared to alprazolam is about 100%. The bioavailability and pharmacokinetics of alprazolam following administration of Alprazolam XR are similar to that for alprazolam, with the exception of a slower rate of absorption.
Effect of Food
A high-fat meal given up to 2 hours before dosing with Alprazolam XR increased the mean Cmax by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase in Tmax by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t½) were not affected by eating.
Distribution
The apparent volume of distribution of alprazolam is similar for Alprazolam XR and Alprazolam. Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.
Elimination
The mean plasma elimination half-life of alprazolam following administration of Alprazolam XR ranges from 10.7 to 15.8 hours in healthy adults.
Metabolism
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites after both Alprazolam XR and Alprazolam are less than 10% and 4% of the parent, respectively. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of Alprazolam. A benzophenone derived from Alprazolam is also found in humans. Their half-lives appear to be similar to that of Alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of Alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for Alprazolam and Alprazolam XR, indicating that the metabolism of alprazolam is not affected by absorption rate.
Excretion
Alprazolam and its metabolites are excreted primarily in the urine.
Specific Populations
Geriatric Patients
The mean T1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects.
Obese Patients
The mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects.
Patients with Hepatic Impairment
The mean T1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease.
Racial or Ethnic Groups
Maximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
Smoking
Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.
Drug Interaction Studies
In Vivo Studies
Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity.
Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.2)]. Other studied drugs include:
Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%.
Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance.
Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%.
Carbamazepine: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T1/2 was shortened (from 17.1±4.9 to 7.7 ±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000–1200 mg per day); the effect at usual carbamazepine doses is unknown.
Ritonavir: Interactions involving HIV protease inhibitors (e.g, ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)].
Sertraline: A single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam.
Imipramine and Desipramine: The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Alprazolam in doses up to 4 mg per day.
Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
In Vitro Studies
Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not been determined.
Carcinogenesis
No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2 years at doses up to 30 and 10 mg/kg/day, respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m2 body surface area, respectively.
Mutagenesis
Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays.
Impairment of Fertility
Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.
Risks from Concomitant Use with Opioids
Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Alprazolam XR 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 and Precautions (5.1), Drug Interactions (7.1)].
Abuse, Misuse, and Addiction
Inform patients that the use of Alprazolam XR, 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 and Precautions (5.2), Drug Abuse and Dependence (9.2)].
Withdrawal Reactions
Inform patients that the continued use of Alprazolam XR may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Alprazolam XR 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 Alprazolam XR may require a slow taper [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].
Effects on Driving and Operating Machinery
Advise patients not to drive a motor vehicle or operate heavy machinery while taking Alprazolam XR due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking Alprazolam XR [see Warnings and Precautions (5.3)].
Patients with Depression
Advise patients, their families and caregivers to look for signs of suicidality or worsening depression, and to inform the patient's healthcare provider immediately [see Warnings and Precautions (5.6)].
Concomitant Medications
Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7)].
Pregnancy
Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using Alprazolam XR to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with Alprazolam XR [see Warnings and Precautions (5.4)]. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Alprazolam XR during pregnancy [see Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed during treatment with Alprazolam XR [see Use in Specific Populations (8.2)].
This product's labeling may have been updated. For the most recent prescribing information, please visit www.greenstonellc.com.
LAB-0318-10.0
