Xanax (alprazolam 1 mg) Dailymed

• •Effects on Driving and Operating Machinery: Patients receiving XANAX should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4)
• •Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.6)
• •Neonatal Sedation and Withdrawal Syndrome: XANAX use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. (5.8, 8.1)

5.1Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including XANAX, 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 XANAX 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 XANAX than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX, 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 XANAX is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].

5.2Abuse, Misuse, and Addiction

The use of benzodiazepines, including XANAX, 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 (9.2)].

Before prescribing XANAX and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of XANAX, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of XANAX 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.

5.3Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3)].

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.

The continued use of benzodiazepines, including XANAX, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of XANAX 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 (9.3)].

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 (9.3)].

Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX. 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 XANAX, 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 XANAX 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 XANAX 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 XANAX 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.

5.4Effects on Driving and Operating Machinery

Because of its CNS depressant effects, patients receiving XANAX should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with XANAX [see Drug Interactions (7.1)].

5.5Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.

XANAX is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [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 XANAX and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of XANAX [see Dosage and Administration (2.6), 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 XANAX, as appropriate, during co-administration with these drugs.

5.6Patients with Depression

Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.

5.7Mania

Episodes of hypomania and mania have been reported in association with the use of XANAX in patients with depression [see Adverse Reactions (6.2)].

5.8Neonatal Sedation and Withdrawal Syndrome

Use of XANAX 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 Use in Specific Populations (8.1)]. Monitor neonates exposed to XANAX during pregnancy or labor for signs of sedation and monitor neonates exposed to XANAX during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.9Risk in Patients with Impaired Respiratory Function

There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with XANAX. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue XANAX.

6 Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

• •Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
• •Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
• •Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]
• •Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]
• •Patients with Depression [see Warnings and Precautions (5.6)]
• •Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]
• •Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

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 practice.

The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in:

• •4-week placebo-controlled clinical studies with XANAX dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1)
• •Short-term (up to 10 weeks) placebo-controlled clinical studies with XANAX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).

Table 1: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety

	XANAX n=565	Placebo n=505
Nervous system disorders
Drowsiness	41%	22%
Light-headedness	21%	19%
Dizziness	2%	1%
Akathisia	2%	1%
Gastrointestinal disorders
Dry mouth	15%	13%
Increased salivation	4%	2%
Cardiovascular disorders
Hypotension	5%	2%
Skin and subcutaneous tissue disorders
Dermatitis/allergy	4%	3%

 

In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

Table 2: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder

	XANAX n=1388	Placebo n=1231
Drowsiness      Fatigue and Tiredness      Impaired Coordination      Irritability      Memory Impairment      Cognitive Disorder      Decreased Libido      Dysarthria      Confusional state	77% 49% 40% 33% 33% 29% 14% 23% 10%	43% 42% 18% 30% 22% 21% 8% 6% 8%
Increased libido	8%	4%
Change in libido (not specified)	7%	6%
Disinhibition	3%	2%
Talkativeness	2%	1%
Derealization	2%	1%
Gastrointestinal disorders
Constipation	26%	15%
Increased salivation	6%	4%
Skin and subcutaneous tissue disorders
Rash	11%	8%
Other
Increased appetite	33%	23%
Decreased appetite	28%	24%
Weight gain	27%	18%
Weight loss	23%	17%
Micturition difficulties	12%	9%
Menstrual disorders	11%	9%
Sexual dysfunction	7%	4%
Incontinence	2%	1%

 

In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANAX, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with XANAX and at a greater rate than the placebo-treated group are shown in Table 3.

Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of XANAX-treated Patients and > Placebo-treated Patients

n=number of patients.
	XANAX-treated Patients n=641
Nervous system disorders
Insomnia	29.5%
Light-headedness	19.3%
Abnormal involuntary movement	17.3%
Headache	17.0%
Muscular twitching	6.9%
Impaired coordination	6.6%
Muscle tone disorders	5.9%
Weakness	5.8%
Psychiatric disorders
Anxiety	19.2%
Fatigue and Tiredness	18.4%
Irritability	10.5%
Cognitive disorder	10.3%
Memory impairment	5.5%
Depression	5.1%
Confusional state	5.0%
Gastrointestinal disorders
Nausea/Vomiting	16.5%
Diarrhea	13.6%
Decreased salivation	10.6%
Metabolism and nutrition disorders
Weight loss	13.3%
Decreased appetite	12.8%
Dermatological disorders
Sweating	14.4%
Cardiovascular disorders
Tachycardia	12.2%
Special Senses
Blurred vision	10.0%

 

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANAX [see Warning and Precautions (5.2) and 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.

6.2Postmarketing Experience

The following adverse reactions have been identified during postapproval use of XANAX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Endocrine disorders: Hyperprolactinemia

General disorders and administration site conditions: Edema peripheral

Hepatobiliary disorders: Hepatitis, hepatic failure

Investigations: Liver enzyme elevations

Psychiatric disorders: Hypomania, mania

Reproductive system and breast disorders: Gynecomastia, galactorrhea

Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome