Xanax XR Side Effects Center

SIDE EFFECTS

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

• Risks from Concomitant Use with Opioids [see WARNINGS AND PRECAUTIONS]
• Abuse, Misuse, and Addiction [see WARNINGS AND PRECAUTIONS]
• Dependence and Withdrawal Reactions [see WARNINGS AND PRECAUTIONS]
• Effects on Driving and Operating Machinery [see WARNINGS AND PRECAUTIONS]
• Patients with Depression [see WARNINGS AND PRECAUTIONS]
• Neonatal Sedation and Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Risks in Patients with Impaired Respiratory Function [see WARNINGS AND PRECAUTIONS]

Clinical 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 information included in the section on Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials with XANAX XR is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse Reactions Observed In Short-Term, Placebo-Controlled Trials Of XANAX XR

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

Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least 1 adverse event that led to discontinuation compared to 8% of 349 placebo-treated 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 XANAX XR at a rate at least twice that of placebo) are shown in Table 1.

Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of XANAX XR-treated Patients and at least twice the Rate of Placebo-treated Patients in Placebo-Controlled Trials

	Percentage of Patients Discontinuing Due to Adverse Reactions
	XANAX XR (n=531)	Placebo (n=349)
Nervous system disorders
Sedation	7.5	0.6
Somnolence	3.2	0.3
Dysarthria	2.1	0
Coordination abnormal	1.9	0.3
Memory impairment	1.5	0.3
General disorders/administration site conditions
Fatigue	1.7	0.6
Psychiatric disorders
Depression	2.5	1.2
n=number of patients

Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR

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 XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with XANAX 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.

Table 2: Adverse Reactions Occuring in ≥ 1% in XANAX-treated Patients and Greater than Placebo-treated Patients in 6 and 8 week Placebo-Controlled Trials Panic Disorder

	XANAX XR (n=531)	XANAX XR (n=531)
Nervous system disorders
Sedation	45%	23%
Somnolence	23%	6%
Memory impairment	15%	7%
Dysarthria	11%	3%
Coordination abnormal	9%	1%
Mental impairment	7%	6%
Ataxia	7%	3%
Disturbance in attention	3%	1%
Balance impaired	3%	1%
Dyskinesia	2%	1%
Hypoesthesia	1%	<1%
Hypersomnia	1%	0%
General disorders/administration site conditions
Fatigue	14%	9%
Lethargy	2%	1%
Psychiatric disorders
Depression	12%	9%
Libido decreased	6%	2%
Disorientation	2%	0%
Confusion	2%	1%
Depressed mood	1%	<1%
Metabolism and nutrition disorders
Appetite increased	7%	6%
Anorexia	2%	0%
Gastrointestinal disorders
Constipation	8%	4%
Nausea	6%	3%
Investigations
Weight increased	5	4
Injury, poisoning, and procedural complications
Road traffic accident	2%	0%
Reproductive system and breast disorders
Dysmenorrhea	4%	3%
Sexual dysfunction	2%	1%
Musculoskeletal and connective tissue disorder
Arthralgia	2%	1%
Myalgia	2%	1%
Pain in limb	1%	0%
Respiratory, thoracic, and mediatinal disorders
Dyspnea	2%	0%

Other Adverse Reactions Observed During The Premarketing Evaluation Of XANAX XR

Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with XANAX 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 XANAX 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 XANAX XR where the incidence in patients treated with XANAX XR was 2 times greater than the incidence in placebo-treated patients.

	XANAX 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 Xanax [see WARNING AND PRECAUTIONS, Drug Abuse And Dependence].

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XANAX and/or XANAX XR. 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, jaundice

Investigations: Liver enzyme elevations

Psychiatric disorders: Hypomania, mania

Reproductive system and breast disorders: Gynecomastia, galactorrhea, menstruation irregular

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

DRUG INTERACTIONS

Drugs Having Clinically Important Interactions With XANAX XR

Table 4 includes clinically significant drug interactions with XANAX XR [see CLINICAL PHARMACOLOGY].

Table 4: Clinically Significant Drug Interactions with XANAX XR

Opioids
Clinical implication	The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gammaaminobutyric acid (GABAA) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Prevention or management	Limit dosage and duration of concomitant use of XANAX XR and opioids, and monitor patients closely for respiratory depression and sedation [see WARNINGS AND PRECAUTIONS].
Examples	Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.
CNS Depressants
Clinical implication	The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.
Prevention or management	Limit dosage and duration of XANAX XR during concomitant use with CNS depressants [see WARNINGS AND PRECAUTIONS].
Examples	Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.
Strong Inhibitors of CYP3A (except ritonavir)
Clinical implication	Concomitant use of XANAX XR with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see CLINICAL PHARMACOLOGY].
Prevention or management	Concomitant use of XANAX XR with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Examples	Ketoconazole, itraconazole, clarithromycin
Moderate or Weak Inhibitors of CYP3A
Clinical implication	Concomitant use of XANAX XR with CYP3A inhibitors may increase the concentrations of XANAX XR, resulting in increased risk of adverse reactions [see CLINICAL PHARMACOLOGY].
Prevention or management	Avoid use and consider appropriate dose reduction when XANAX XR is coadministered with a moderate or weak CYP3A inhibitor [see WARNINGS AND PRECAUTIONS].
Examples	Nefazodone, fluvoxamine, cimetidine, erythromycin
CYP3A Inducers
Clinical implication	Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see CLINICAL PHARMACOLOGY].
Prevention or management	Caution is recommended during coadministration with alprazolam.
Examples	Carbamazepine, phenytoin
Ritonavir
Clinical implication	Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (> 10 - 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir.
Prevention or management	Reduce XANAX XR dose when a patient is initiated with ritonavir and XANAX XR concomitantly, or when ritonavir is added to a regimen where XANAX XR is stabilized.
	Increase XANAX XR dosage to the target dosage after 10 to 14 days of dosing ritonavir and XANAX XR concomitantly. No dosage adjustment of XANXR XR is necessary in patients receiving ritonavir for more than 10 to 14 days [see DOSAGE AND ADMINISTRATION].
	Concomitant use of XANAX XR with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Digoxin
Clinical implication	Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).
Prevention or management	In patients on digoxin therapy, measure serum digoxin concentrations before initiating XANAX XR. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.

Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

Drug Abuse And Dependence

Controlled Substance

XANAX XR contains alprazolam, which is a Schedule IV controlled substance.

Abuse

XANAX XR is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see WARNINGS AND PRECAUTIONS].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Physical Dependence

XANAX 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].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

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 XANAX 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 XANAX XR may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Read the entire FDA prescribing information for Xanax XR (Alprazolam)