Alprazolam (Page 3 of 9)

5.8 Neonatal Sedation and Withdrawal Syndrome

Use of alprazolam 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 alprazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.9 Risk 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 alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam.

6 ADVERSE REACTIONS

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

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Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]

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Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]

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Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]

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Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]

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Patients with Depression [see Warnings and Precautions (5.6)]

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Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]

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Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

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

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4-week placebo-controlled clinical studies with alprazolam dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1)

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Short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).

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

	Alprazolam n=565	Placebo n=505
Nervous system disorders Drowsiness Light-headedness Dizziness Akathisia Gastrointestinal disorders Dry mouth Increased salivation	41% 21% 2% 2% 15% 4%	22% 19% 1% 1% 13% 2%
Cardiovascular disorders Hypotension Skin and subcutaneous tissue disorders Dermatitis/allergy	5% 4%	2% 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 Occuring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder

	Alprazolam n=1388	Placebo n=1231
Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization	77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2%	43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1%
Gastrointestinal disorders Constipation Increased salivation Skin and subcutaneous tissue disorders Rash	26% 6% 11%	15% 4% 8%
Other Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence	33% 28% 27% 23% 12% 11% 7% 2%	23% 24% 18% 17% 9% 9% 4% 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 alprazolam: 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 alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam 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 Alprazolam-treated Patients and > Placebo-treated Patients

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

n = number of patients.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [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.