The following clinically significant adverse reactions are described elsewhere in the labeling:
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 information included in the section on Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets are 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 Alprazolam Extended-Release Tablets
Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Approximately 17% of the 531 patients who received alprazolam extended-release tablets 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 alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in Table 1.
| n=number of patients | ||
| Percentage of Patients Discontinuing Due to Adverse Reactions | ||
| Alprazolam extended-release tablets (n=531) | Placebo (n=349) | |
| Nervous system disorders Sedation Somnolence Dysarthria Coordination abnormal Memory impairment | 7.5 3.2 2.1 1.9 1.5 | 0.6 0.3 0 0.3 0.3 |
| General disorders/administration site conditions Fatigue | 1.7 | 0.6 |
| Psychiatric disorders Depression | 2.5 | 1.2 |
Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets
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 extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (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.
| Alprazolam extended-release tablets (n=531) | Placebo (n=349) | |
| Nervous system disorders Sedation Somnolence Memory Impairment Dysartharia Coordination abnormal Mental impairment Ataxia Disturbance in attention Balance impaired Dyskinesia Hypoesthesia Hypersomnia | 45% 23% 15% 11% 9% 7% 7% 3% 3% 2% 1% 1% | 23% 6% 7% 3% 1% 6% 3% 1% 1% 1% <1% 0% |
| General disorders/administration site conditions Fatigue Lethargy | 14% 2% | 9% 1% |
| Psychiatric disorders Depression Libido decreased Disorientation Confusion Depressed mood | 12% 6% 2% 2% 1% | 9% 2% 0% 1% <1% |
| Metabolism and nutrition disorders Appetite increased Anorexia | 7% 2% | 6% 0% |
| Gastrointestinal disorders Constipation Nausea | 8% 6% | 4% 3% |
| Investigations Weight increased | 5 | 4 |
| Injury, poisoning, and procedural complications Road traffic accident | 2% | 0% |
| Reproductive system and breast disorders Dysmenorrhea Sexual dysfunction | 4% 2% | 3% 1% |
| Musculoskeletal and connective tissue disorder Arthralgia Myalgia Pain in limb | 2% 2% 1% | 1% 1% 0% |
| Respiratory, thoracic, and mediatinal disorders Dyspnea | 2% | 0% |
Other Adverse Reactions Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets
Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam extended-release tablets. 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 l/l00 patients (frequent); those occurring in less than l/100 patients but at least l/1000 patients (infrequent); those occurring in fewer than l/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, psychom*otor 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 Extended-Release Tablets
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 extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was 2 times greater than the incidence in placebo-treated patients.
| Alprazolam extended-release tablets n=422 (%) | Placebo n=261(%) | |
| Nervous system disorders Tremor Headache Hypoesthesia Paraesthesia | 28.2 26.5 7.8 7.1 | 10.7 12.6 2.3 2.7 |
| Psychiatric disorders Insomnia Nervousness Depression Derealization Anxiety Depersonalization | 24.2 21.8 10.9 8.0 7.8 5.7 | 9.6 8.8 5.0 3.8 2.7 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.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of alprazolam and/or alprazolam extended-release tablets. 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
