Niravam

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• drowsiness
• confusion
• problems with coordination
• loss of consciousness

• Benzodiazepines, such as alprazolam, can cause fetal abnormalities and should not be used in pregnancy.
• Alprazolam is excreted in breast milk and can affect nursing infants. Therefore, it should not be used by women who are nursing.

Included as part of the PRECAUTIONS section.

Human Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

Management of Overdose

For the most up to date information on management of alprazolam overdose, contact a certified poison center in your area (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

Clinical Trial Experience

The most commonly reported ( ≥ 5% and ~ twice the rate of placebo) adverse reactions with NIRAVAM treatment are: sedation, impaired coordination, dysarthria, and increased libido.

The data cited in the two tables below are estimates of adverse reactions occurring in patients who participated in clinical trials under the following conditions: relatively short duration (four weeks) placebo-controlled clinical studies with dosages up to 4 mg per day of (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg per day of in patients with panic disorder, with or without agoraphobia.

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.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce dry mouth in others.)

Table 1: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Generalized Anxiety Disorder ( > 2% and at a rate greater than placebo)

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, 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 Reported in Placebo-Controlled Trials of Alprazolam in Panic Disorder ( > 2% and greater than placebo)

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, 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.

Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of NIVARAM. 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. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia, and galactorrhea.

Read the entire FDA prescribing information for Niravam (Alprazolam)

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Dizziness.
• Dry mouth.
• Feeling more or less hungry.
• Upset stomach.
• Hard stools (constipation).
• Change in sex ability.
• Lowered interest in sex.
• Feeling tired or weak.
• A change in weight without trying.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg per day. In such cases, the dosage should be increased cautiously to avoid adverse reactions. In general, benzodiazepines should be prescribed for short periods. Reevaluate the need for continued therapy before extending the treatment period.

Generalized Anxiety Disorder

Initiate treatment with a dose of 0.25 mg to 0.5 mg three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose, and periodically reassess the need for continued treatment. The risk of dependence can increase with dose and duration of treatment.

The dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

Panic Disorder

The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg per day, including approximately 100 patients who received maximum dosages of greater than 9 mg per day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration

Initiate treatment with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg per day may be advisable to allow full expression of the pharmacodynamic effect of Niravam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, (i.e., administered three or four times daily).

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. The dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

For patients receiving doses greater than 4 mg per day, periodically reassess treatment and consider a reduction of dosage. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg per day for 3 months were able to taper to 50% of their total daily maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, avoid abrupt discontinuation of treatment. [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

The necessary duration of treatment for panic disorder patients responding to Niravam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, reinstitute the previous stable dosing schedule. After stabilization, consider using a less rapid schedule of discontinuation. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, there was no difference between the groups in the proportion of patients who tapered and completely discontinued treatment with alprazolam; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. Reduce the dose by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease (e.g., severe pulmonary disease), the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dose, the dose may be lowered.

Instructions to be Given to Patients for Use/Handling Niravam Tablets

Just prior to administration, with dry hands, remove the tablet from the bottle. Immediately place the Niravam tablet on top of the tongue where it will disintegrate and be swallowed with saliva. Administration with liquid is not necessary.

Discard any cotton that was included in the bottle and reseal the bottle tightly to prevent introducing moisture that might cause the tablets to disintegrate.

Anxiety Disorders

The efficacy of alprazolam in the treatment of anxiety symptoms was demonstrated in five short-term (4 weeks), randomized, double-blind, placebo-controlled studies. The studies included patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam doses ranged from 0.5 to 4 mg per day. The mean daily doses ranged from 1.6 to 2.4 mg. Treatment with alprazolam was statistically significantly superior to placebo treatment, as measured by the following psychometric instruments: Hamilton Anxiety Rating Scale, Physician’s Global Impressions, Target Symptoms, Patient’s Global Impressions and Self-Rating Symptom Scale.

Panic Disorder

The efficacy of alprazolam in the treatment of panic disorder was demonstrated in three short-term (up to 10 weeks), randomized, double-blind, placebo-controlled studies. Patients in the studies had diagnoses corresponding closely to DSM-III-R criteria for panic disorder (with or without agoraphobia).

The average dose of alprazolam was 5 mg to 6 mg per day in two of the studies, and the doses of alprazolam were fixed at 2 mg and 6 mg per day in the third study. In all three studies, alprazolam was superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37 - 83% met this criterion), as well as on a global improvement score. In two of the three studies, alprazolam was superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3 - 5.2), and also on a phobia rating scale. A subgroup of patients who were improved on alprazolam during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

Common side effects of Niravam include: ataxia, constipation, difficulty in micturition, dysarthria, fatigue, memory impairment, menstrual disease, sedation, skin rash, weight gain, decreased appetite, decreased libido, increased appetite, and irritability. Other side effects include: hypotension, sexual disorder, sialorrhea, weight loss, and increased libido. See below for a comprehensive list of adverse effects.

Applies to alprazolam: oral solution, oral tablet, oral tablet disintegrating, oral tablet extended release

Along with its needed effects, alprazolam (the active ingredient contained in Niravam) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking alprazolam:

• Being forgetful
• changes in patterns and rhythms of speech
• clumsiness or unsteadiness
• difficulty with coordination
• discouragement
• drowsiness
• feeling sad or empty
• irritability
• lack of appetite
• lightheadedness
• loss of interest or pleasure
• relaxed and calm
• shakiness and unsteady walk
• sleepiness or unusual drowsiness
• slurred speech
• tiredness
• trouble concentrating
• trouble performing routine tasks
• trouble sleeping
• trouble speaking
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual tiredness or weakness

• Abdominal or stomach pain
• blurred vision
• body aches or pain
• burning, crawling, itching, numbness, prickling, "pins and needles, or tingling feelings
• changes in behavior
• chills
• clay-colored stools
• confusion about identity, place, and time
• cough
• dark urine
• decrease in frequency of urination
• decrease in urine volume
• diarrhea
• difficult or labored breathing
• difficulty in passing urine (dribbling)
• difficulty with concentration
• difficulty with moving
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• ear congestion
• environment seems unreal
• fainting
• fear or nervousness
• feeling of unreality
• feeling warm
• fever
• general feeling of discomfort or illness
• headache
• hyperventilation
• inability to move the eyes
• inability to sit still
• increased blinking or spasms of the eyelid
• irregular heartbeats
• itching or rash
• joint pain
• lack or loss of self-control
• loss of bladder control
• loss of coordination
• loss of memory
• loss of voice
• mood or mental changes
• muscle aching or cramping
• muscle pain or stiffness
• muscle weakness
• nasal congestion
• nausea
• need to keep moving
• painful urination
• problems with memory
• restlessness
• runny nose
• seeing, hearing, or feeling things that are not there
• seizures
• sense of detachment from self or body
• shaking
• shivering
• sneezing
• sore throat
• sticking out of the tongue
• sweating
• swollen joints
• talkativeness
• tightness in the chest
• trouble with balance
• twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unpleasant breath odor
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusual facial expressions
• unusually deep sleep
• unusually long duration of sleep
• vomiting of blood
• yellow eyes or skin

• Actions that are out of control
• attack, assault, or force
• chest pain
• continuing ringing or buzzing or other unexplained noise in the ears
• decreased awareness or responsiveness
• deep or fast breathing with dizziness
• ear pain
• false or unusual sense of well-being
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling jittery
• feeling unusually cold
• generalized slowing of mental and physical activity
• hearing loss
• hoarseness
• lack of feeling or emotion
• loss of control of the legs
• loss of strength or energy
• nightmares
• numbness of the feet, hands, and around mouth
• severe sleepiness
• shakiness in the legs, arms, hands, or feet
• sleep talking
• swelling
• talking, feeling, and acting with excitement
• thoughts of killing oneself
• uncaring
• unusual weak feeling
• voice changes

• General tiredness and weakness
• light-colored stools
• stomach pain, continuing
• upper right abdominal or stomach pain

Some side effects of alprazolam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Absent, missed, or irregular menstrual periods
• decreased appetite
• decreased interest in sexual intercourse
• decreased sexual performance or desire abnormal ejaculation
• difficulty having a bowel movement (stool)
• inability to have or keep an erection
• increased appetite
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• increased weight
• loss in sexual ability, desire, drive, or performance
• stopping of menstrual bleeding
• watering of the mouth
• weight loss

• Abdominal or bloating and cramping
• blistering, crusting, irritation, itching, or reddening of the skin
• change in taste bad unusual or unpleasant (after) taste
• cracked, dry, or scaly skin
• cramps
• double vision
• feeling of warmth
• heavy bleeding
• menstrual changes
• pain
• pelvic pain
• redness of the face, neck, arms, and occasionally, upper chest
• seeing double
• sudden sweating
• unexplained runny nose or sneezing

• Acid or sour stomach
• belching
• bigger, dilated, or enlarged pupils (black part of the eye)
• change in color vision
• difficulty seeing at night
• feeling of constant movement of self or surroundings
• feeling of relaxation
• heartburn
• hives or welts
• increased sensitivity of the eyes to sunlight
• indigestion
• redness of the skin
• runny nose
• sensation of spinning
• stomach discomfort, upset, or pain
• stuffy nose

• Blistering, peeling, or loosening of the skin
• red, irritated eyes
• red skin lesions, often with a purple center
• sores, ulcers, or white spots in the mouth or on the lips
• swelling of the breasts or breast soreness in both females and males
• unexpected or excess milk flow from the breasts