v2.8, Oct 2008
by Mr. Egomaniac
1.0 DESCRIPTION
1.1 HOW SUPPLIED
1.2 BRAND NAMES
1.3 CATEGORIES
1.4 INACTIVE INGREDIENTS
2.0 CLINICAL PHARMACOLOGY
2.1 PHARMACODYNAMICS
2.2 PHARMACOKINETICS
2.3 CLINICAL STUDIES
2.4 CLINICAL EFFICACY TRIALS
2.5 ANIMAL STUDIES
3.0 INDICATIONS AND USAGE
3.1 CONTRAINDICATIONS
3.2 WARNINGS
3.3 PRECAUTIONS
3.4 INTERACTIONS
3.5 ADVERSE REACTIONS
4.0 DOSAGE AND ADMINISTRATION
4.1 OVERDOSAGE
5.0 ABUSE AND DEPENDENCE
6.0 FREQUENTLY ASKED QUESTIONS
7.0 REVISION HISTORY
1.0 DESCRIPTION
GENERIC NAME: alprazolam
CHEMICAL NAME: 8-chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-a)(1,4) benzodiazepine
MOLECULAR FORMULA: C17H13ClN4
MOLECULAR WEIGHT: 308.7695 g/mol
SYNONYMS: AP-1002; APRD00280; AZ-002; BB_SC-2025; BRN 1223125; C06817; CAS 28981-97-7; D-65MT; D00225; DB00404; DEA No. 2882; EINECS 2493492; FDA No. 018276; HSDB 7207; MeSH D000525; nchembio747-comp35; RTECS XZ5473000; TUS-1; U-31889; CTV3 READ-Code y01yC; ZINC00000903
ATC CLASSIFICATION: N05BA12 Psycholeptics (N05)/ Anxiolytics (N05B)/ Benzodiazepine derivatives (N05BA)
ATCvet CLASSIFICATION: QN05BA12 Nervous system (QN)/ Psycholeptics (QN05)/ Anxiolytics (QN05B)/ Benzodiazepine derivatives (QN05BA)
MeSH CLASSIFICATION: D03.438.079.080.030 Chemicals and Drugs (D)/ Heterocyclic Compounds (D03)/ Heterocyclic Compounds, 2-Ring (D03.438)/ Benzazepines (D03.438.079)/ Benzodiazepines (D03.438.079.080)
Alprazolam (al-PRAZ-oh-lam) belongs to the class of psychoactive drugs called Central Nervous System Agents/Anxiolytics, Sedatives and Hypnotics/Benzodiazepines. It is a benzodiazepine (ben-zoe-dye-AZ-e-peen) anxiolytic used in the treatment of anxiety disorders. Benzodiazepines are the most commonly used antianxiety drugs because they are fairly safe, they rapidly reduce the symptoms of anxiety and they don't have to be taken on an ongoing basis in order to be effective. All benzodiazepines cause dose-related suppression of the central nervous system, varying from slight impairment to hypnosis.
Alprazolam tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.
Alprazolam is a white to off-white crystalline powder, which is soluble in methanol or ethanol; sparingly soluble in acetone; freely soluble in chloroform; slightly soluble in ethyl acetate but which has no appreciable solubility in water at physiological pH.
Alprazolam is often preferable to other benzodiazepines, such as chlordiazepoxide, clorazepate and prazepam because alprazolam has a relatively shorter half-life and does not have active metabolites that can lead to accumulation, particularly in the elderly.
Alprazolam was invented by the Upjohn Company (Kalamazoo, MI). Its patent #3,987,052 was filed on October 29, 1969, granted on October 19, 1976, and approved by the U.S. Food and Drug Administration (FDA) on October 16, 1981. It was the first benzodiazepine to be approved by the FDA for the treatment of panic disorder in late 1990. It became available as a generic in September 1993 by the patent holder, one month before the patent expired.
1.1 HOW SUPPLIED
Each alprazolam (immediate-release) tablet, for oral administration, contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Alprazolam brand name Xanax (immediate-release) tablets were first introduced in the U.S. in 1981 (approved by the FDA on October 16, 1981). The 2 mg tablets were approved by the FDA on November 27, 1985. Generic versions of alprazolam (immediate-release) tablets were introduced in 1993. Alprazolam brand name Xanax (immediate-release) tablets are available as follows:
Tablet, 0.25 mg
Tablet, 0.5 mg
Tablet, 1 mg
Tablet, 2 mg
Each alprazolam XR (extended-release) tablet, for oral administration, contains either 0.5 mg, 1 mg, 2 mg, or 3 mg of alprazolam. Alprazolam XR brand name Xanax (extended-release) tablets were first introduced in the U.S. in 2003 (approved by the FDA on January 17, 2003). Generic versions of alprazolam (extended-release) tablets were introduced in 2006 (approved by the FDA on January 27, 2006) and may have additional dosage strengths (e.g., 1.5 mg tablets). Its benefits, in addition to once-daily dosing, include a rapid onset of action and all-day efficacy. Alprazolam XR brand name Xanax (extended-release) tablets are available as follows:
Tablet, 0.5 mg (white, pentagonal-shaped tablet, imprint "X" on one side and "0.5" on the other side) or (blue, round-shaped tablet, imprint "P&U" and "57" on one side)
Tablet, 1 mg (yellow, square-shaped tablet, imprint "X" on one side and "1" on the other side) or (white, round-shaped tablet, imprint "P&U" and "59" on one side)
Tablet, 2 mg (blue, round-shaped tablet, imprint "X" on one side and "2" on the other side) or (blue, pentagonal-shaped tablet, imprint "P&U" and "66" on one side)
Tablet, 3 mg (green, triangular-shaped tablet, imprint "X" on one side and "3" on the other side)
Each alprazolam (orally disintegrating) tablet, for oral administration, contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Alprazolam brand name Niravam (orally disintegrating) tablets were first introduced in the U.S. in 2005 (approved by the FDA on January 19, 2005). Alprazolam orally disintegrating is an orally administered formulation of alprazolam which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. It can be taken discreetly, while in social settings. Alprazolam brand name Niravam (orally disintegrating) tablets are available as follows:
Tablet, 0.25 mg (yellow, round-shaped tablet, orange-flavored, scored and imprint "SP 321" on the unscored side and "0.25" on the scored side)
Tablet, 0.5 mg (yellow, round-shaped tablet, orange-flavored, scored and imprint "SP 322" on the unscored side and "0.5" on the scored side)
Tablet, 1 mg (white, round-shaped tablet, orange-flavored, scored and imprint "SP 323" on the unscored side and "1" on the scored side)
Tablet, 2 mg (white, round-shaped tablet, orange-flavored, scored and imprint "SP 324" on the unscored side and "2" on the scored side)
Each alprazolam Intensol Oral Solution (concentrate) mL, for oral administration, contains 1 mg of alprazolam. Alprazolam Intensol Oral Solution (concentrate) was first introduced in the U.S. in 1993 (approved by the FDA on October 31, 1993). Alprazolam Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food. A liquid form is used if you cannot swallow pills. Alprazolam Intensol Oral Solution (concentrate) is available as follows:
Solution, 0.5 mg/5 mL in bottles of 500 mL – Discontinued preparation
Concentrate, 1 mg/mL in bottles of 30 mL (flavorless, colorless solution)
For use with the calibrated dropper. (Graduations of 0.25 mL (0.25 mg), 0.5 mL (0.5 mg), 0.75 mL (0.75 mg), and 1 mL (1 mg) on the dropper)
New forms for administration of alprazolam include ATD Gel, Topical Patch (transdermal); Staccato Oral Aerosol Inhaler (inhalational); Panistat Nasal Spray (intranasal).
1.2 BRAND NAMES
Abaxon; Aceprax; Adax; Afobam; Alganax; Alkrazil; Alpam; Alpaz; Alplax; Alpralid-; Alpram; Alpranax; Alpraquil; Alpraphar; Alprastad; Alpratyrol; Alpravecs; Alprax; Alpraz; Alprazig; Alprazomed; Alprazomerck; Alprim; Alprocontin; Alpronax; Alprose; Alprox; Alcelam; Algad; Alnax; Altraxic; Altrox; Alti-Alprazolam; Alzam; Alzolam; Alzomax; Alzon; Alzopax; Alzor; Amziax; Anax; Anpress; Ansielix; Ansielix Digest+; Ansiopax; Antanax-; Anxirid; Anxit; Anzilum; Anzion; Anzofree; Apotex; Apox-; Afobam; Alplax Digest+; Alplax Net+; Alviz; Apo-Alpraz; Apo-Alprax; Apraz; Aprazo; Azaxol; Azor; B-Dual; Becede; Besquil; Bestrol; Calmax; Calmdown; Calmlet; Calmol; Cassadan; Constan; Daclor; Danox; Dixin; Dizolam-; Dizolam Atlantic; Docalprazo; Dominium; Drimpam-; Duazolan; Emeral; Esparon-; Euciton Stress+; Eurelax; Farmapram; Feprax; Fludep Plus+; Frixitas; Frontal; Frontin; Gabazolamine Convenience Pack+; Gen-Alprazolam; Gendergin; Gerax; Grifoalpram; Helex; Huma-Alprazol; Ibizolam; Irizz; Kalma; Kelaxanal; Kinax; Krama; Ksalol; Librazolam; Manorest; Marzolam; Medepolin; Medronal; Meprax; Misar; Mitranax; Mialin; Nalion; Neurol; Niravam; Nirvan; Normapal; Novo-Alprazol; Novo-Vegestabil+; Neupax; Nu-Alpraz; Pacyl; Panix-; Paxal; Pazolam; Pharnax; Poize; Praxal; Prazam; Prazin; Prazol; Prazolex; Prenadona; Prinox; Pruden; Psicosedol; PTA; Raloxam; Ralozam-; Relaxol; Renax; Retan; Restyl; Restyl Forte+; Restyl Plus+; Rian; Sanerva; Saturnil; Sedipral; Siampraxol; Sidomal+; Solanax; Soxietas; Stresnil+; Tafil; Tagat; Tatanka; Tazun; Tensium; Tensium Gastric+; Tensivan; Thiprazolan; Topazolam; Tranax; Tranisol; Trankimazin; Tranquinal; Tranquinal Soma+; Tricalma; Trika; Trizo; Unilan; Valeans; Xanacine; Xanagis; Xanan; Xanas; Xanax; Xanolam-; Xanor; Xiemed; Xycalm; Xyren; Zacetin; Zallpam; Zamhexal; Zamitol; Zanapam; Zaxan; Zeftra; Zenax; Zenoprax, Zolam; Zolan; Zolarem; Zolax; Zoldac; Zoldax; Zomiren; Zopax; Zopax Plus+; Zopic; Zotran.
+ Multi-ingredient preparation
- Discontinued preparation
Abaxon (Venezuela)
Aceprax (Paraguay; Uruguay)
Adax (Chile)
Afobam (Poland)
Alcelam (Thailand)
Algad (Israel)
Alganax (Indonesia)
Alkrazil (Guatemala)
Alnax (Thailand)
Alpam (India)
Alpaz (Peru)
Alplax (Argentina)
Alplax Digest+ (Argentina)
Alplax Net+ (Argentina)
Alpralid- (Israel; Sweden)
Alpram (Korea)
Alpranax (Malaysia)
Alpraphar (Belgium)
Alpraquil (India)
Alpravecs (Italy)
Alprax (Australia; Hong Kong; India; Thailand)
Alpraz (Belgium)
Alprazig (Italy)
Alprazomed (Belgium)
Alprazomerck (Poland)
Alprastad (Austria)
Alpratyrol (Austria)
Alprim (Australia)
Alprocontin (India)
Alpronax (Portugal)
Alprose (India)
Alprox (Denmark; Ireland; Israel; Finland)
Alti-Alprazolam (Canada)
Altraxic (Philippines)
Altrox (Brazil)
Alviz (Indonesia)
Alzam (Mexico; South-Africa)
Alzolam (India; Malaysia; Russia; Singapore)
Alzomax (India)
Alzon (Denmark)
Alzopax (India)
Amziax (Argentina)
Anax (Thailand)
Anpress (Thailand)
Ansielix (Argentina)
Ansielix Digest+ (Argentina)
Ansilan (Venezuela)
Ansiopax (Chile)
Antanax- (Greece)
Anxirid (South Africa)
Anxit (India)
Anzilum (India)
Anzion (Thailand)
Anzofree (India)
Apo-Alpraz (Canada; Malaysia; Singapore)
Apotex (Canada)
Apox- (Israel)
Apraz (Belgium; Brazil)
Aprazo (Taiwan)
Azaxol (Cyprus)
Azor (South-Africa)
Becede (Argentina)
Besquil (India)
Bestrol (Argentina)
Cassadan (Germany)
Calmax (Ireland)
Calmlet (India)
Calmol (Argentina)
Constan (Japan)
Daclor (Dominican Republic)
Danox (Venezuela)
Dixin (Colombia)
Dizolam- (Singapore; Thailand)
Dizolam Atlantic (Thailand)
Drimpam- (South Africa)
Duazolam (Dominican Republic)
Docalprazo (Belgium)
Dormonoct (Portugal)
Emeral (Argentina)
Esparon- (Germany)
Euciton Stress+ (Argentina)
Eurelax (India)
Farmapram (Mexico)
Feprax (India)
Fludep Plus+ (India)
Frixitas (India)
Frontal (Brazil; Italy)
Frontin (Hungary; Slovak Republic; Czech Republic)
Gabazolamine Convenience Pack+ (United States)
Gendergin (Taiwan)
Gerax (Ireland)
Grifoalpram (Chile)
Helex (Croatia; Czech Republic; Russia; Slovenia)
Huma-Alprazol (Hungary)
Ibizolam (Italy)
Irizz (Mexico)
Jialeding (China)
Kalma (Australia; New-Zealand)
Kelaxanal (Belgium)
Kinax (Taiwan)
Krama (Argentina)
Ksalol (Serbia)
Librazolam (Ecuador)
Manorest (Sri Lanka)
Marzolam (Thailand)
Medepolin (Japan)
Medronal (Argentina)
Meprax (Dominican Republic)
Mialin (Italy)
Misar (Croatia)
Mitranax (Thailand)
Nalion (Hong Kong)
Neupax (Mexico)
Neurol (Czech Republic; Slovak Republic)
Niravam (United States)
Nirvan (Colombia)
Novo-Alprazol (Canada)
Novo-Vegestabil+- (Argentina)
Nu-Alpraz (Canada)
Pacyl (India)
Panix- (South-Africa)
Pazolam (Portugal)
Paxal (Iceland)
Pharnax (Thailand)
Poize (India)
Praxal (India)
Prazam (Chile; Portugal)
Prazin (Egypt; Jordan; Kuwait; Lebanon; Syria)
Prazol (Bahrain; Cyprus; Egypt; Israel; Iraq; Iran; Jordan; Kuwait; Lebanon; Libya; Oman; Qatar; Saudi Arabia; Syria; United-Arab-Emirates; Yemen)
Prazolan (Mexico)
Prazolex (Romania)
Prenadona (Argentina)
Prinox (Argentina)
Pruden (Chile)
Psicosedol (Argentina)
PTA (Argentina)
Ralozam- (Australia; New-Zealand)
Relaxol (Peru)
Renax (Hong Kong)
Restyl (Bahrain; Cyprus; Egypt; India; Iran; Iraq; Jordan; Kuwait; Lebanon; Libya; Oman; Qatar; Republic-of-Yemen; Saudi-Arabia; Syria; United-Arab-Emirates)
Restyl Forte+ (India)
Restyl Plus+ (India)
Retan (Argentina)
Rian (India)
Sanerva (Chile)
Saturnil (Greece)
Sedipral (Paraguay)
Siampraxol (Thailand)
Sidomal+ (Argentina)
Solanax (Japan)
Soxietas (India)
Stresnil+ (India)
Tafil (Costa-Rica; Denmark; El-Salvador; Germany; Guatemala; Honduras; Mauritius; Mexico; Nicaragua; Panama; Venezuela)
Tagat (India)
Tazun (Mexico)
Tensium (Argentina)
Tensium Gastric+ (Argentina)
Tensivan (Colombia)
Thiprazolan (Argentina)
Topazolam (Belgium)
Tranax (India)
Tranisol (India)
Trankimazin (Spain)
Tranquinal (Argentina; Brazil; Costa-Rica; Dominican Republic; Ecuador; El Salvador; Guatemala; Honduras; Nicaragua; Paraguay; Panama; Peru; Uruguay)
Tranquinal Soma+ (Argentina)
Tricalma (Chile)
Trika (India)
Trizo (India)
Unilan (Portugal)
Valeans (Italy)
Xanacine (Thailand)
Xanagis (Israel)
Xanax (Argentina; Australia; Bahamas; Bahrain; Barbados; Belgium; Belize; Benin; Bermuda; Bulgaria; Burkina Faso; Canada; Croatia; Colombia; Croatia; Cyprus; Czech Republic; Ecuador; Estonia; Egypt; Ethiopia; France; Gambia; Germany; Ghana; Greece; Guinea; Guyana; Honduras; Hong Kong; Hungary; Indonesia; Iraq; Iran; Ireland; Israel; Italy; Ivory Coast; Jamaica; Jordan; Kenya; Kuwait; Lebanon; Liberia; Libya; Luxembourg; Malawi; Malaysia; Mali; Mauritania; Mauritius; Morocco; Netherlands; New Zealand; Niger; Nigeria; Oman; Pakistan; Peru; Poland; Portugal; Qatar; Romania; Russia; Saudi Arabia; Senegal; Seychelles; Sierra Leone; Singapore; Slovenia; South Africa; Sudan; Suriname; Syria; Switzerland; Taiwan; Tanzania; Thailand; Trinidad/Tobago; Tunisia; Turkey; Uganda; United-Arab-Emirates; United Kingdom; United States; Yemen; Yugoslavia; Zambia; Zimbabwe)
Xanolam- (South Africa)
Xanor (Austria; Finland; Norway; Philippines; South-Africa; Sweden)
Xiemed (Thailand)
Xycalm (India)
Xyren (Korea)
Zacetin (Korea; Singapore)
Zallpam (India)
Zamhexal (Australia)
Zamitol (India)
Zanapam (Bahrain; Cyprus; Egypt; Israel; Iraq; Iran; Jordan; North Korea; Kuwait; Lebanon; Libya; Oman; Qatar; Saudi Arabia; Syria; United-Arab-Emirates; Yemen)
Zaxan (Yugoslavia)
Zeftra (India)
Zenax (India)
Zenoprax (India)
Zolam (India)
Zolarem (Bahrain; Benin; Burkina-Faso; Cyprus; Egypt; Ethiopia; Gambia; Ghana; Guinea; Iran; Iraq; Israel; Ivory-Coast; Jordan; Kenya; Kuwait; Lebanon; Liberia; Libya; Malawi; Mali; Mauritania; Mauritius; Morocco; Niger; Nigeria; Oman; Qatar; Republic-Of-Yemen; Saudi-Arabia; Senegal; Seychelles; Sierra-Leone; South-Africa; Sudan; Syria; Tanzania; Tunisia; Uganda; United-Arab-Emirates; Zambia; Zimbabwe)
Zoldac (Benin; Burkina-Faso; Ethiopia; Gambia; Ghana; Guinea; India; Ivory-Coast; Kenya; Liberia; Malawi; Mali; Mauritania; Mauritius; Morocco; Niger; Nigeria; Senegal; Seychelles; Sierra-Leone; South-Africa; Sudan; Tanzania; Tunisia; Uganda; Zambia; Zimbabwe)
Zolax (India)
Zomiren (Poland)
Zopax (South Africa)
Zopax Plus+ (India)
Zopic (Nepal)
Zotran (Chile)
Zypraz (Indonesia)
1.3 CATEGORIES
Antianxiety Drugs; Anxiety; Anxiolytics; Sedatives; Hypnotics; Benzodiazepines; Central Nervous System Agents; Depression; Nausea; Pain; Panic Disorder; Psychotropic Agents; Tension; Tinnitus*; Schedule C-IV controlled substance; Pregnancy Category D; FDA Approval 1981 Oct; Patent Expiration 1993 Oct.
*Indication not approved by FDA
1.4 INACTIVE INGREDIENTS
Alprazolam brand name Xanax (immediate-release) tablets contain cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablets contain FD&C yellow no. 6, and the 1 mg tablets contain FD&C blue no. 2.
Alprazolam XR brand name Xanax (extended-release) tablets contain lactose, magnesium stearate, colloidal silicon dioxide, and hypromellose. In addition, the 1 mg and 3 mg tablets contain FD&C yellow no. 10 and the 2 mg and 3 mg tablets contain FD&C blue no. 2.
Alprazolam brand name Niravam (orally disintegrating) tablets contain colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, mannitol, methacrylic acid copolymer, microcrystalline cellulose, natural and artificial orange flavor, sucralose and sucrose. In addition, the 0.25 mg and 0.5 mg tablets contain yellow iron oxide.
Alprazolam Intensol Oral Solution (concentrate) contains propylene glycol, succinic acid, succinic acid disodium salt and water.
2.0 CLINICAL PHARMACOLOGY
2.1 PHARMACODYNAMICS
Central nervous system (CNS) agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at the level of the limbic, thalamic and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity and coma. Their exact mechanism of action is unknown. The action of these drugs is mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and increasing the inhibition of the ascending reticular activating system. Benzodiazepines block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.
GABA is the most widely distributed inhibitory neurotransmitter in the central nervous system. GABA opens chloride (Cl) channels, causing an influx of Cl ions. The influx of Cl ions causes hyperpolarization of the neuron, subsequently inhibiting neuronal discharge. Benzodiazepines potentiate the actions of GABA in a similar fashion via specific receptors, which are located near the GABA receptors. The GABAA receptor subunit, composed of multiple forms (e.g., alpha, beta, gamma) has been proposed as the functional unit on which benzodiazepines operate.
GABAA is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to pharmacological and clinical effects. Benzodiazepines bind only to alpha subunits which contain a histidine amino acid residue (i.e., a1, a2, a3 and a5 containing GABAA receptors). For this reason benzodiazepines show no affinity for a4 and a6 subunits containing GABAA receptors, which contain an arginine instead of a histidine residue. Other sites on the GABAA receptor also bind barbiturates, ethanol, furosemide, kavalactones, neurosteroids, picrotoxin and certain anesthetics.
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an a and a g subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the neuron. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects. As mentioned above, different benzodiazepines can have different affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the a1 subunit are associated with sedative, amnestic and anticonvulsant properties, whereas those with higher affinity for GABAA receptors containing a2 and/or a3 subunits have greater anxiolytic activity. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility, vasodilation and enhanced perfusion. The action of hyperpolarization is reversed by the influx of calcium into the cell.
The long-term pharmacodynamics interaction of benzodiazepines with GABA receptors is thought to be extremely complex. Long-term use of benzodiazepines is thought to result in down-regulation of inhibitory GABA receptors and configurational changes of the receptor-agonist complex, resulting in diminished agonist sensitivity. These changes are potential mechanisms of tolerance, dependence and withdrawal. The abrupt cessation of benzodiazepines, as in the case of a patient discontinuing a benzodiazepine after long-term use, is thought to result in the classically described acute withdrawal symptoms as the inhibitory pressure is removed, leaving a relative excitatory state.
2.2 PHARMACOKINETICS
Absorption
Following oral administration, alprazolam is readily absorbed. The peak plasma concentration is reached about 1.5 to 2 hours after administration of alprazolam given with or without water. When taken with water, mean Tmax occurs about 15 minutes earlier than when taken without water with no change in Cmax or AUC. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL are observed.
There were significant differences in absorption rate, depending on the time of day administered, with the Cmax increased by 30% and the Tmax decreased by an hour following dosing at night, compared to morning dosing.
Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be approximately 12.5 hours (range 7.9-19.2 hours) after administration in healthy adults.
The mean absolute bioavailability of alprazolam from alprazolam XR tablets is approximately 90%, and the relative bioavailability compared to alprazolam tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of alprazolam XR tablets are similar to that for alprazolam tablets, with the exception of a slower rate of absorption. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active metabolites (4-hydroxyalprazolam and a-hydroxyalprazolam) are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products.
Food has a significant influence on the bioavailability of alprazolam XR tablets. A high-fat meal given up to 2 hours before dosing with alprazolam XR tablets increased the mean Cmax by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase in Tmax by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t1/2) were not affected by eating.
Distribution
In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.
Metabolism
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and a-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and a-hydroxyalprazolam) were similar for alprazolam and alprazolam XR tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and a-hydroxyalprazolam relative to unchanged alprazolam concentration after both alprazolam XR and alprazolam tablets were always less than 10% and 4%, respectively. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and a-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and a-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
Elimination
Alprazolam and its metabolites are excreted primarily in the urine as glucuronides. Some of the drug is also excreted in unchanged form.
Special populations
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0-26.9 hours, n = 16) compared to 11.0 hours (range: 6.3-15.8 hours, n = 16) in healthy adult subjects. The co-administration of oral contraceptives to healthy women increased the half-life of alprazolam as compared to that in healthy control women (mean: 12.4 hours, n = 11 versus 9.6 hours, n = 9). There was a prolongation in the mean half-life of alprazolam from 12.4 hours (range: 7.2-18.4 hours, n = 9) to 16.6 hours (range: 10.0- 24.3 hours, n = 9) by the co-administration of cimetidine to the same healthy adults. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n = 17) as compared to between 6.3 and 26.9 hours (mean = 11.4 hours, n = 17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean = 21.8 hours, n = 12) as compared to between 6.3 and 15.8 hours (mean = 10.6 hours, n = 12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.
Race - Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
Gender - Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking - Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.
Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itra-conazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold.
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1±4.9 to 7.7±1.7 h) following administration of 300mg/day carbamazepine for 10 days. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
2.3 CLINICAL STUDIES
Anxiety Disorders
Alprazolam was compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these four week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.
Panic Disorder
Support for the effectiveness of alprazolam in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R/IV criteria for panic disorder.
The average dose of alprazolam was 5-6 mg/day in two of the studies and the doses of alprazolam were fixed at 2 and 6 mg/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.
2.4 CLINICAL EFFICACY TRIALS
The efficacy of alprazolam XR tablets in the treatment of panic disorder was established in two 6-week, placebo-controlled studies of alprazolam XR in patients with panic disorder.
In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III/IV criteria for panic disorder, patients were treated with alprazolam XR in a dose range of 1 to 10 mg/day, on a once-a-day basis. The effectiveness of alprazolam XR was assessed on the basis of changes in various measures of panic attack frequency, on various measures of the Clinical Global Impression and on the Overall Phobia Scale. In all, there were seven primary efficacy measures in these studies, and alprazolam XR was superior to placebo on all seven outcomes in both studies. The mean dose of alprazolam XR at the last treatment visit was 4.2mg/day in the first study and 4.6 mg/day in the second.
In addition, there were two 8-week, fixed-dose, placebo-controlled studies of alprazolam XR in patients with panic disorder, involving fixed alprazolam XR doses of 4 and 6 mg/day, on a once-a-day basis, that did not show a benefit for either dose of alprazolam XR.
The longer-term efficacy of alprazolam XR in panic disorder has not been systematically evaluated.
Analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender.
2.5 ANIMAL STUDIES
When rats were treated with alprazolam at 3, 10 and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.
3.0 INDICATIONS AND USAGE
Anxiety Disorders
Alprazolam is indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual (DSM-III-R/IV) diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: MOTOR TENSION: Trembling, twitching or feeling shaky; muscle tension, aches or soreness; restlessness; easy fatigability. AUTONOMIC HYPERACTIVITY: Shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating or cold clammy hands; dry mouth; dizziness or lightheadedness; nausea, diarrhea or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or 'lump in throat'). VIGILANCE AND SCANNING: Feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank' because of anxiety; trouble falling or staying asleep; irritability. These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to alprazolam.
Panic Disorder
Alprazolam is also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder.
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to four months duration for anxiety disorder and four to ten weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit. Periodically reassess the usefulness of the drug for the individual patient.
3.1 CONTRAINDICATIONS
Alprazolam is contraindicated in patients with known sensitivity to this drug or other benzodiazepines.
Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.
Alprazolam is contraindicated with ketaconazole and itraconzole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A).
Alprazolam should be used with extreme caution in patients with respiratory depression, pulmonary disease such as severe COPD (chronic obstructive pulmonary disease) or sleep apnea because the drug can exacerbate ventilatory failure.
Alprazolam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition.
Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease.
The administration of alprazolam can exacerbate acute intermittent porphyria, so the drug should be used with caution in patients with this condition.
Alprazolam is occasionally beneficial for patients with major depression, psychosis or suicidal ideation. The drug should be administered to these patients with careful monitoring.
Alprazolam is classified as pregnancy category D because it could harm the fetus when administered to pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties and weight loss, alprazolam generally is not recommended during breast-feeding.
Alprazolam should be administered cautiously to patients with severe hepatic disease because the elimination half-life of the drug can be prolonged, possibly resulting in toxicity. Patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages. Concomittant administration of alprazolam and potent inhibitors of CYP3A4 such as ketoconazole and itraconazole are contraindicated. Concurrent administration of alprazolam and drugs that inhibit cytochrome P450 3A (CYP3A) should be approached with caution.
Patients with renal impairment should be carefully monitored during prolonged treatment with benzodiazepines to avoid the adverse reactions that may occur from drug accumulation.
The clearance and/or elimination of many drugs are reduced in the elderly. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. Benzodiazepines have been associated with falls in the elderly. The impairment of cognitive and motor function may be more marked in this patient group and lower initial dosage is recommended together with close monitoring.
3.2 WARNINGS
Dependence and Withdrawal Reactions, Including Seizures:
Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure. Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75-4.0 mg per 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, 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 alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.
The Importance Of Dose And The Risks Of Alprazolam As A Treatment For Panic Disorder
Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
The rate of relapse, rebound and withdrawal in patients with panic disorder who received alprazolam tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received alprazolam tablets showed a high rate of rebound and withdrawal symptoms compared to placebo treated patients.
In a controlled clinical trial in which 63 patients were randomized to alprazolam 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.
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 were as follows:
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TABLE 1
Discontinuation-Emergent Symptom Incidence
Percentage of 641 Alprazolam-Treated Panic Disorder Patients
Reporting Events
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Body System/Event
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NEUROLOGIC GASTROINTESTINAL
Insomnia 29.5 Nausea/Vomiting 16.5
Light-headedness 19.3 Diarrhea 13.6
Abnormal involuntary movement 17.3 Decreased salivation 10.6
Headache 17.0 METABOLIC-NUTRITIONAL
Muscular twitching 6.9 Weight loss 13.3
Impaired Co-ordination 6.6 Decreased appetite 12.8
Muscle tone disorders 5.9
Weakness 5.8 DERMATOLOGICAL
PSYCHIATRIC Sweating 14.4
Anxiety 19.2 CARDIOVASCULAR
Fatigue and Tiredness 18.4 Tachycardia 12.2
Irritability 10.5 SPECIAL SENSES
Cognitive disorder 10.3 Blurred vision 10.0
Memory impairment 5.5
Depression 5.1
Confusional state 5.0
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From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder.In two controlled trials of six to eight weeks duration where the ability of patients to discontinue medication was measured, 71%-93% of alprazolam treated patients tapered completely off therapy compared to 89%-96% of placebo treated patients. The ability of patients to completely discontinue therapy with alprazolam after long-term therapy has not been reliably determined. However, in a controlled post marketing discontinuation study of panic disorder patients, the duration of treatment (three months compared to six months) had no effect on the ability to taper to zero dose.
Seizures were reported for three patients in panic disorder clinical trials with alprazolam XR. In two cases, the patients had completed 6 weeks of treatment with alprazolam XR 6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued alprazolam XR, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with alprazolam XR 4 mg/day and missed taking the medication on the first day of taper. All three patients recovered without sequelae. Seizures have also been observed in association with dose reduction or discontinuation of alprazolam tablets, the immediate release form of alprazolam. Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24-72 hours after discontinuation.
Status Epilepticus
The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of intravenous benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.
Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. 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. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations.
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually.
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving alprazolam 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 simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their prescriber about the desirability of discontinuing the drug.
Alprazolam Interaction 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. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents: Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The co-administration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the co-administration of alprazolam with them is not recommended.
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam (caution and consideration of appropriate alprazolam dose reduction are recommended during co-administration with the following drugs):
Nefazodone: Co-administration of nefazodone increased alprazolam concentration twofold.
Fluvoxamine: Co-administration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71% and decreased measured psychomotor performance.
Cimetidine: Co-administration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42% and increased half-life by 16%.
3.3 PRECAUTIONS
If alprazolam tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines.
Suicide
As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason toexpect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.
Mania
Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.
Uricosuric Effect
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation, which may be a particular problem in elderly or debilitated patients. The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam.
Information for Patients
To assure safe and effective use of alprazolam, the physician should provide the patient with the following guidance.
1. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
5. Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
7. Some patients may find it very difficult to discontinue treatment with alprazolam due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg/day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure.
Laboratory Tests
Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable in keeping with good medical practice.
3.4 INTERACTIONS
Use with Other CNS Depressants
If alprazolam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
Drugs Affecting Salivary Flow and Stomach pH
Because alprazolam disintegrates in the presence of saliva and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption.
Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
Drugs that inhibit alprazolam metabolism via cytochrome P450 3A:
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during co-administration with alprazolam):
Fluoxetine (Prozac): Co-administration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.
Propoxyphene: Co-administration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.
Oral Contraceptives: Co-administration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.
Digoxin (Lanoxin): May increase serum digoxin levels, increasing toxicity. An interaction between digoxin with alprazolam has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. Pending further clarification of this interaction, patients receiving alprazolam and digoxin concurrently should be monitored for increased serum digoxin levels.
Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during co-administration with alprazolam): Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine and nifedipine.
Drugs demonstrated to be inducers of CYP3A
Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).
Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.
Pregnancy
Teratogenic Effects: Pregnancy Category D - Positive evidence of risk.
Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery
Alprazolam has no established use in labor or delivery.
Nursing Mothers
Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.
Pediatric Use
Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.
Geriatric Use
The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation.
3.5 ADVERSE REACTIONS
Side effects of alprazolam tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam (e.g., drowsiness or light-headedness).
The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (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/day of alprazolam in patients with panic disorder, with or without agoraphobia.
These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.
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 untoward event 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 it (an untoward event) in others.
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TABLE 2
ANXIETY DISORDERS
Treatment-Emergent Incidence of
Symptom Incidence x intervention
Because of Symptom
Alprazolam Placebo Alprazolam
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Number of Patients 565 505 565
% of Patients Reporting:
CENTRAL NERVOUS SYSTEM
Drowsiness 41.0 21.6 15.1
Light-headedness 20.8 19.3 1.2
Depression 13.9 18.1 2.4
Headache 12.9 19.6 1.1
Confusion 9.9 10.0 0.9
Insomnia 8.9 18.4 1.3
Nervousness 4.1 10.3 1.1
Syncope 3.1 4.0 *
Dizziness 1.8 0.8 2.5
Akathisia 1.6 1.2 *
Tiredness/Sleepiness * * 1.8
GASTROINTESTINAL
Dry Mouth 14.7 13.3 0.7
Constipation 10.4 11.4 0.9
Diarrhea 10.1 10.3 1.2
Nausea/Vomiting 9.6 12.8 1.7
Increased Salivation 4.2 2.4 *
CARDIOVASCULAR
Tachycardia/Palpitations 7.7 15.6 0.4
Hypotension 4.7 2.2 *
SENSORY
Blurred Vision 6.2 6.2 0.4
MUSCULOSKELETAL
Rigidity 4.2 5.3 *
Tremor 4.0 8.8 0.4
CUTANEOUS
Dermatitis/Allergy 3.8 3.1 0.6
OTHER
Nasal Congestion 7.3 9.3 *
Weight Gain 2.7 2.7 *
Weight Loss 2.3 3.0 *
* None reported.
x Events reported by 1% or more of alprazolam patients are included.
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In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events 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 3
Panic Disorders
Treatment-Emergent Symptom Incidence*
Alprazolam PLACEBO
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Number of Patients 1388 1231
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% of Patients Reporting:
CENTRAL NERVOUS SYSTEM
Drowsiness 76.8 42.7
Fatigue and Tiredness 48.6 42.3
Impaired Coordination 40.1 17.9
Irritability 33.1 30.1
Memory Impairment 33.1 22.1
Light-headedness /Dizziness 29.8 36.9
Insomnia 29.4 41.8
Headache 29.2 35.6
Cognitive Disorder 28.8 20.5
Dysarthria 23.3 6.3
Anxiety 16.6 24.9
Abnormal Involuntary Movement 14.8 21.0
Decreased Libido 14.4 8.0
Depression 13.8 14.0
Confusional State 10.4 8.2
Muscular Twitching 7.9 11.8
Increased Libido 7.7 4.1
Change in Libido (Not Specified) 7.1 5.6
Weakness 7.1 8.4
Muscle Tone Disorders 6.3 7.5
Syncope 3.8 4.8
Akathisia 3.0 4.3
Agitation 2.9 2.6
Disinhibition 2.7 1.5
Paresthesia 2.4 3.2
Talkativeness 2.2 1.0
Vasomotor Disturbances 2.0 2.6
Derealisation 1.9 1.2
Dream Abnormalities 1.8 1.5
Fear 1.4 1.0
Feeling Warm 1.3 0.5
GASTROINTESTINAL
Decreased Salivation 32.8 34.2
Constipation 26.2 15.4
Nausea/Vomiting 22.0 31.8
Diarrhea 20.6 22.8
Abdominal Distress 18.3 21.5
Increased Salivation 5.6 4.4
CARDIORESPIRATORY
Nasal Congestion 17.4 16.5
Tachycardia 15.4 26.8
Chest Pain 10.6 18.1
Hyperventilation 9.7 14.5
Upper Respiratory Infection 4.3 3.7
SENSORY
Blurred Vision 21.0 21.4
Tinnitus 6.6 10.4
MUSCULOSKELETAL
Muscular Cramps 2.4 2.4
Muscle Stiffness 2.2 3.3
CUTANEOUS
Sweating 15.1 23.5
Rash 10.8 8.1
OTHER
Increased Appetite 32.7 22.8
Decreased Appetite 27.8 24.1
Weight Gain 27.2 17.9
Weight Loss 22.6 16.5
Micturition Difficulties 12.2 8.6
Menstrual Disorders 10.4 8.7
Sexual Dysfunction 7.4 3.7
Edema 4.9 5.6
Incontinence 1.5 0.6
Infection 1.3 1.7
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* Events reported by 1% or more of alprazolam patients are included.
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In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events 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. Therefore, the same precaution must be exercised when using the higher doses of alprazolam in treating patients with panic disorders as is exercised with the use of any psychotropic drug in treating depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans.
Laboratory analyses were performed on patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown below were observed in patients receiving alprazolam and in patients in the corresponding placebo group. Few of these abnormalities were considered to be of physiological significance.
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TABLE 4
Alprazolam, Adverse Reactions
Alprazolam Placebo
Low High Low High
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HEMATOLOGY
Hematocrit * * * *
Hemoglobin * * * *
Total WBC Count 1.4 2.3 1.0 2.0
Neutrophil Count 2.3 3.0 4.2 1.7
Lymphocyte Count 5.5 7.4 5.4 9.5
Monocyte Count 5.3 2.8 6.4 *
Eosinophil Count 3.2 9.5 3.3 7.2
Basophil Count * * * *
URINALYSIS
Albumin - * - *
Sugar - * - *
RBC/HPF - 3.4 - 5.0
WBC/HPF - 25.7 - 25.9
BLOOD CHEMISTRY
Creatinine 2.2 1.9 3.5 1.0
Bilirubin * 1.6 * *
SGOT * 3.2 1.0 1.8
Alkaline Phosphatase * 1.7 * 1.8
* Less than 1%
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When treatment with alprazolam is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable. Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance.
Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Alprazolam XR
The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Alprazolam XR is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.
Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Approximately 17% of the 531 patients who received alprazolam XR in placebo-controlled clinical trials for panic disorder had at least one 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 XR at a rate at least twice that of placebo) are shown in the following table.
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Common Adverse Events Leading to
Discontinuation of Treatment
in Placebo-Controlled Trials
System Organ Percentage of Patients
Class/Adverse Discontinuing Due
Event to Adverse Events
alprazolam XR Placebo
(n=531) (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
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Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam XRBe aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam XR where the incidence in patients treated with alprazolam XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with alprazolam 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.
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Treatment-Emergent Adverse Events:
Incidence in Short-Term, Placebo-Controlled
Clinical Trials with alprazolam XR
System Organ Percentage of Patients
Class/Adverse Reporting Adverse
Event Event
alprazolam XR Placebo
(n=531) (n=349)
NERVOUS SYSTEM DISORDERS
Sedation 45.2 22.6
Somnolence 23.0 6.0
Memory impairment 15.4 6.9
Dysarthria 10.9 2.6
Coordination abnormal 9.4 0.9
Mental impairment 7.2 5.7
Ataxia 7.2 3.2
Disturbance in attention 3.2 0.6
Balance impaired 3.2 0.6
Paresthesia 2.4 1.7
Dyskinesia 1.7 1.4
Hypoesthesia 1.3 0.3
Hypersomnia 1.3 0
GENERAL DISORDERS/ADMINISTRATION SITE CONDITIONS
Fatigue 13.9 9.2
Lethargy 1.7 0.6
INFECTIONS AND INFESTATIONS
Influenza 2.4 2.3
Upper respiratory tract infections 1.9 1.7
PSYCHIATRIC DISORDERS
Depression 12.1 9.2
Libido decreased 6.0 2.3
Disorientation 1.5 0
Confusion 1.5 0.9
Depressed mood 1.3 0.3
Anxiety 1.1 0.6
METABOLISM AND NUTRITION DISORDERS
Appetite decreased 7.3 7.2
Appetite increased 7.0 6.0
Anorexia 1.5 0
GASTROINTESTINAL DISORDERS
Dry mouth 10.2 9.7
Constipation 8.1 4.3
Nausea 6.0 3.2
Pharyngolaryngeal pain 3.2 2.6
INVESTIGATIONS
Weight increased 5.1 4.3
Weight decreased 4.3 3.7
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Road traffic accident 1.5 0
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Dysmenorrhea 3.6 2.9
Sexual dysfunction 2.4 1.1
Premenstrual syndrome 1.7 0.6
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia 2.4 0.6
Myalgia 1.5 1.1
Pain in limb 1.1 0.3
VASCULAR DISORDERS
Hot flushes 1.5 1.4
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dyspnea 1.5 0.3
Rhinitis allergic 1.1 0.6
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Pruritis 1.1 0.9
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Other Adverse Events Observed during the Premarketing Evaluation of Alprazolam XR tabletsFollowing is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with alprazolam XR. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with alprazolam XR, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/100 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients.
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
The categories of adverse events reported in the clinical development program for alprazolam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam XR tablets because the clinical trials with alprazolam tablets and alprazolam XR tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam XR tablets.
Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam XR
The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam XR where the incidence in patients treated with alprazolam XR was two times greater than the incidence in placebo-treated patients.
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Discontinuation-Emergent Symptoms:
Incidence in Short-Term, Placebo-Controlled Trials
with alprazolam XR
System Organ Percentage of Patients
Class/Adverse Reporting Adverse
Event Event
alprazolam XR Placebo
(n=422) (n=261)
NERVOUS SYSTEM DISORDERS
Tremor 28.2 10.7
Headache 26.5 12.6
Hypoesthesia 7.8 2.3
Paresthesia 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
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Muscle twitching 7.4 2.7
VASCULAR DISORDERS
Hot flushes 5.9 2.7
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To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.As with all benzodiazepines, 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.
Post Introduction Reports
Various adverse drug reactions have been reported in association with the use of alprazolam since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia and galactorrhea.
4.0 DOSAGE AND ADMINISTRATION
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 higher doses. In such cases, dosage should be increased cautiously to avoid adverse effects.
Alprazolam XR tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed or broken.
Anxiety Disorders and Transient Symptoms of Anxiety
Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given 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. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
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 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating at the panic disorder development program, about 300 received maximum alprazolam dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.
Dosing in Special Populations
In elderly patients, in patients with advanced liver disease, or in patients with debilitating 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 side effects occur at the recommended starting dose, the dose may be lowered.
Dose Titration
Treatment may be initiated 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 higher dose levels may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.
Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. 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/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.
The necessary duration of treatment for panic disorder patients responding to alprazolam 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.
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 3 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, the previous dosing schedule should be reinstituted and, only after stabilisation, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawl syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
Switch from Alprazolam (immediate-release) Tablets to Alprazolam XR (extended-release) Tablets
Patients who are currently being treated with divided doses of alprazolam (immediate-release) tablets, for example 3 to 4 times a day, may be switched to alprazolam XR tablets at the same total daily dose taken once daily. If the therapeutic response after switching is inadequate, the dosage may be titrated as outlined above.
Instructions to be Given to Patients for Use/Handling Alprazolam (orally disintegrating) Tablets
Just prior to administration, with dry hands, remove the tablet from the bottle. Immediately place the alprazolam (orally disintegrating) 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.
Proper Use of an Intensol
An Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.
Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose. Then squeeze the dropper contents into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds. The Intensol formulation blends quickly and completely. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use.
4.1 OVERDOSAGE
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.
The acute oral LD50 in rats is 331-2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.
Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.
General Treatment of Overdose
Overdosage reports with alprazolam tablets are limited. As in all cases of drug overdosage, respiration, pulse rate and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.
Flumazenil (Mazicon), a specific benzodiazepine receptor antagonist at central GABA-ergic receptors, 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. Flumazenil is a short-acting drug; therefore, sedation after an initial awakening may recur. If necessary, this can be treated by repeating doses at 20-minute intervals.
Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated. Use of flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of flumazenil may precipitate seizures. It must be used with some caution; in some cases, it has not completely reversed respiratory depression. Adverse effects associated with flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The complete flumazenil prescribing information should be consulted prior to use.
5.0 ABUSE AND DEPENDENCE
Physical and Psychological Dependence
Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.
While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late and they will persist.
While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (e.g., 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day.
Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision.
Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at higher doses and with longer-term use and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.
Controlled Substance Class
Alprazolam is a controlled substance under the Controlled Substance Act of 1970 by the Drug Enforcement Administration and alprazolam has been assigned to Schedule IV on November 12, 1981. Internationally, alprazolam is a Schedule IV controlled substance under the United Nations Convention on Psychotropic Substances of 1971.
6.0 FREQUENTLY ASKED QUESTIONS
1. What do alprazolam tablets do?
This medication has a calming effect. It is used to relieve anxiety, nervousness and tension in the treatment of anxiety disorders and panic disorder, with or without agoraphobia. Primarily for short-term relief of mild to moderate anxiety and nervous tension. Alprazolam is also effective in the treatment of activity depression, specific phobias, anticipatory anxiety, hyperventilation or panic attacks. It can be useful in treating irritable bowel syndrome, to manage spasticity in Lesch-Nyhan Syndrome, anxiety related to symptoms of esophageal motility disorders, anxiety comorbid with hypochondriasis and anxiety due to a neurosis as well. Alprazolam may help the symptoms of PMS if extreme, some cancer pains if given with various narcotics, essential tremor, fibromyalgia, restless legs syndrome, Ménière's disease and tinnitus.
2. What do they do to the brain?
People with serious forms of anxiety demonstrate chronic over-activity in the areas of the brain associated with fear or nervousness. An inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) works in these areas to diminish this excessive nerve cell activity. There is evidence that benzodiazepines cause an increase in the activity of GABA, thereby returning the system to a normal level and reducing the associated symptoms of anxiety. Benzodiazepines bind to a specific receptor on the GABAA receptor complex, which facilitates the binding of GABA to its specific receptor site. Benzodiazepine binding causes increased frequency of opening of the chloride channel complexed with the GABAA receptor. Chloride channel opening results in membrane hyperpolarization, which inhibits cellular excitation. Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis and anticonvulsant effects. They are also believed to decrease the turnover rate of the neurotransmitters, serotonin and norepinephrine.
3. What are the names of the benzodiazepines?
Several thousand different benzodiazepines have been synthesized since the first benzodiazepine chlordiazepoxide in 1957, of which about 50 are currently marketed. The benzodiazepines used most often include alprazolam (Xanax, Niravam); bromazepam (Lexotan); chlordiazepoxide (Librium, Librax, Libritabs); clobazam (Frisium); clonazepam (Klonopin); clorazepate (Tranxene); diazepam (Valium); estazolam (Prosom); flunitrazepam (Rohypnol); flurazepam (Dalmane); halazepam (Paxipam); ketazolam (Anxon); lorazepam (Ativan); nitrazepam (Mogadon); nordiazepam (Nordaz); oxazepam (Serax); prazepam (Centrax); quazepam (Doral); temazepam (Restoril); triazolam (Halcion).
Their generic names are easy to recognize because many of them end in the suffixes –zepam for 1,4-benzodiazepines, -zolam for 1,4-triazolo-benzodiazepines and -bazam for 1,5-benzodiazepines.
4. How fast do they take effect?
Like the barbiturates, benzodiazepines differ from one another in how fast they take effect and how long the effects last. The lipophilic (fat-soluble) benzodiazepines, including alprazolam, usually are absorbed more rapidly and produce a faster onset of action than the hydrophilic (water-soluble) benzodiazepines. Absorption is especially rapid when ethanol is present and the stomach is empty. After a single dose, the lipophilic benzodiazepines have a shorter duration of action than the hydrophilic benzodiazepines because of a rapid redistribution from the CNS to peripheral sites (e.g., adipose tissue).
Short-acting benzodiazepines include triazolam (Halcion). Intermediate-acting benzodiazepines include alprazolam (Xanax, Niravam); bromazepam (Lexotan); clonazepam (Klonopin); estazolam (ProSom); lorazepam (Ativan); nitrazepam (Mogadon); oxazepam (Serax); temazepam (Restoril). Long-acting benzodiazepines include chlordiazepoxide (Librium, Librax, Libritabs); clobazam (Frisium); clorazepate (Tranxene); diazepam (Valium); flunitrazepam (Rohypnol); flurazepam (Dalmane); halazepam (Paxipam); ketazolam (Anxon); nordiazepam (Nordaz); prazepam (Centrax); quazepam (Dormalin).
Benzodiazepine equivalence schedule5. For which illnesses or problems are these medicines used?
------------------------------------------------------------------------------------ Benzodiazepine Comparative Time Half-life dose to peak plasma level ------------------------------------------------------------------------------------ Alprazolam .5 1 - 2 9 - 20 Bromazepam 3.0 .5 - 4 8 - 30 Chlordiazepoxide 25 1 - 4 24 - 100 Clonazepam .25 1 - 4 19 - 60 Clorazepate 10 variable 1.3 - 120 * (unreliable absorption) Diazepam 5 1 - 2 30 - 200 * Estazolam 1 .5 - .6 8 - 24 Flurazepam 15 .5 - 1 40 - 250 * Halazepam 40 1 - 3 30 - 96 * Ketazolam 7.5 3.2 30 - 200 Lorazepam 1 2 4 8 - 24 Nitrazepam 2.5 .5 - 7 15 - 48 Oxazepam 15 2 - 3 3 - 25 Prazepam 10 2.5 - 6 30 - 100 Quazepam 7.5 1.5 39 - 120 * Temazepam 10 2.5 3 - 25 Triazolam .25 1 - 2 1.5 - 5 * metabolites ------------------------------------------------------------------------------------
These medicines are used to treat anxiety, seizures, panic attacks, severe agitation and insomnia. When someone is addicted to alcohol or other sedatives, the benzodiazepines are given in gradually smaller amounts to detoxify the person. Some are useful as vestibular suppressants, such as alprazolam and diazepam, for the treatment of dizziness and vertigo by dulling the brain's response to signals from the inner ear. To reduce pain-related anxiety, anxiolytics allow a smaller analgesic dose to achieve the same effect. Some are used to neutralize the anxiety-related symptoms that may accompany the initial use of selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) and other antidepressants. They are also used to treat akathisia, a severe restlessness sometimes caused by antipsychotic medicines.
6. Are benzodiazepines used for mental illness?
Benzodiazepines may be useful, in low doses, for patients with schizophrenia who are beginning to show signs of relapse, and may help to avoid the necessity of major increases in neuroleptic medication. They may also be useful in treating mania.
7. Do they treat muscle spasms and epileptic attacks?
Yes. They have been successful in treating the toxic psychoses caused by hallucinogenic drugs, to treat symptoms of acute alcohol withdrawal, to help control epilepsy, to relieve muscle spasms and as pre- or post-operative sedation. They have many possible safe medical uses.
8. Are they also effective in treating insomnia?
Yes. However, sleeping problems are often a symptom of other medical conditions. It is important that the cause of poor sleep is diagnosed so that appropriate treatment can be given. Once diagnosed and treated, sleep generally returns to normal. Alprazolam can help in some cases, but it is not a cure for insomnia. It is best used when required or every few days (e.g., alternate nights). Regular use can lead to rebound insomnia. On a side note, the use of myorelaxant anxiolytic compounds, such as alprazolam, may affect snoring severity. Alprazolam resulted in increased snoring and changes in sleep architecture, and it produced a shortened sleep latency and an improvement in sleep efficiency. Alprazolam may cause a higher frequency of nighttime heartburn.
9. How was my benzodiazepine chosen?
Some are used more often in certain conditions; for example, alprazolam (Xanax, Niravam) is often used to treat panic attacks. Some are most often used to treat insomnia, for example flurazepam (Dalmane), triazolam (Halcion) and temazepam (Restoril). Some are safer for the elderly because they are not as likely to build up in the blood, for example, oxazepam (Serax) and lorazepam (Ativan).
10. What about addiction to benzodiazepines?
Dependence on benzodiazepines has been reported when they have been used continuously for many months or years. This does not mean that patients are "addicted" to their medication. Addiction is a pattern of drug abuse characterized by an overwhelming preoccupation with the use of a drug, including build up of a physical tolerance to the drug's effects and intense drug-seeking behaviour. Addiction to benzodiazepines is considered rare, except among persons who have been addicted to other substances, such as cocaine or alcohol. Patients with a history of substance abuse, multiple episodes of lost prescriptions, psychiatric illness or antisocial acts will increase the suspicion of benzodiazepine drug-seeking behavior (i.e., malingering). Evidence indicates that the great majorities of patients who use benzodiazepines appropriately for long periods do not tend to increase their doses, do not use medicines for recreational purposes and do not become dependent on them. These patients are safely maintained at the same dose for many years without apparent loss of efficacy. In some cases, patients requiring long-term benzodiazepine therapy can become dependent on their medication to function normally, in the same way a diabetic patient is dependent on insulin to function normally.
Patients who abuse or become dependent on benzodiazepines may fall into two broad categories. The first category contains patients being prescribed benzodiazepines for the symptomatic treatment of a psychiatric disorder. Such individuals risk developing dependence, particularly if they have a history of alcohol or prescription drug abuse, are being prescribed high doses or are prescribed the anxiolytic for more than one month. Patients with a family history of alcoholism may be genetically predisposed to benzodiazepine dependence.
The second category contains patients who use benzodiazepines in the setting of alcohol or polydrug abuse or dependence. These individuals may use benzodiazepines to manage chronic anxiety or insomnia, to enhance the euphoriant effects of opioids (e.g., methadone), to lessen the withdrawal symptoms of other drugs (e.g., methamphetamine) or when no other drugs are available.
11. How should I use this medicine?
Take this medication by mouth and swallow the immediate-release tablets with a drink of water. Swallow the extended-release tablets whole. Do not crush, chew, or break the extended-release tablets. Do not