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Alprazolam FAQ
by Mr. Egomaniac
v 3.2 - Apr 2011
TABLE OF CONTENTS

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; alpratsolaami (Finland); alprazolamas (Lithuania); alprazolamum (INN-Latin)1
CHEMICAL NAME (IUPAC): 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: AHFS 28.24.08; AP-1002; APRD00280; AZ-002; BB_SC-2025; BRN 1223125; C06817; CAS 28981-97-7; D-65MT; D00225; DB00404; DEA No. ACSCN 2882; DIN 02248706; EINECS 2493492; FDA No. 018276; HSDB 7207; MeSH D000525; nchembio747-comp35; RTECS XZ5473000; TUS-1; U-31889; UNII YU55MQ3IZY; CTV3 READ-Code y01yC; ZINC00000903
ATC CLASSIFICATION: N05BA12 Nervous system (N)/ Psycholeptics (N05)/ Anxiolytics (N05B)/ Benzodiazepine derivatives (N05BA)
ATCvet CLASSIFICATION: QN05BA12 Veterinary (Q)/ 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-zo-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; freely soluble in dichloromethane 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, approved by the U.S. Food and Drug Administration (FDA) on October 16, 1981 and assigned to Schedule IV of the Controlled Substance Act (CSA) on November 12, 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 (bulk) powder, in its purest form, is used as an active ingredient in various types of pharmaceutical formulations:

Each alprazolam IR (immediate-release) tablet, for oral administration, contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Alprazolam IR brand name Xanax 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 IR tablets were introduced in 1993 and may have additional dosage strengths (e.g., 0.4 mg and 0.8 mg tablets). Alprazolam IR brand name Xanax tablets are available as follows:

Tablet, 0.25 mg (white, ovoid-shaped tablet, imprint "Upjohn 29") or (white, ovoid-shaped tablet, imprint "XANAX 0.25") These tablets can be broken into 2 equal parts of 0.125 mg each.
Tablet, 0.5 mg (pink, ovoid-shaped tablet, imprint "Upjohn 55") or (peach, ovoid-shaped tablet, imprint "XANAX 0.5") These tablets can be broken into 2 equal parts of 0.25 mg each.
Tablet, 1 mg (lavender, ovoid-shaped tablet, imprint "Upjohn 90") or (blue, ovoid-shaped tablet, imprint "XANAX 1.0") These tablets can be broken into 2 equal parts of 0.5 mg each.
Tablet, 2 mg (white, tri-scored tablet, imprint "2" on one side and "XANAX" on the other side) These tablets can be broken into 4 equal parts of 0.5 mg each.

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 tablets were first introduced in the U.S. in 2003 (approved by the FDA on January 17, 2003). Generic versions of alprazolam XR 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 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 OD (orally disintegrating) tablet, for oral administration, contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Alprazolam OD brand name Niravam 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 OD brand name Niravam 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 either 0.75 mg, or 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 tablets. Alprazolam Intensol Oral Solution (concentrate) is available as follows:

Solution, 0.5 mg/5 mL in bottles of 500 mL – Discontinued preparation
Concentrate, 0.75 mg/mL in bottles of 20 mL (1 mL = 30 drops)
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)

Other forms for administration of alprazolam include SL Tablets (sublingual); ATD Gel, Topical Patch (transdermal); Staccato Oral Aerosol Inhaler (inhalational); Panistat Nasal Spray (intranasal).

1.2 BRAND NAMES

Aalp; Aaram; Abaxon; Aceprax; Actazolam; Actirax; Adax; Adco-Alzam; Afobam; Aipratex; Akrozolam; Alajol; Alam; Alamflu+; Alap; Alark; Alax; Albiz; Alcalm; Alcelam; Aldep; Aldip; Aleez; Alep; Alexan; Alfresh; Alfron; Algad; Alganax; Alkrazil; Allam; Alltop; Alltop P+; Alltop S+; Almax+; Almee; Alnax; Alopram; Aloram; Alp; Alp FT+; Alpam; Alparazole; Alpax; Alpaz; Alpazol; Alpex; Alpkair; Aplacaina; Alplacin; Alplacin Digest+; Alplax; Alplax Digest+; Alplax Net+; Alpose; Alpra; Alpradol; Alpragen; Alpragin; Alpralan; Alpralid-; Alpraline; Alpram; Alpramax; Alpramed; Alpranax; Alpranks; Alpraphar; Alpraquil; Alprascan; Alprasedon; Alpraser+; Alprastad; Alprasyn; Alpratech; Alpratyrol-; Alpravecs; Alprawin; Alprax; Alprax Forte+; Alprax Plus+; Alprax Z+; Alpraz; Alprazan; Alprazig; Alprazol; Alprazomed; Alprazomerck; Alprazone; Alprim; Alprine H+; Alprine Plus+; Alprizalp; Alpro Forte+; Alprocalm; Alprocontin; Alproenar; Alpronax-; Alpronit; Alprop+; Alprorest; Alprose; Alprose Plus+; Alprosym; Alprotame; Alprox; Alproz; Alpviram; Alrelax; Alrif; Altalin+; Altaur; Alti-Alprazolam; Altin+; Altraxic; Altrox; Altus; Alviz; Alz; Alzac; Alzam; Alzax; Alzep; Alzex; Alzex Forte+; Alzex Plus+; Alzin; Alzo; Alzoact; Alzocum; Alzoft; Alzokam; Alzol; Alzolam; Alzolam Forte+; Alzolex; Alzolite; Alzomax; Alzomil; Alzon; Alzonex; Alzopax; Alzoset+; Alzot; Alzotime Plus+; Alzy; Alzy Plus+; Ambulax+; Ambulax HD+; Ambulax M+; Amisleep; Amprazo; Amziax; Anax; Ancolol+; Anilam; Anlzium; Anpra; Anpress; Anquil; Ansidan; Ansielix; Ansielix Digest+; Ansilan; Ansiolin; Ansiolit; Ansionil; Ansiopax; Ansiopral; Ansiox; Antanax-; Anxeron; Anxicalm; Anxico; Anxifen; Anxigon; Anxilam; Anximex; Anxirid-; Anxit; Anxit Forte+; Anxit Plus+; Anxnil; Anxorel; Anxyl; Anzal; Anzal Plus+; Anzal Plus H+; Anzi; Anzi P+; Anzilum-; Anzion; Anzity; Anzofree; Anzolam; Apazol; Apna; Apo-Alprax; Apo-Alpraz; Apo-Alprazolam; Apoalsol; Apotex; Apox-; Apraz; Aprazo; Apsolam; Apz; Aram; Argest; Arivics-; Arprax; Asolan; Atam; Atarax; Ateez; Ateez F+; Atrest; Avatak; Avizolem; Axal; Axor; Azaxol; Azo F+; Azo O+; Azo S+; Azolac; Azolam; Azolex; Azolitan; Azor; Azoslip; Azox; B-Kalm; Balmusa; Balmusa Plus+; Bayzolam; Be-Relax; Be-Relax Plus+; Becalm; Becede; Belfa+; Beloc Plus+; Benex; Benzolam; Benzolam Forte; Benzolam Plus+; Besquil; Bestrol; Betapax+; Betapax M+; Biozolam; Bliz; Brazo; Breez; Calam; Calmax; Calmdown; Calmezin; Calmlet; Calmol; Calmtec; Calmzol; Canax; Cassadan; Censir Forte+; Constan; Constante; Coolam; Coral F+; Cozac AZ+; Cqlam; Daclor; Dalbos; Dalp LA; Danox-; Deminy Plus+; Deplam F; Deprezrelax; Depten AZ+; Derolam; Desper Plus; Destres+; Dial; Diazecalm; Digeprax+; Din Plus+; Diprex; Diprolam; Dixin; Dizolam-; Dizolam Atlantic; Docalprazo; Drimpam-; Duazolam; Duazolam Plus+; Ducalm; Dzolam; Ecsit; Elam; Elzopam; Emeral; Endax; Endolam; Enzo; Esparon-; Esteem; Euciton Stress+; Eurelax; Eutransil+; Exiten Plus+; Exprex; Ezilax; Ezoprax; Faa Plus+; Fad; Farmapram; Faxtin A+; Feprax; Fiden AZ+; Finezol; Finezol AX+; Fludep AZ+; Fludep Plus+; Flumusa+; Flumusa Forte+; Fluwel+; Fluxin AL+; Fluxitech A+; Frixitas; Frontal; Frontin; Fultop+; G-Prax; Gabazolamine Convenience Pack+; Gen-Alprazolam; Gendergin; Geneprax; Gerax; Getzpraz; Grazolam; Grifoalpram; Helex; Hilaxin; Hiprazole; Huma-Alprazol; Ibizolam-; Indolam; Inzolam; Irizz; Isoproxal; Jialeding; Jolystar; Kalm; Kalma; Kamudan; Kaprolam; Kavin; Kelaxanal; Kentium; Keprax; Kinax; Krama; Ksalol; Kurelam F+; L-Peez; L-Peez F+; L-Peez S+; L-Pro; Labox; Lam; Lamoz; Lapranx; Larprax; Lazolam; Lenit; Lexopam; Librazolam; Libzam; Loral; Luzaran; Luzarn; Malcoz; Manex; Manorest; Manorest Forte+; Manorest Plus+; Manzolam; Marzolam; Mazolam; Mcalm+; Mcalm Forte+; Mebasal AL+; Mebrin AZ+; Med-Alprazolam; Medepolin; Medronal; Meloprax+; Menbit; Mentolift Plus+; Meprax; Merck-Alprazolam; Mialin; Min A+; Misar; Mitranax-; Moderex; Modilam; Morecalm; Movarest; Moxinax; Mspil; Nalion; Neonax; Neozolam; Nervin; Neupax; Neupax Duo S+; Neurol; Neuxam; Niravam; Nirvan; Nitril; Nivelan N; Norex; Normapal; Normatine Plus+; Nostress+; Novizolam; Novo-Alprazol; Novo-Vegestabil+-; Noxalam; Noxeprom; Noxit; Nu-Alpraz; Numi; Nyndra; Onapract; Onax; Ondil; Optizole; Oriprex Fl+; Orten; Orten Forte; Ozolam; P-Kalm; P-Lam+; P-Lam H+; P-Zolam; Paaz; Pacific; Pacific H+; Pacific Plus+; Pacyl; Panix-; Pax; Paxal; Paxor; Paz+; Pazolam; Pazz; Pharnax; Pifzot; Pisalpra; Pizolam; Pizolam P+; Plaxid; Pleazam; Plenisedan; Poex; Poize; Pralam; Pranax; Praxal; Praz; Prazam; Prazil; Prazin; Prazine; Prazol; Prazolam; Prazole; Prazolex; Prazovex; Prenadona; Prinox; Prizm Plus+; Pro Xanti+; Proalem+; Procalm; Prolam; Pronext+; Pronil Plus+; Proprazolam+; Proprazolam M+; Prosanti; Prozam; Prozim; Pruden; Psicosedol; Psicozolam; PTA; Q-Rest; Quiet; Quite; Ralgex; Ralozam-; Razol; Recalm; Relax; Relax F+; Relax S+; Relaxol; Relaxten; Relish; Renax; Rescalm AZ+; Resit; Resolin; Rest; Resta+; Restam; Restin; Resto; Restyl; Restyl Forte+; Restyl Plus+; Retan-; Rezolam; Rian; Richpram; Rileez; Rilow; Rivcam+; Romipraz; Rosam; Runrest; Salirest; Samprex; Sanerva; Sanit; Sanprazole; Sapram; Saturnil; Secam; Sedaler; Sedasmyl; Sedatival; Sedicepan; Sedipral; Seez; Sehr; Selam; Selamb; Sentrazolam AM Convenience Pack+; Serenil; Serenium; Serex; Sertagen Plus+; Sertakem AZ+; Serxanti+; Setex A+; Shanti; Siampraxol; Sidomal+; Sinner+; Sinzolam; Skoon; Sliplex; Solan; Solanax; Somnia; Sopor; Soranakkusu; Sowel; Soxietas; Srtl A+; Stable; Starnok; Steet Plus+; Stresnil+; Stressban; Sts+; Sukoon; Sunax; Synar; Synozolam; Tafel; Tafil; Tafla; Tagat; Tagefin; Taky+; Tanschem; Taz SR+; Tazun; Telecam Forte+; Telecam Plus+; Ten; Tenan; Tenfree; Tenil+; Tenolam; Tenolam Plus+; Tenrid; Tenscure; Tensefree; Tensi AZ; Tensium; Tensium Gastric+; Tensivan; Tensyl; Tensyn AZ+; Tenzo; Tenzole; Texidep; Thiprasolan; Tiox; Tiza; Tizax+; Topazolam; Tranax; Tranisol; Trankimazin; Tranquinal; Tranquinal Soma+; Trans; Traxil; Trazopin; Tresanil; Tresanil Digest+; Tresanil S+; Tri-Neurin; Tricalma; Trika; Trika Forte+; Trika Plus+; Trilam; Trizo; Trizolam; Tryzo; Ulpram; Unilan; Uniprox; Valeans; Vanipen; Visram; Welnorm; Wycalm; Wycalm Forte; Xan; Xanacine; Xanagis; Xanapam; Xanax; Xanolam-; Xanor; Xanti; Xepam; Xiemed; Xietnax; Xycalm; Xyren; Zacetin; Zafram; Zallpam; Zam; Zamhexal; Zamitol; Zamoprax; Zanapam; Zaxan; Zeftra; Zelam; Zenax; Zenith; Zenoprax; Zepic+; Zeprax; Zepro+; Zepro M+; Zocalme; Zocam; Zodia DS; Zola; Zolam; Zolampax; Zolap; Zolaram; Zolarem; Zolark; Zolastin; Zolax; Zoldac; Zolent; Zolin; Zolipax; Zolmax; Zoloid; Zolorel; Zoltra; Zoman; Zomark; Zomiren; Zoom; Zopax; Zopax Plus+; Zopic; Zopral; Zoram; Zorax; Zorest; Zotam; Zotin Plus+; Zotran; Zozo; Zypraz; Zyren.
+Multi-ingredient preparation
-Discontinued preparation

Aalp (India)
Aaram (India)
Abaxon (Ecuador; Venezuela)
Aceprax (Bolivia; Paraguay; Uruguay)
Actazolam (Indonesia)
Actirax (India)
Adax (Bolivia; Chile; Ecuador)
Adco-Alzam (South Africa)
Afobam (Hungary; Poland)
Aipratex (Mexico)
Akrozolam (Uruguay)
Alajol (Korea)
Alam (India; Nepal)
Alamflu+ (India)
Alap (India)
Alark (India)
Alax (Pakistan)
Albiz (India)
Alcalm (India)
Alcelam (Thailand)
Aldep (India)
Aldip (India)
Aleez (India)
Alep (India)
Alexan (Korea)
Alfresh (India)
Alfron (Brazil)
Algad (Israel)
Alganax (Indonesia)
Alkrazil (Guatemala)
Allam (Thailand)
Alltop (India)
Alltop P+ (India)
Alltop S+ (India)
Almax+ (India)
Almee (India)
Alnax (Thailand)
Alopram (Pakistan)
Aloram (Pakistan)
Alp (India; Pakistan)
Alp FT+ (India)
Alpam (India; Pakistan)
Alparazole (India)
Alpax (Pakistan)
Alpaz (India; Peru)
Alpazol (Peru)
Alpex (Kenya)
Alpkair (India)
Aplacaina (Argentina)
Alplacin (Uruguay)
Alplacin Digest+ (Uruguay)
Alplax (Argentina; Bolivia; Paraguay)
Alplax Digest+ (Argentina)
Alplax Net+ (Argentina)
Alpose (India)
Alpra (India)
Alpradol (India)
Alpragen (Ecuador)
Alpragin (Taiwan)
Alpralan (Thailand)
Alpralid- (Israel; Sweden)
Alpraline (Malaysia; Taiwan)
Alpram (India; Korea; Pakistan; Venezuela)
Alpramax (India)
Alpramed (Pakistan; Thailand)
Alpranax (Hong Kong; Malaysia)
Alpranks (Korea)
Alpraphar (Belgium)
Alpraquil (India)
Alprascan (Denmark)
Alprasedon (Estonia; Latvia; Lithuania)
Alpraser+ (Mexico)
Alprastad (Austria; Sweden)
Alprasyn (Colombia)
Alpratech (India)
Alpratyrol- (Austria)
Alpravecs (Italy; Russia)
Alprawin (India)
Alprax (Australia; Hong Kong; Hungary; India; Nepal; Pakistan; Thailand; Vietnam)
Alprax Forte+ (India)
Alprax Plus+ (India)
Alprax Z+ (India)
Alpraz (Belgium; India; Luxembourg; Morocco)
Alprazan (India)
Alprazig (Italy)
Alprazol (Argentina)
Alprazomed (Belgium)
Alprazomerck (Hungary; Poland)
Alprazone (India; Nepal)
Alprim (Australia)
Alprine H+ (India)
Alprine Plus+ (India)
Alprizalp (India)
Alpro Forte+ (India)
Alprocalm (India)
Alprocontin (India; Nepal)
Alproenar (India)
Alpronax- (Korea; Pakistan; Portugal)
Alpronit (India)
Alprop+ (India)
Alprorest (India)
Alprose (India)
Alprose Plus+ (India)
Alprosym (India)
Alprotame (India)
Alprox (Denmark; Finland; Hungary; Ireland; Israel; Pakistan; Poland; Taiwan)
Alproz (India; Nepal)
Alpviram (India)
Alrelax (Peru)
Alrif (India)
Altalin+ (India)
Altaur (India)
Alti-Alprazolam (Canada)
Altin+ (India)
Altraxic (Philippines)
Altrox (Brazil; India; Philippines)
Altus (India)
Alviz (Indonesia)
Alz (India)
Alzac (India)
Alzam (India; Kenya; Mexico; Nepal; Pakistan; South Africa)
Alzax (Korea)
Alzep (India)
Alzex (India)
Alzex Forte+ (India)
Alzex Plus+ (India)
Alzin (India)
Alzo (India)
Alzoact (India)
Alzocum (India)
Alzoft (India)
Alzokam (India)
Alzol (India; Nepal)
Alzolam (India; Kenya; Malaysia; Nepal; Pakistan; Russia; Singapore)
Alzolam Forte+ (India)
Alzolex (India)
Alzolite (India; Nepal)
Alzomax (India)
Alzomil (India)
Alzon (Denmark)
Alzonex (India)
Alzopax (India)
Alzoset+ (India)
Alzot (India)
Alzotime Plus+ (India)
Alzy (India)
Alzy Plus+ (India)
Ambulax+ (India)
Ambulax HD+ (India)
Ambulax M+ (India)
Amisleep (India)
Amprazo (Taiwan)
Amziax (Argentina)
Anax (India; Thailand)
Ancolol+ (India)
Anilam (India)
Anlzium (India)
Anpra (Afghanistan; Pakistan)
Anpress (Thailand)
Anquil (India)
Ansidan (Bolivia)
Ansielix (Argentina)
Ansielix Digest+ (Argentina)
Ansilan (Venezuela)
Ansiolin (Peru)
Ansiolit (Ecuador)
Ansionil (Uruguay)
Ansiopax (Chile)
Ansiopral (Bolivia)
Ansiox (Turkey)
Antanax- (Greece)
Anxeron (India)
Anxicalm (India)
Anxico (India)
Anxifen (Pakistan)
Anxigon (India)
Anxilam (Nepal)
Anximex (India)
Anxirid- (South Africa)
Anxit (India; Nepal)
Anxit Forte+ (India)
Anxit Plus+ (India)
Anxnil (Pakistan)
Anxorel (India)
Anxyl (India; Lebanon; Nepal)
Anzal (India)
Anzal Plus+ (India)
Anzal Plus H+ (India)
Anzi (India)
Anzi P+ (India)
Anzilum- (India)
Anzion (Thailand)
Anzity (Pakistan)
Anzofree (India)
Anzolam (India; Nepal)
Apazol (Indonesia)
Apna (India)
Apo-Alprax (Tobago; Trinidad)
Apo-Alpraz (Canada; Malaysia; Singapore)
Apo-Alprazolam (South Africa)
Apoalsol (Mexico)
Apotex (Canada)
Apox- (Israel)
Apraz (Belgium; Brazil)
Aprazo (Taiwan)
Apsolam (India)
Apz (India)
Aram (Pakistan)
Argest (India)
Arivics- (Belgium; Luxembourg)
Arprax (India)
Asolan (Malaysia)
Atam (India)
Atarax (Indonesia)
Ateez (India)
Ateez F+ (India)
Atrest (India; Kenya)
Avatak (Mexico)
Avizolem (India)
Axal (Pakistan)
Axor (Pakistan)
Azaxol (Cyprus)
Azo F+ (India)
Azo O+ (India)
Azo S+ (India)
Azolac (Korea)
Azolam (India; Pakistan)
Azolex (Pakistan)
Azolitan (Japan)
Azor (South Africa)
Azoslip (India)
Azox (India)
B-Kalm (India)
Balmusa (India)
Balmusa Plus+ (India)
Bayzolam (Argentina)
Be-Relax (India)
Be-Relax Plus+ (India)
Becalm (India)
Becede (Argentina)
Belfa+ (India)
Beloc Plus+ (India)
Benex (Pakistan)
Benzolam (Colombia; India; Nepal)
Benzolam Forte (India)
Benzolam Plus+ (Colombia; India; Nepal)
Besquil (India; Malaysia)
Bestrol (Argentina)
Betapax+ (India)
Betapax M+ (India)
Biozolam (India)
Bliz (India; Nepal)
Brazo (India)
Breez (Pakistan)
Calam (Pakistan)
Calmax (Ireland)
Calmdown (Japan)
Calmezin (Colombia)
Calmlet (India; Indonesia)
Calmol (Argentina)
Calmtec (India)
Calmzol (India)
Canax (Pakistan)
Cassadan (Germany; Russia)
Censir Forte+ (India)
Constan (Japan)
Constante (Brazil)
Coolam (India)
Coral F+ (India)
Cozac AZ+ (India)
Cqlam (India)
Daclor (Dominican Republic)
Dalbos (Peru)
Dalp LA (India)
Danox- (Venezuela)
Deminy Plus+ (India)
Deplam F (India)
Deprezrelax (Peru)
Depten AZ+ (India)
Derolam (Nepal)
Desper Plus (India)
Destres+ (India)
Dial (India)
Diazecalm (Nepal)
Digeprax+ (Uruguay)
Din Plus+ (India)
Diprex (India)
Diprolam (India)
Dixin (Colombia)
Dizolam- (Peru; Singapore; Thailand)
Dizolam Atlantic (Thailand)
Docalprazo (Belgium; Luxembourg)
Drimpam- (South Africa)
Duazolam (Dominican Republic)
Duazolam Plus+ (Dominican Republic)
Ducalm (India)
Dzolam (India)
Ecsit (India)
Elam (Pakistan)
Elzopam (India)
Emeral (Argentina)
Endax (India)
Endolam (India)
Enzo (Pakistan)
Esparon- (Germany)
Esteem (India)
Euciton Stress+ (Argentina)
Eurelax (India)
Eutransil+ (Uruguay)
Exiten Plus+ (India)
Exprex (India)
Ezilax (Pakistan)
Ezoprax (India)
Faa Plus+ (India)
Fad (India)
Farmapram (Mexico)
Faxtin A+ (India)
Feprax (India; Indonesia)
Fiden AZ+ (India)
Finezol (India)
Finezol AX+ (India)
Fludep AZ+ (India)
Fludep Plus+ (India)
Flumusa+ (India)
Flumusa Forte+ (India)
Fluwel+ (India)
Fluxin AL+ (India)
Fluxitech A+ (India)
Frixitas (India; Indonesia)
Frontal (Brazil; Italy)
Frontin (Czech Republic; Hungary; Latvia; Lithuania; Poland; Romania; Slovakia)
Fultop+ (India)
G-Prax (India)
Gabazolamine Convenience Pack+ (United States)
Gen-Alprazolam (Canada)
Gendergin (Taiwan)
Geneprax (India)
Gerax (Ireland)
Getzpraz (Vietnam)
Grazolam (Indonesia)
Grifoalpram (Chile; Ecuador; Paraguay; Peru)
Helex (Croatia; Czech Republic; Hungary; Romania; Russia; Slovakia; Slovenia; Yugoslavia)
Hilaxin (Pakistan)
Hiprazole (India)
Huma-Alprazol (Hungary)
Ibizolam- (Italy)
Indolam (India)
Inzolam (Thailand)
Irizz (Mexico)
Isoproxal (Argentina)
Jialeding (China)
Jolystar (India)
Kalm (India)
Kalma (Australia; Hong Kong; New Zealand; Taiwan)
Kamudan (Japan)
Kaprolam (India)
Kavin (Pakistan)
Kelaxanal (Belgium)
Kentium (Uruguay)
Keprax (India)
Kinax (Taiwan)
Krama (Argentina)
Ksalol (Serbia; Yugoslavia)
Kurelam F+ (India)
L-Peez (India)
L-Peez F+ (India)
L-Peez S+ (India)
L-Pro (India)
Labox (Peru)
Lam (India)
Lamoz (Russia)
Lapranx (Pakistan)
Larprax (India)
Lazolam (India)
Lenit (India)
Lexopam (Pakistan)
Librazolam (Ecuador)
Libzam (India)
Loral (India)
Luzaran (India)
Luzarn (India; Indonesia; Nepal; Thailand)
Malcoz (India)
Manex (Thailand)
Manorest (India; Sri Lanka)
Manorest Forte+ (India)
Manorest Plus+ (India)
Manzolam (India)
Marzolam (Thailand)
Mazolam (Pakistan)
Mcalm+ (India)
Mcalm Forte+ (India)
Mebasal AL+ (India)
Mebrin AZ+ (India)
Med-Alprazolam (Canada)
Medepolin (Japan)
Medronal (Argentina)
Meloprax+ (India)
Menbit (Japan)
Mentolift Plus+ (India)
Meprax (Dominican Republic; Mexico)
Merck-Alprazolam (South Africa)
Mialin (Italy)
Min A+ (India)
Misar (Albania; Croatia; Yugoslavia)
Mitranax- (Thailand)
Moderex (Paraguay)
Modilam (Pakistan)
Morecalm (India)
Movarest (India)
Moxinax (Thailand)
Mspil (Pakistan)
Nalion (Cyprus; Hong Kong)
Neonax (Pakistan)
Neozolam (Brazil)
Nervin (Pakistan)
Neupax (Mexico)
Neupax Duo S+ (Mexico)
Neurol (Czech Republic; Estonia; Hungary; Latvia; Poland; Romania; Russia; Slovakia)
Neuxam (Pakistan)
Niravam (United States)
Nirvan (Colombia)
Nitril (India)
Nivelan N (Argentina)
Norex (India)
Normapal (Chile)
Normatine Plus+ (India)
Nostress+ (India)
Novizolam (Pakistan)
Novo-Alprazol (Canada)
Novo-Vegestabil+- (Argentina)
Noxalam (Pakistan)
Noxeprom (Mexico)
Noxit (Pakistan)
Nu-Alpraz (Canada)
Numi (Pakistan)
Nyndra (India)
Onapract (India)
Onax (Pakistan)
Ondil (Bolivia; Peru; Uruguay)
Optizole (India)
Oriprex Fl+ (India)
Orten (India)
Orten Forte (India)
Ozolam (India)
P-Kalm (India)
P-Lam+ (India)
P-Lam H+ (India)
P-Zolam (India)
Paaz (Nepal)
Pacific (India)
Pacific H+ (India)
Pacific Plus+ (India)
Pacyl (India)
Panix- (South Africa)
Pax (India)
Paxal (Iceland)
Paxor (India)
Paz+ (India)
Pazolam (Portugal)
Pazz (Nepal)
Pharnax (Thailand)
Pifzot (India)
Pisalpra (Mexico)
Pizolam (India)
Pizolam P+ (India)
Plaxid (India)
Pleazam (Pakistan)
Plenisedan (Bolivia)
Poex (Kenya)
Poize (India)
Pralam (India)
Pranax (Pakistan)
Praxal (India; Nepal)
Praz (Pakistan; Philippines)
Prazam (Chile; India; Portugal)
Prazil (India)
Prazin (Egypt; Jordan; Kuwait; Lebanon; Syria)
Prazine (Tunisia)
Prazol (Bahrain; Cyprus; Egypt; Israel; Iraq; Iran; Jordan; Kuwait; Lebanon; Libya; Oman; Qatar; Saudi Arabia; Syria; United Arab Emirates; Yemen)
Prazolam (Bolivia; India)
Prazole (India)
Prazolex (Romania)
Prazovex (Malaysia)
Prenadona (Argentina)
Prinox (Argentina)
Prizm Plus+ (India)
Pro Xanti+ (India)
Proalem+ (India)
Procalm (India)
Prolam (India; Pakistan)
Pronext+ (India)
Pronil Plus+ (India)
Proprazolam+ (India)
Proprazolam M+ (India)
Prosanti (India)
Prozam (India; Pakistan)
Prozim (Pakistan)
Pruden (Chile)
Psicosedol (Argentina)
Psicozolam (Paraguay)
PTA (Argentina)
Q-Rest (India)
Quiet (India)
Quite (India)
Ralgex (Pakistan)
Ralozam- (Australia; New Zealand)
Razol (India)
Recalm (India)
Relax (India)
Relax F+ (India)
Relax S+ (India)
Relaxol (Peru)
Relaxten (Argentina)
Relish (India)
Renax (Hong Kong)
Rescalm AZ+ (India)
Resit (Pakistan)
Resolin (India)
Rest (Pakistan)
Resta+ (India)
Restam (India)
Restin (Nepal)
Resto (India)
Restyl (Bahrain; Cyprus; Egypt; India; Iran; Iraq; Jordan; Kuwait; Lebanon; Libya; Nepal; Oman; Qatar; Yemen; Saudi Arabia; Syria; United Arab Emirates)
Restyl Forte+ (India)
Restyl Plus+ (India)
Retan- (Argentina)
Rezolam (India; Nepal)
Rian (India)
Richpram (India)
Rileez (India)
Rilow (Argentina)
Rivcam+ (India)
Romipraz (India)
Rosam (Pakistan)
Runrest (India)
Salirest (India)
Samprex (India)
Sanerva (Chile)
Sanit (India)
Sanprazole (India)
Sapram (Korea)
Saturnil (Greece)
Secam (India)
Sedaler (Paraguay)
Sedasmyl (Peru)
Sedatival (Paraguay)
Sedicepan (Peru)
Sedipral (Paraguay)
Seez (Nepal)
Sehr (Pakistan)
Selam (India)
Selamb (India)
Sentrazolam AM Convenience Pack+ (United States)
Serenil (Peru)
Serenium (Pakistan)
Serex (India)
Sertagen Plus+ (India)
Sertakem AZ+ (India)
Serxanti+ (India)
Setex A+ (India)
Shanti (India)
Siampraxol (Thailand)
Sidomal+ (Argentina)
Sinner+ (Uruguay)
Sinzolam (India)
Skoon (Pakistan)
Sliplex (Pakistan)
Solan (Colombia)
Solanax (Japan)
Somnia (India)
Sopor (Pakistan)
Soranakkusu (Japan)
Sowel (India)
Soxietas (India; Indonesia)
Srtl A+ (India)
Stable (Pakistan)
Starnok (Pakistan)
Steet Plus+ (India)
Stresnil+ (India)
Stressban (India)
Sts+ (India)
Sukoon (India)
Sunax (Thailand)
Synar (Pakistan)
Synozolam (India)
Tafel (Nepal)
Tafil (Costa Rica; Denmark; Dominican Republic; El Salvador; Germany; Guatemala; Honduras; Mauritius; Mexico; Nicaragua; Panama; Venezuela)
Tafla (Iceland)
Tagat (India)
Tagefin (Mexico)
Taky+ (India)
Tanschem (India)
Taz SR+ (India)
Tazun (Mexico)
Telecam Forte+ (India)
Telecam Plus+ (India)
Ten (India)
Tenan (India)
Tenfree (India)
Tenil+ (India)
Tenolam (India)
Tenolam Plus+ (India)
Tenrid (India)
Tenscure (India)
Tensefree (India)
Tensi AZ (India)
Tensium (Argentina)
Tensium Gastric+ (Argentina)
Tensivan (Colombia)
Tensyl (India)
Tensyn AZ+ (India)
Tenzo (India)
Tenzole (India)
Texidep (India)
Thiprasolan (Argentina)
Tiox (India)
Tiza (India)
Tizax+ (India)
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; Vietnam)
Tranquinal Soma+ (Argentina)
Trans (India)
Traxil (Honduras)
Trazopin (India)
Tresanil (Paraguay)
Tresanil Digest+ (Paraguay)
Tresanil S+ (Paraguay)
Tri-Neurin (Paraguay)
Tricalma (Bolivia; Chile; Peru)
Trika (India; Nepal)
Trika Forte+ (India)
Trika Plus+ (India)
Trilam (India)
Trizo (India)
Trizolam (Nepal)
Tryzo (India)
Ulpram (Nepal)
Unilan (Portugal)
Uniprox (Pakistan)
Valeans (Italy)
Vanipen (Taiwan)
Visram (India)
Welnorm (India)
Wycalm (India)
Wycalm Forte (India)
Xan (Pakistan)
Xanacine (Thailand)
Xanagis (Israel)
Xanapam (Malaysia)
Xanax (Argentina; Australia; Bahamas; Bahrain; Barbados; Belgium; Belize; Benin; Bermuda; Bolivia; Bulgaria; Burkina Faso; Canada; 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; Latvia; Lebanon; Liberia; Libya; Lithuania; Luxembourg; Malawi; Malaysia; Mali; Malta; Mauritania; Mauritius; Morocco; Netherlands; New Zealand; Niger; Nigeria; Oman; Pakistan; Peru; Poland; Portugal; Qatar; Romania; Russia; Saudi Arabia; Senegal; Seychelles; Sierra Leone; Singapore; Slovakia; Slovenia; South Africa; Sudan; Suriname; Syria; Switzerland; Taiwan; Tanzania; Thailand; Tobago; Trinidad; Tunisia; Turkey; Uganda; United Arab Emirates; United Kingdom; United States; Vietnam; Yemen; Yugoslavia; Zambia; Zimbabwe)
Xanolam- (South Africa)
Xanor (Austria; Finland; Norway; Philippines; South Africa; Sweden)
Xanti (India; Nepal)
Xepam (Pakistan)
Xiemed (Thailand)
Xietnax (Pakistan)
Xycalm (India)
Xyren (Korea)
Zacetin (Korea; Singapore)
Zafram (Korea)
Zallpam (India)
Zam (India)
Zamhexal (Australia)
Zamitol (India)
Zamoprax (Mexico)
Zanapam (Bahrain; Cyprus; Egypt; Israel; Iraq; Iran; Jordan; Korea; Kuwait; Lebanon; Libya; Oman; Qatar; Saudi Arabia; Syria; United Arab Emirates; Yemen)
Zaxan (Yugoslavia)
Zeftra (India)
Zelam (India)
Zenax (India)
Zenith (Pakistan)
Zenoprax (India)
Zepic+ (India)
Zeprax (India)
Zepro+ (India)
Zepro M+ (India)
Zocalme (India)
Zocam (India)
Zodia DS (India)
Zola (India)
Zolam (India; Pakistan; Thailand)
Zolampax (Bolivia)
Zolap (Nepal)
Zolaram (Cyprus; Malta; Moldova)
Zolarem (Bahrain; Benin; Burkina Faso; Cyprus; Egypt; Ethiopia; Gambia; Ghana; Guinea; Hong Kong; Iran; Iraq; Israel; Ivory Coast; Jordan; Kenya; Kuwait; Lebanon; Liberia; Libya; Malawi; Mali; Mauritania; Mauritius; Morocco; Niger; Nigeria; Oman; Pakistan; Qatar; Yemen; Romania; Saudi Arabia; Senegal; Seychelles; Sierra Leone; South Africa; Sudan; Syria; Tanzania; Tunisia; Uganda; United Arab Emirates; Yugoslavia; Zambia; Zimbabwe)
Zolark (India)
Zolastin (Indonesia)
Zolax (India; Nepal)
Zoldac (Benin; Burkina Faso; Ethiopia; Gambia; Ghana; Guinea; India; Ivory Coast; Kenya; Liberia; Malawi; Mali; Mauritania; Mauritius; Morocco; Nepal; Niger; Nigeria; Senegal; Seychelles; Sierra Leone; South Africa; Sudan; Tanzania; Tunisia; Uganda; Zambia; Zimbabwe)
Zolent (India)
Zolin (India)
Zolipax (Hong Kong; India; Indonesia; Nepal)
Zolmax (India)
Zoloid (India)
Zolorel (India)
Zoltra (India)
Zoman (Pakistan)
Zomark (India)
Zomiren (Hungary; Latvia; Lithuania; Poland)
Zoom (India)
Zopax (South Africa)
Zopax Plus+ (India)
Zopic (India; Nepal)
Zopral (Peru)
Zoram (Pakistan)
Zorax (India)
Zorest (India)
Zotam (India)
Zotin Plus+ (India)
Zotran (Chile)
Zozo (India)
Zypraz (Indonesia)
Zyren (Korea)

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 IR (immediate-release) brand name Xanax tablets contain cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablets in the U.S. contain FD&C yellow no. 6; erythrosine (E127) in the E.U., and the 1 mg tablets in the U.S. contain FD&C blue no. 2; indigotin (E132) in the E.U.

Alprazolam XR (extended-release) brand name Xanax tablets contain lactose, magnesium stearate, colloidal silicon dioxide and hypromellose. In addition, the 1 mg and 3 mg tablets in the U.S. contain FD&C yellow no. 10, and the 2 mg and 3 mg tablets contain FD&C blue no. 2; the 0.5 mg and 2 mg tablets contain indigotin (E132) in the E.U.

Alprazolam OD (orally disintegrating) brand name Niravam 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 300 mg/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 4.2 mg/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. 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:

--------------------------------------------------------------------------
TABLE 1
Discontinuation-Emergent Symptom Incidence
Percentage of 641 Alprazolam-Treated Panic Disorder Patients
                 Reporting Events
--------------------------------------------------------------------------
Body System/Event
--------------------------------------------------------------------------
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
--------------------------------------------------------------------------
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 to expect 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.

Additional Advice for Panic Disorder Patients
The use of alprazolam at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that need to be carefully considered. When used at doses greater than 4 mg/day, which may or may not be required for treatment, alprazolam has the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7–29% of patients treated with alprazolam did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important to have a physician's help in discontinuing this medication in a careful and safe manner to avoid overly extended use of alprazolam.

In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when alprazolam is discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.

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
--------------------------------------------------------------------------
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.
--------------------------------------------------------------------------
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.

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TABLE 3
Panic Disorders
                                  Treatment-Emergent Symptom Incidence*
                                      Alprazolam             PLACEBO
--------------------------------------------------------------------------
Number of Patients                       1388                 1231
--------------------------------------------------------------------------
% 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
--------------------------------------------------------------------------
* Events reported by 1% or more of alprazolam patients are included.
--------------------------------------------------------------------------
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
--------------------------------------------------------------------------
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%
--------------------------------------------------------------------------
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.

--------------------------------------------------------------------------
                      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
--------------------------------------------------------------------------
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam XR
Be 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.

--------------------------------------------------------------------------
                    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
--------------------------------------------------------------------------
Other Adverse Events Observed during the Premarketing Evaluation of Alprazolam XR tablets
Following 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.

--------------------------------------------------------------------------
                        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
--------------------------------------------------------------------------
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 withdrawal 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 alcohol withdrawal, specific phobias, psychogenic headaches, anticipatory anxiety, hypersensitivity, hyperventilation or panic attacks. It can be useful in treating irritable bowel syndrome, to manage spasticity in Lesch-Nyhan syndrome, anxiety associated with depression, 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. Anxiety disorders and panic disorder remain the primary indications for alprazolam use, see DESCRIPTION, CATEGORIES, CLINICAL STUDIES, CLINICAL EFFICACY TRIALS and INDICATIONS AND USAGE.

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. It was not until 1974 that researchers showed 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. In 1977 it was discovered that the 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. The mechanism of action of alprazolam is described in more detail in PHARMACODYNAMICS.

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 throughout the world. 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); midazolam (Versed); nitrazepam (Mogadon); 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, -bazam for 1,5-benzodiazepines and -sopam for 2,3-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).

Alprazolam is well absorbed from the gastrointestinal tract after oral doses, peak plasma concentrations being achieved within 1-2 hours of a dose. The mean plasma half-life ranges from 9-20 hours. Alprazolam is 70-80% bound to plasma proteins, mainly albumin. It is metabolised in the liver, primarily by the cytochrome P450 isoenzyme CYP3A4. Metabolites include a-hydroxyalprazolam, which is reported to be about half as active as the parent compound, 4-hydroxyalprazolam, and an inactive benzophenone. Plasma concentrations of metabolites are very low. Alprazolam is excreted in urine as unchanged form and metabolites. A range of factors may influence ADME (absorption, distribution, metabolism and elimination) of alprazolam, see PHARMACOKINETICS.

Short-acting benzodiazepines, with half-life values of less than 5 hours, include midazolam (Versed) and triazolam (Halcion). Intermediate-acting benzodiazepines, with half-life values of 5-24 hours, include alprazolam (Xanax, Niravam); bromazepam (Lexotan); clonazepam (Klonopin); estazolam (ProSom); lorazepam (Ativan); nitrazepam (Mogadon); oxazepam (Serax); temazepam (Restoril). Long-acting benzodiazepines, with half-life values usually exceeding 24 hours (especially through formation of active metabolites), include chlordiazepoxide (Librium, Librax, Libritabs); clobazam (Frisium); clorazepate (Tranxene); diazepam (Valium); flunitrazepam (Rohypnol); flurazepam (Dalmane); halazepam (Paxipam); ketazolam (Anxon); prazepam (Centrax); quazepam (Dormalin).

Benzodiazepine equivalence schedule
------------------------------------------------------------------------------------ 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 Clobazam 10 1 - 4 12 - 60 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 Flunitrazepam 1 1 - 2 36 - 200 * 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 Midazolam 5 .5 - 1.5 2 - 6 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 ------------------------------------------------------------------------------------
5. For which illnesses or problems are these medicines used?
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. They are useful in the treatment of acute intoxications of solvents/inhalants, hallucinogens and GHB. 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. Although they may be useful for associated anxiety, benzodiazepines are not usually considered appropriate for treatment of depression. Some may be useful as adjuvant antiemetics, such as lorazepam, to decrease the development of anticipatory emesis. 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-, intra- 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.

Cyclopyrrolones (often called "z-benzodiazepines" or "z drugs") are sometimes used as an alternative option to benzodiazepines for the treatment of insomnia. These medicines are part of the nonbenzodiazepines, a family of psychoactive drugs whose pharmacological actions are similar to those of the benzodiazepines, but are chemically unrelated to benzodiazepines. They share similar side effects, benefits and risks as the benzodiazepines.

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. Some degree of tolerance to the therapeutic effects of benzodiazepines may occur with continuous or long-term use. 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 three months. Therefore, the risk of alprazolam 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) and this risk is further increased in patients with a history of alcohol or prescription drug abuse. Because the treatment of panic disorder often requires higher doses of alprazolam (more than 4 mg/day), the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. 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: high doses of alprazolam taken after maintenance doses of methadone produced a "high" without pronounced sedation), to potentiate the relaxing effects of other drugs (e.g., cannabis, heroin), to enhance and increase intoxication (e.g., alcohol), to lessen the withdrawal symptoms (often called "come down") and to help induce sleep after using drugs that impair the user's ability to sleep (e.g., cocaine, ecstasy (MDMA), methamphetamine, prescription stimulants such as methylphenidate (Ritalin) or hallucinogens such as LSD), to decrease anxiety, panic attacks, agitation and paranoia during a psychedelic crisis (often called "bad trip") from using hallucinogens (e.g., LSD, DMT, psilocybin, mescaline, ketamine and others), or when no other drugs are available. This combining of drugs can be extremely dangerous. For more information on alprazolam dependence, see ABUSE AND DEPENDENCE.

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 swallow the orally disintegrating tablets whole. Allow the orally disintegrating tablets to dissolve in your mouth without chewing. Measure the liquid form of alprazolam with the calibrated dropper provided with the medicine. Drop the dose into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds. Immediately drink all of the liquid or eat all of the food containing the medicine. Do not store the mixture for future use. Do not crush, chew, or break the sublingual tablets. Do not swallow the sublingual tablets whole. The sublingual tablets are meant to be absorbed through the lining of the mouth. Place the tablet under your tongue and let it slowly dissolve there. Do not swallow for at least 2 minutes. If alprazolam upsets your stomach, take it with food or milk. For more information on proper use, see DOSAGE AND ADMINISTRATION.

12. What do I need to watch for while I take alprazolam?
You may get drowsy or dizzy. Do not drive, use machinery or do anything that needs mental alertness until you know how alprazolam affects you. To reduce the risk of dizzy and fainting spells, do not stand or sit down quickly, especially if you are an older patient. Alcohol may increase dizziness and drowsiness. Avoid alcoholic drinks. Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects. Avoid drinking grapefruit juice. If you are having surgery, including dental surgery, inform your doctor or dentist that you are taking alprazolam. Some patients may require more specific precautions, see PRECAUTIONS.

13. What if I miss a dose?
If you miss a dose, take it as soon as remembered; do not take it if it is near the time for the next dose, instead, skip the missed dose and resume your usual dosing schedule. Do not "double-up" the dose to catch up.

14. What if the drug is abruptly stopped?
It is important to know that a sudden stop in taking the drug can produce a seizure. Patients should discontinue the medicine gradually. When the dosage is tapered off gradually, the effects are minimal. Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. In addition, individuals with a history of seizures or epilepsy, should not be abruptly discontinued from alprazolam. Discontinuation symptoms are frequently confused with rebound symptoms and relapse. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided, see WARNINGS, PRECAUTIONS, ABUSE AND DEPENDENCE and DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule.

15. What other medicines can interact with alprazolam?
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 medicines, anticonvulsants, antihistaminics, sedatives/hypnotics, narcotic analgesics and other drugs or herbs which themselves produce CNS depression.

Most of the interactions that have been documented with alprazolam are with medicines that are inducers, inhibitors or substrates of cytochrome P450 3A4 (CYP3A4). Inducers of CYP3A4 can markedly decrease the plasma concentrations of alprazolam leading to decreased clinical efficacy, and inhibitors can markedly increase plasma concentrations leading to toxicities. The triazolobenzodiazepines are all exclusively substrates of CYP3A4 (differing from other benzodiazepines, which are metabolized through multiple pathways). Medicines which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam, see PHARMACOKINETICS, WARNINGS, INTERACTIONS and CONTRAINDICATIONS for additional medicines of this type.

The following list is not complete and there may be other drugs that can interact with alprazolam. Consult the package insert of your medicines for possible interactions with alprazolam. In some cases this precaution may apply to medicines used hours or even days before. For some medicines, an interaction with alprazolam has been quantified with clinical data; for other medicines, interactions are predicted from in vitro data and/or experience with similar medicines in the same pharmacologic class.

Amiodarone (Cordarone, Pacerone)
Antibiotics (esp. macrolide antibiotics) including azithromycin (Zithromax); clarithromycin (Biaxin); erythromycin (E.E.S., E-Mycin, Erythrocin); josamycin (Iosalide, Josacine, Josalid); telithromycin (Ketek); roxithromycin (Roxo, Surlid); and troleandomycin (Tekmisin, Triocetin) - potent CYP3A4 inhibitors
Fluoroquinolone antibiotics - the GABA antagonistic effect of fluoroquinolones may result in displacing benzodiazepines from their receptors which can precipitate acute withdrawal symptoms in the benzodiazepine dependent. Adverse reactions from fluoroquinolones are similar to those seen in benzodiazepine withdrawal and may persist for weeks or months before subsiding. In addition, concomitant use of NSAIDs may increase seizure risk
Antihistamines, especially first generation H1 antagonists, including clemastine (Tavist); diphenhydramine (Benadryl); hydroxyzine (Atarax, Vistaril); and triprolidine (Actidil, Myidil) - exaggerate the sedating effects
Antipsychotic medicines including chlorpromazine (Thorazine); clozapine (Clozaril); haloperidol (Haldol); and thioridazine (Mellaril)
Antiseizure medicines including carbamazepine (Tegretol); ethotoin (Peganone); fosphenytoin (Cerebyx); mephenytoin (Mesantoin); oxcarbazepine (Trileptal); and phenytoin (Dilantin)
Aprepitant (Emend)
Azole antifungal agents including fluconazole (Diflucan); itraconazole (Sporanox); ketoconazole (Nizoral); posaconazole (Noxafil); and voriconazole (Vfend) - potent CYP3A4 inhibitors, concurrent use with alprazolam is contraindicated
Barbiturates including, but not limited to amobarbital (Amytal); aprobarbital (Oramon); butabarbital (Butisol); butalbital + acetaminophen and caffeine (Fioricet); butalbital + aspirin and caffeine (Fiorinal); mephobarbital (Mebaral); methohexital (Brevital); pentobarbital (Nembutal); phenobarbital (Luminal); secobarbital (Seconal); and thiopental sodium (Trapanal)
Benzodiazepines of any other type - result in additive CNS depressant effects
Buspirone (BuSpar)
Chloral hydrate (Noctec)
Cimetidine (Tagamet)
Cyclosporine (Neoral, Sandimmune)
Digoxin (Lanoxin) - may increase serum digoxin concentrations
Diltiazem (Cardizem, Dilacor, Tiazac)
Disulfiram (Antabuse)
Ergotamine derivatives including Cafatine; Cafergot; Wigraine
Ethchlorvynol (Placidyl)
Gamma hydroxybutyrate or sodium oxybate (GHB, Xyrem)
Herbs including centella asiatica (Gotu kola); echinacea angustifolia (Coneflower); hypericum perforatum (St John's wort); passiflora incarnata (Passion flower); piper methysticum (Kava); valeriana officinalis (Valerian); and other herbs that have a sedative effect
HIV medicines including amprenavir (Agenerase); atazanavir (Reyataz); darunavir (Prezista); delavirdine (Rescriptor); efavirenz (Sustiva); etravirine (Intelence); fosamprenavir (Lexiva); indinavir (Crixivan); lopinavir (Aluvia, Kaletra); nelfinavir (Viracept); nevirapine (Viramune); ritonavir (Norvir); saquinavir (Fortovase, Invirase); and tipranavir (Aptivus) - alprazolam should not be used with HIV-protease inhibitors
Imatinib (Glivec)
Isoniazid (INH, Nydrazid); rifabutin (Mycobutin); isoniazid + rifampin (Rifamate); isoniazid + pyrazinamide and rifampin (Rifater); rifapentine (Priftin)
Levodopa (Dopar, Larodopa)
MAO inhibitors including the antidepressants phenelzine (Nardelzine, Nardil); tranylcypromine (Parnate)
Meprobamate (Miltown)
Narcotic analgesics including, but not limited to alfentanil (Alfenta); anileridine (Leritine); buprenorphine (Buprenex, Subutex, Temgesic); butorphanol (Stadol); codeine (Codate, Tylenol w/Codeine); dezocine (Dalgan); fentanyl (Actiq, Duragesic, Fentora, Sublimaze); hydrocodone (Anexsia, Lorcet, Lortab, Vicodin); hydromorphone (Dilaudid, Palladone); levorphanol (Levo-Dromoran); meperidine (Demerol); methadone (Dolophine); morphine (Avinza, Kadian, MS Contin, MSIR, Oramorph, Roxanol); nalbuphine (Nubain); oxycodone (OxyContin, OxyIR, Percocet, Percodan, Precolone, Roxicet, Roxicodone, Tylox); oxymorphone (Numorphan, Opana); pentazocine (Fortral, Talacen, Talwin); propoxyphene (Darvocet, Darvon, Wygesic); remifentanil (Ultiva); sufentanil (Sufenta, Sufentil); tapentadol (Nucynta); and tramadol (Ultram) - result in additive CNS depressant effects
Nefazodone (Serzone) - potent CYP3A4 inhibitor, co-administration has resulted in increased alprazolam concentration two-fold, resulting in increased sedation and impairment of psychomotor performance
Nicardipine (Cardene)
Nicotine - may reduce the effectiveness of your treatment
Nifedipine (Adalat, Procardia)
Oral contraceptives including Desogestrel; Drospirenone; Ethinyl Estradiol; Ethynodiol Diacetate; Levonorgestrel; Medroxyprogesterone Acetate; Mestranol; Norethindrone; Norethynodrel; Norgestimate; and Norgestrel
Etonogestrel (Implanon, NuvaRing); Norelgestromin (Ortho Evra)
Omeprazole (Losec, Prilosec) - may increase serum levels of alprazolam
Orphenadrine (Norflex)
Primidone (Mysoline)
Propranolol (Inderal) - no significant pharmacokinetic interaction has been seen between propranolol and alprazolam although the rate of alprazolam absorption may be decreased
Selective serotonin reuptake inhibitors (SSRIs) including citalopram (Celexa); fluoxetine (Prozac); fluvoxamine (Luvox); paroxetine (Paxil); and sertraline (Zoloft)
Skeletal muscle relaxants including carisoprodol (Soma); chlorzoxazone (Muscol); cyclobenzaprine (Flexeril); dantrolene sodium (Dantrium, Dantrolen); mephenesin (Tolserol); metaxalone (Skelaxin); and methocarbamol (Robaxin)
Sleep medicines including zaleplon (Sonata); zolpidem (Ambien)
Smarts including DHEA; Melatonin
Theophylline (Respbid, Slo-Bid, Theo-Dur) - may partially antagonize some of the effects of benzodiazepines
Trazodone (Desyrel)
Tricyclic antidepressants including amitriptyline (Elavil); amoxapine (Asendin); clomipramine (Anafranil); desipramine (Norpramin, Pertofrane); doxepin (Sinequan); imipramine (Tofranil); nortriptyline (Aventyl, Pamelor); protriptyline (Vivactil); and trimipramine (Surmontil) - the US manufacturers have reported that alprazolam may increase the steady-state plasma concentrations of tricyclic antidepressants, although the clinical significance of such changes is unknown
Verapamil (Calan).

16. What side effects may I notice from taking alprazolam?
Like all medicines, alprazolam can cause side effects. In many cases, the side effects of alprazolam occur at the beginning of treatment and usually lessen or disappear upon continued medication. Some are dose-related, and become more likely as the dose increases. Serious side effects with alprazolam, if they occur, include confusion, forgetfulness; light-headedness or fainting spells; depression; mood changes, excitability or aggressive behavior; difficulty pasing urine; muscle cramps; difficulty sleeping; staggering or jerky movements, tremors; difficulty speaking; weakness or tiredness. Minor side effects with alprazolam, if they occur, include constipation or diarrhea; menstrual changes; drowsiness, dizziness; sexual dysfunction; weight changes; dry mouth, decrease or increase in amount of saliva; increase or decrease in appetite.

An allergic reaction to alprazolam is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction may include rash; itching; swelling; severe dizziness; closing of the throat; difficulty breathing. Medical attention should also be sought immediately if signs of jaundice appear (e.g., yellowing of the skin or eyes). There have been some reports of alprazolam-induced photosensitivity. For adverse events reported on patients participating in clinical trials involving alprazolam and placebo, see ADVERSE REACTIONS.

Paradoxical reactions to alprazolam, characterized by stimulation; increased muscle spasticity; sleep disturbances; increased talkativeness; emotional release; disinhibition; agitation; excessive movement; racing thoughts; seizures; hallucinations and even hostility and rage, are relatively uncommon, encountered mostly in short-term use and appear to be dose related. 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. The exact mechanism of paradoxical reactions remains unclear. Should any of the above paradoxical reactions occur, alprazolam should be discontinued.

17. What are the most common side effects?
The most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam (e.g., drowsiness or light-headedness). The side effects that most often cause problems include daytime hangover or sleepiness; dizziness; drowsiness; poor coordination; reduced mental alertness; impaired judgment; reduced physical alertness; trouble paying attention; problems with memory or learning; excitement; restlessness; reduced tolerance for alcohol, narcotics and other sedatives.

18. Where can I store my medicine?
Keep out of the reach of pets and children in a container that small children cannot open. Keep your medicine in a safe place to protect it from theft: consider storing it somewhere other than your bathroom. Store at room temperature between 15 and 30C (59 and 86F) away from heat, light and moisture. Alprazolam extended-release tablets should be stored at 25C (77F), but may be exposed to temperatures ranging from 15 and 30C (59 and 86F). The orally disintegrating tablets should be stored in tight containers, protected from moisture, at temperatures ranging from 20 and 25C (68 and 77F), but may be exposed to temperatures ranging from 15 and 30C (59 and 86F); any unused half of a scored orally disintegrating tablet should be immediately discarded because it may not remain stable. The sublingual tablets should be stored at room temperature between 15 and 30C (59 and 86F) away from heat, light and moisture. Store the liquid form of alprazolam at room temperature between 15 and 30C (59 and 86F) away from heat, light and moisture. Dispense in a tight, light-resistant container. Throw away any unused medicine after the expiration date. In addition, the minimum shelf life of alprazolam is 3 years from the date of manufacture.

19. How long does alprazolam stay in my system once I have stopped taking it?
Depending on other drugs you are taking from 24-36 hours. It can be detected in a urine test for up to a week or so depending on the test. The usual urine toxicology screens for benzodiazepines often give false-negative results for alprazolam because of the extremely low concentrations of metabolites excreted, making abuse difficult to detect. Valerian (Valeriana officinalis) is reported to cause false-positive results for benzodiazepines. Other herbs such as Kava (Piper methysticum) and St John's Wort (Hypericum perforatum) may also affect body chemistry such that false-positive results are produced. Medicines such as oxaprozin (Daypro) and sertraline (Zoloft) are capable of producing false-positive results for benzodiazepines.

20. How do I know if it works?
The patient should show signs of decreased sense of anxiety and increased ability to cope.

21. Why can't I take more pills than it says on the label?
Since this pill works on depressing your central nervous system, if you take too many you may become very drowsy.

22. What happens if I overdose?
Seek emergency medical attention. Symptoms of an alprazolam overdose include sleepiness, dizziness, somnolence, confusion, blurred vision, a slow heartbeat, difficulty breathing, difficulty walking and talking, impaired coordination, diminished reflexes, an appearance of being drunk, unconsciousness and coma. Benzodiazepines are considered safer because of a higher therapeutic index ratio and flatter dose-response curves. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Most cases of coma or respiratory depression usually occur in conjunction with other CNS depressants. Alcohol, cocaine and methadone are the most common cointoxicants. The abuse of alprazolam alone is rarely a cause of death in overdose. Severe CNS depression can be reversed by the use of flumazenil, but this drug is contraindicated if there is a co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (e.g., aminophylline and cocaine), history of epilepsy or in long-term benzodiazepine use. For clinical experience and general treatment of overdose, see OVERDOSAGE.

A retrospective analysis of 2063 hospital admissions for benzodiazepine overdosage in one region of Australia between January 1987 and October 2002 found that patients who took an overdose of alprazolam were about twice as likely to require admission to intensive care. Flumazenil was required in 14% of the 131 alprazolam overdoses, and ventilation in 16%, which was significantly more than for other benzodiazepines. Given the apparently greater toxicity of alprazolam in overdosage, its increasing prescription to groups at risk of self-poisoning was of concern.

23. What is the usual course of treatment?
You're given a very low dose to begin with. The dose is slowly increased to a standard level. Dosage should be individualized for maximum beneficial effect. The manufacturer does not recommend taking more than 4 mg/day unless being treated for panic disorder. The maximum recommended daily human dose of alprazolam is 10 mg/day. For insomnia, these medicines may be used only when required or every few days (e.g., alternate nights). When used to treat chronic disorders like panic disorder, phobias or some of the other anxiety disorders, they are often used safely and effectively for long periods of time. When stopped, the dose is always slowly and gradually reduced. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. For standard dosing instructions, dosing in special populations, dose titration, maintenance and reduction, see DOSAGE AND ADMINISTRATION.

24. Does grapefruit juice potentiate the effects of alprazolam?
Grapefruit juice has been scientifically proven to potentiate benzodiazepines, including alprazolam. Bergamottin, an active constituent of grapefruit juice, inhibits the CYP3A4 enzymes, which affects the clearance of some drugs. Grapefruit juice could lead to extra sedation, increase the effects and make the dose more unpredictable. It could be dangerous if you consume grapefruit juice and alprazolam every day for a long time. Doing this for a long time could cause a toxic build-up. Regardless, it would take a long time for this build-up to occur. It is dangerous, especially for the elderly.

25. Are benzodiazepines affected by antacids use?
As a general rule it is best to separate antacid use and any other medications by at least 1 hour, because it may delay or alter absorption. When antacids are only taken occasionally, this seldom presents a serious problem. Since there are so many good medications to reduce stomach acid, some of them over-the-counter, it is unusual to require frequent antacid use during the day and night.

26. Can I combine alcohol with alprazolam?
Alcohol must not be consumed with benzodiazepine tranquillizers under any circumstances. Alcohol and alprazolam taken in combination have a dose-related synergistic effect on one another, which can cause severe sedation, behavioral changes, respiratory depression and intoxication. Not only does alcohol spoil the positive effects of the drug, but practically all benzodiazepine-related deaths have something to do with alcohol.

27. What are the street names for alprazolam?
Zannies - also spelled Xannies - term for brand name Xanax.
Footballs - 0.25 mg (white), 0.5 mg (peach or pink) and 1 mg (blue or purple) ovoid-shaped tablets.
Blue Bombers - 1 mg blue ovoid-shaped tablets; based on the videogame Mega Man.
Dips, Jellybeans - refers to the ovoid-shaped alprazolam tablets.
Bars, Candy Bars, Coffins, Dogbones, French Fries, Handlebars, Handles, Ladders, Monkey-Bars, Nutragrain Bars, Quad-Bars, Sticks, T-Bars, Tombstones, Tonka Toys, Totem Poles, White Bars, White Tees, X-Boxes, Xan-Bars, Z-Bars, Zan-Bars, Zanny-Bars - 2 mg long rectangular tablets.
Four Bars (often pronounced "Fo' Bars" or simply shortened to "Fo's") - 2 mg long rectangular tablets; so-called because of its tri-score segmentation which can provide four separate doses of 0.5 mg each.
Gold Bars - 2 mg long rectangular tablets manufactured by Purepac Pharmaceuticals; so-called because of its yellow color which distinguishes it from other, usually white, generics.
Green Bars - 2 mg long rectangular tablets manufactured by ESI Lederle; so-called because of its green color which distinguishes it from other, usually white, generics.
School Buses - 3 mg extended-release alprazolam tablets.
X3 - refers to the 3 mg triangular-shaped extended-release tablets.
Pali, Palitroque - refers to alprazolam tablets in Puerto Rico.
Tranks, Tranqs - the term tranquilizer refers to the "minor" tranquilizers mainly of the benzodiazepine family.
Forgetful Pills - refers to alprazolam tablets; so-called because of its anterograde amnesic effect.
Chill Pills, Downers, Sleepers - any of a number of benzodiazepines, barbiturates, or other CNS depressants.
Bennies, Benzoids, Benzos - any of a number of benzodiazepines.
Barred-Out - an adjectival construction which refers to someone under the effects of alprazolam bars.

28. What does "generic" mean?
When a company invents a new formula they give that medication a "brand name" (Xanax). After their exclusive rights to sell that formula expire, other companies may produce and market the product under the "generic name" (alprazolam), or under a different brand name.

29. Are generics the same as brand names?
Generics are usually cheaper than the brand name product and may have additional dosage strengths. While generics often look different than the brand name product, the generics provide the same active ingredient, therefore the same results. For a list of brand names used for alprazolam around the world, see BRAND NAMES.

30. Where can I find information on the synthesis of alprazolam?
Synthesis and chemistry of N-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium derivatives
Jackson B. Hester Jr., Constance G. Chidester and Jacob Szmuszkovicz
Journal of Organic Chemistry; 1979; 44(15) pp 2688 - 2693.

31. Is taking alprazolam safe during pregnancy?
Alprazolam should be avoided in pregnant mothers and during lactation. Alprazolam is classified as pregnancy category D because it could harm the fetus when administered. Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus. Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of alprazolam during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Alprazolam is excreted in breast milk in significant amounts and may result in lethargy and weight loss in neonates. From a study of the distribution of alprazolam into breast milk in 8 lactating women it was estimated that the average daily dose of alprazolam ingested by a breast-fed infant would range from 0.3-5 micrograms/kg or about 3% of a maternal dose. See WARNINGS.

32. Is it beneficial to take alprazolam sublingually (under the tongue)?
A rapid onset of drug action is desirable for patients experiencing panic attacks or episodes of acute anxiety and in decreasing latency time to conceal sleep for insomnia associated with anxiety. Although minimal research has been done, only a small amount of the substance can be entered in this way, limited by excessive salivation washing the chemical down the throat and often a large amount remains to be swallowed. If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract and avoiding hepatic first-pass metabolism, reaching suitable plasmatic concentrations in less time and giving rise to a rapid onset of drug action. Patients with severe nausea may not benefit from this form. In addition, alprazolam may have a bitter taste, creating further nausea. The sublingual route may be a useful alternative for patients who cannot swallow tablets or for those who do not have access to a liquid at the time of dosing. A safe, user friendly, and fast-disintegrating sublingual form of alprazolam is available under various brand names.

33. May alprazolam help to suppress tinnitus?
It appears that alprazolam is beneficial in treating some patients with tinnitus. A double-blind study with placebo control showed 76% of the subjects benefited with tinnitus reductions of at least 40%, whereas only 5% of the placebo subjects had an improvement. Withdrawal will frequently result in symptom reemergence of tinnitus, or exacerbation of pre-existing tinnitus.

34. Is alprazolam appropriate for elderly people?
Benzodiazepines have been associated with falls in the elderly. The smallest effective dose of alprazolam should be used to preclude the development of ataxia and oversedation. The elderly exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. Alprazolam is preferred over long-acting benzodiazepines because it does not have any pharmacologically active metabolites that can lead to accumulation, particularly in the elderly. See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

35. May discontinuation of alprazolam cause rebound anxiety?
When taking a benzodiazepine like alprazolam, the patient should be aware of the possibility of transient rebound anxiety when discontinuing therapy. Rebound anxiety is a temporary condition whereby the symptoms that led to treatment return with increased intensity upon withdrawal of the medication. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal symptoms and rebound effects is greater after abrupt discontinuation of treatment, most physicians usually prescribe a gradual tapering of dosage. The symptoms may last from days to weeks but will subside over time.

36. Is symptom reemergence the same as rebound anxiety?
While not a withdrawal syndrome, symptom reemergence describes the reappearance of symptoms of an underlying mood or anxiety disorder after discontinuation of the medication. Unlike symptom rebound, these symptoms will not subside over time.

37. May alprazolam be helpful for patients with fibromyalgia?
Alprazolam may be effective for the treatment of insomnia and pain in some fibromyalgia patients if taken in low doses. Administration of alprazolam at night offers the benefit of improved sleep for patients with fibromyalgia. It has been found to be more effective in combination with ibuprofen.

38. What kind of withdrawal symptoms can I expect from alprazolam?
Withdrawal symptoms similar in character to those noted with anxiolytics, sedatives and hypnotics (e.g., alcohol, bromide salts, chloral hydrate, glutethimide, paraldehyde, barbiturates, meprobamate, methaqualone, ethchlorvynol and nonbenzodiazepines) have occurred following discontinuance of benzodiazepines, including alprazolam.

Low-dose withdrawal (therapeutic dose withdrawal or benzodiazepine discontinuation syndrome): This is withdrawal in the setting of therapeutic doses (e.g., 0.75 to 4 mg/day) being prescribed. 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 but will subside over time. It is thought that withdrawal symptoms generally do not appear if the duration of the treatment is less than three months, but it may appear earlier if higher doses are used. While some patients can abruptly discontinue their medications without withdrawal, symptoms associated with this syndrome are the same as high-dose withdrawal, minus seizures and delirium. Depersonalization, heightened perceptions and illusions have also been described. Symptoms may vary from mild to severe and a protracted withdrawal syndrome may develop. Patients with a family or personal history of alcoholism or those who also use other sedatives may be at increased risk for this syndrome. Instances of irritability, hostility and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

High-dose withdrawal (e.g., 4 to 10 mg/day): Symptoms include anxiety, insomnia, headache, postural hypotension, nausea, vomiting, tremor, incoordination, restlessness, blurred vision, sweating, hyperpyrexia, anorexia, appetite decrease and weight loss, dysphoria, heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, diarrhea, muscle cramps, muscle twitch, convulsions, seizures and delirium. Severe dependence confers increased risk for medical complications, including death. Alprazolam can trigger withdrawal in 1-2 days, with symptoms peaking between 1-3 days. The risk of withdrawal seizures may be increased at doses above 4 mg/day and seems to be greatest 24-72 hours after discontinuation. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms.

Protracted withdrawal syndrome: Some patients who have been maintained on therapeutic doses of alprazolam for extended periods may experience a relatively mild form of withdrawal, marked by symptoms of anxiety, irritability and insomnia, which can last for weeks or months. Symptoms may fluctuate throughout this time, making it difficult to assess whether the symptoms are due to withdrawal, symptom reemergence or symptom rebound. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction.

Interdose withdrawal (often called "breakthrough" anxiety): These are withdrawal symptoms such as early morning anxiety and emergence of anxiety symptoms which occur between doses when the previous dose wears off. 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. 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 or the same total daily dose given once daily as an extended-release formulation (alprazolam XR). Patients who are currently being treated with divided doses of alprazolam IR tablets, for example three or four times per day, may be switched to alprazolam XR tablets at the same total daily dose taken once daily, see DOSAGE AND ADMINISTRATION. For a detailed description of alprazolam XR tablets, see HOW SUPPLIED.

Repeated benzodiazepine withdrawals, like with alcohol withdrawal, may lead to sensitisation or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Dependence, abuse and withdrawal from anxiolytics, sedatives and hypnotics may cause injury or damage to the brain and contribute to organic brain syndrome. For additional details, see WARNINGS, PRECAUTIONS and ABUSE AND DEPENDENCE.

39. May alprazolam cause anterograde amnesia and cognitive decline?
Alprazolam may cause dose-related anterograde amnesia; significantly impairing the ability to learn new information while the retrieval of previously learned information remains intact. This effect is exploited when patients undergo uncomfortable procedures, as comfort and postoperative amnesia are beneficial. Cases of transient global amnesia and "traveler's amnesia" have also been associated with alprazolam in patients taking the drug to induce sleep while traveling and/or concomitant use of alcohol.

Long-term treatment with benzodiazepines has been described as causing impairment in several cognitive domains, such as visuospatial ability, speed of processing, verbal learning, IQ and concentration. It is not clear whether this decline in cognitive skills is reversible after withdrawal. Clinical observations however suggest that recovery is slow over a period of 12 months or longer. Such findings suggest that patients should be advised of potential cognitive effects when treated long-term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients. Vinpocetine, an extract of periwinkle, was shown to improve memory and cognitive function among people taking benzodiazepines.

40. What is adinazolam?
Adinazolam (Deracyn) is a triazolobenzodiazepine and dimethylamino derivative of alprazolam. It is chemically designated as 8-chloro-1-(dimethylamino)methyl-6-phenyl-4H-s-triazolo (4,3-a)(1,4) benzodiazepine (C19H18ClN5). Developed to enhance the antidepressant properties of alprazolam, it possesses anxiolytic and reputedly antidepressant effects. Because it has a short half-life (approximately 2-4 hours) and a very short duration of therapeutic action (approximately 3 hours), it usually is administered in extended-release form. The major adinazolam metabolite, N-desmethyladinazolam (NDMAD), is more than 25 times as potent as adinazolam as a benzodiazepine agonist, suggesting that the metabolite, and not the parent drug, may mediate antianxiety actions. Upjohn has filed for regulatory approval in generalized anxiety disorder and panic disorder. A review by an FDA advisory panel did not recommend approval of adinazolam for use in panic disorder.

41. Can I snort crushed alprazolam tablets?
Nasal insufflation (often called "snorting") sometimes occurs, but due to the drug's chemical structure and excipients in the ground tablets it is possible that these could act as a buffer, preventing the active ingredient from being absorbed through the mucous membranes. Instead, the powdered tablets and mucous drip down the back of the throat into the stomach, where they are absorbed as they would have been if taken orally. Therefore, insufflation of crushed alprazolam tablets is no more potent than when taken orally. This method of administration can be very unpredictable because it often requires a higher dose to produce an effect and side-effects such as memory loss, loss of motor-function and slurred speech are more likely to become present. Furthermore, nasal insufflation may be significantly less potent than other means of administrations, because the mucous drip enters the stomach at a slower rate than traditional ingestion. Because of fillers, snorting crushed alprazolam tablets causes moderate nasal inflammation. For a list of excipients in alprazolam tablets, see INACTIVE INGREDIENTS. Note: The composition and amount of excipients in generics may be different from those in the brand name product. Panistat, an intranasal formulation of alprazolam is safely and effectively absorbed through the nasal passages and acts more quickly.

42. Is it safe to inject dissolved alprazolam tablets intravenously?
Intravenous administration of alprazolam is considered especially dangerous by medical professionals. When crushed in water, it will not dissolve, potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, have the potential to cause a serious and potentially fatal overdose.

43. May other drugs influence the withdrawal effects of alprazolam?
Alcohol, benzodiazepines, nonbenzodiazepines, corticosteroids and barbiturates that influence the GABAA system show cross-tolerance and similar withdrawal patterns. Cross-tolerance typically means that one drug will alleviate the withdrawal effects of another. Because of cross-tolerance within this class of sedatives and hypnotics, an alcoholic or barbiturate addict can be withdrawn using a benzodiazepine. For the same reason, phenobarbital can be used to manage benzodiazepine withdrawal. Compared to other benzodiazepines, however, alprazolam withdrawal may be inadequately covered by substitution. There have been reports of failure of other benzodiazepines to fully suppress the withdrawal symptoms of alprazolam. 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 drugs. Alprazolam detoxification should include an estimation of daily use and a slow withdrawal over a period of weeks. Clonazepam has been found helpful in this condition.

44. Is alprazolam effective for PMS-related anxiety?
Although none are FDA-approved for treatment of premenstrual syndrome (PMS), benzodiazepines have long been prescribed for PMS symptoms. Among the benzodiazepines, the best studied for this indication is alprazolam. Alprazolam has been shown to be effective in helping the anxiety-related symptoms of PMS, reducing depression, irritability and anxiety. It has been reported to have positive effects on one or more symptoms of premenstrual dysphoric disorder (PMDD), a severe form of PMS. Because of its rapid onset of action, alprazolam can be used on an as-needed basis for occasional symptomatic days. Continuous or long-term use may cause tolerance and dependence, which limits the therapeutic efficacy. Therefore, the use of alprazolam should be restricted to the luteal phase of the cycle in selected patients to minimise the risk of dependence and tolerance. Women with PMS, particularly restrained eaters, are more sensitive to the food-intake increasing effects of alprazolam premenstrually.

45. For which illnesses or problems is alprazolam contraindicated?
The most significant contraindications include alcohol intoxication; allergy to any drug of the benzodiazepine family; allergy to any inactive ingredients of the medicine; labor and delivery; lactating mother; myasthenia gravis; narrow angle glaucoma; pregnancy. Significant contraindications include depression; fainting; psychosis; glaucoma; sleep apnea; substance abuse; suicidal ideation. Possibly significant contraindications include borderline personality disorder; chronic obstructive pulmonary disease; disease of liver; epilepsy or history of seizures; obesity; organic brain syndrome; Parkinson's disease; porphyria; renal disease; respiratory depression. Alprazolam is contraindicated for those age 18 and under, safety and efficacy in this age group have not been established. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy. Alprazolam is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in vitro systems. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam.

Alprazolam may interfere with some diagnostic tests, including alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenase, resulting in elevated levels. 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. See PRECAUTIONS and CONTRAINDICATIONS.

46. Is alprazolam effective in treating parasomnias?
The most common drugs used to treat these disorders are benzodiazepines and anticonvulsants. The general aim of medication treatment is to prevent arousal out of sleep or to suppress REM sleep. Currently, no medications are available that are indicated for these disorders; all medications used for these disorders are used off-label. Alprazolam is used successfully as a good alternative option to diazepam for parasomnias. Advantages are its brief duration of action and decreased likelihood of morning effects (e.g., grogginess). Disadvantages include potential for exacerbating symptoms at lower doses when effects attenuate (symptom rebound).

47. Is alprazolam used in veterinary medicine?
Alprazolam is not approved for use in animals by the FDA but may be prescribed off-label by veterinarians. The most common veterinary use is probably the pro re nata treatment of panic disorder in dogs. Panic disorder differs from other forms of anxiety in that it has a more acute basis and seems to be associated with loud noise stimuli like fireworks or thunderstorms. Other uses of alprazolam may include separation anxiety or situational fears (such as car travel and veterinary office visits). In cats, alprazolam is used to treat anxiety associated with inappropriate elimination, fear aggression and overgrooming, as well as to stimulate appetite. Dose rate cats 0.125-0.25 mg/kg po bid, dogs 0.02-0.1 mg/kg po. Not to exceed 4 mg/day.


Notes #
  1. INN refers to International Nonproprietary Names.
7.0 REVISION HISTORY

  • May 14, 2000 - First public release
  • June 2000 - Revised v1.8
    Changed layout, updated brand names, added pronunciations, detailed description of alprazolam tablets
  • September 2000 - Revised v1.9
    Updated clinical pharmacology, contraindications, drug interactions, added revision history
  • October 2000 - Revised v2.0
    Added foreign brand availability, removed duplicate and unnecessary info
  • March 2001 - Revised v2.1
    Updated contact information
  • May 2002 - Revised v2.2
    Various updates, text fits to window now
  • June 2003 - Revised v2.3
    Added links to images of alprazolam tablets, updated brand names, updated frequently asked questions
  • February 2007 - Revised v2.4
    Various updates, added street names
  • March 2007 - Revised v2.5
    Added synonyms, added subs to interactions, question #30
  • Dec. 2007 - Revised v2.6
    Updated pharmacodynamics, overdosage, questions #31-33
  • Mar. 2008 - Revised v2.7
    Added how supplied, updated description, brand names, layout 3.0'd, questions #34-39
  • Oct. 2008 - Revised v2.8
    Updated brand names, pharmacodynamics, dosage and administration, questions #40-47
  • May 14 2009 - Revised v2.9
    Updated brand names, minor revisions throughout
  • May 15 2009 - Revised v2.9.1
    Re-arranged q15 so that generic names are first
  • May 26 2009 - Revised v2.9.2
    Minor typo corrections and edits
  • Nov 2009 - Revised v3.0
    Updated brand names and precautions, added internal links to questions
  • Feb 2010 - Revised v3.1
    Updated brand names
  • Apr 2011 - Revised v3.2
    Updated brand names and street names, fixed typos, updated and added to drug interactions


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