ID
`
`Pharmacology
`
`Interactions
`
`References
`
`Trials
`
`Economics
`
`Properties
`
`Spectra
`
`Taxonomy
`
`0 Comments
`
`Targets (7) Transporters (1) Biointeractions (8)
`
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`
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`
`Identification
`Identification
`
`Name
`
`Hydrochlorothiazide
`
`Accession Number DB00999 (APRD00092)
`
`Type
`
`Groups
`
`Description
`
`Structure
`
`Small Molecule
`
`Approved, Vet Approved
`
`A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes
`from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium,
`chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes
`insipidus, and hypoparathyroidism. [PubChem]
`
`NH
`
`HN
`
`S
`
`O
`
`O
`
`O
`
`Cl
`
`S
`
`O
`
`H2N
`
` MOL
`
`SDF
`
`3D-SDF
`
`PDB
`
`SMILES
`
`InChI
`
`
`
` View 3D Structure
`
`Synonyms
`
`Esidrix
`
`HCTZ
`
`Microzide
`
`External IDs
`
`
`
`Not Available
`
`Product
`
`Ingredients
`
`Approved
`Prescription
`Products
`
`Not Available
`
`Show 10
`
` entries
`
`Search
`
`Name
`
`Dosage
`
`Strength
`
`Route
`
`Labeller
`
`Marketing
`Start
`
`Marketing
`End
`
`2011-10-11
`
`2014-08-21
`
`Ava-hydrochlorothiazide
`
`Tablet
`
`12.5 mg
`
`Ava-hydrochlorothiazide
`
`Tablet
`
`25 mg
`
`Ava-hydrochlorothiazide
`
`Tablet
`
`50 mg
`
`Bio-hydrochlorothiazide
`
`Tablet
`
`25 mg
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Bio-hydrochlorothiazide
`
`Tablet
`
`100 mg
`
`Oral
`
`Avanstra Inc
`
`Avanstra Inc
`
`2011-10-11
`
`2014-08-21
`
`Avanstra Inc
`
`2011-10-11
`
`2014-08-21
`
`Biomed Pharma
`
`2003-04-11 Not
`applicable
`
`Biomed Pharma Not
`applicable
`
`Not
`applicable
`
`Bio-hydrochlorothiazide
`
`Tablet
`
`50 mg
`
`Oral
`
`Biomed Pharma
`
`Diuchlor H Tab 50mg
`
`Tablet
`
`50 mg
`
`Oral
`
`Medic
`Laboratory LtÉe
`
`2003-04-11 Not
`applicable
`
`1964-12-31
`
`1996-09-09
`
`Dom-hydrochlorothiazide
`
`Tablet
`
`25 mg
`
`Dom-hydrochlorothiazide
`
`Tablet
`
`50 mg
`
`Dom-hydrochlorothiazide
`
`Tablet
`
`12.5 mg
`
`Oral
`
`Oral
`
`Oral
`
`Biomed Pharma
`
`2004-02-06
`
`2013-08-02
`
`Biomed Pharma
`
`2004-02-06
`
`2013-08-02
`
`Dominion
`
`2006-08-02
`
`2007-11-02
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 001
`
`

`

`Showing 1 to 10 of 59 entries
`
`Pharmacal
`
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`
`Approved Generic
`Prescription
`Products
`
`Show 10
`
` entries
`
`Search
`
`Name
`
`Dosage
`
`Strength
`
`Route
`
`Labeller
`
`Apo Hydro Tab 100mg
`
`Tablet
`
`100 mg
`
`Oral
`
`Apo Hydro Tab 25mg
`
`Tablet
`
`25 mg
`
`Oral
`
`Apo Hydro Tab 50mg
`
`Tablet
`
`50 mg
`
`Oral
`
`Apo-hydro
`
`Tablet
`
`12.5 mg
`
`Oral
`
`Hydrochlorothiazide
`
`Tablet
`
`50 mg/1
`
`Oral
`
`Apotex
`Corporation
`
`Apotex
`Corporation
`
`Apotex
`Corporation
`
`Apotex
`Corporation
`
`Contract
`Pharmacy
`Services Pa
`
`Marketing
`Start
`
`Marketing
`End
`
`1988-12-31 Not
`applicable
`
`1975-12-31 Not
`applicable
`
`1974-12-31 Not
`applicable
`
`2009-07-02 Not
`applicable
`
`2010-08-16 Not
`applicable
`
`Hydrochlorothiazide
`
`Tablet
`
`50 mg/1
`
`Oral
`
`Hydrochlorothiazide
`
`Capsule
`
`12.5 mg/1 Oral
`
`Rebel
`Distributors
`
`1977-02-01 Not
`applicable
`
`Physicians Total
`Care, Inc.
`
`2002-05-23 Not
`applicable
`
`12.5 mg/1 Oral
`
`Hydrochlorothiazide
`
`Capsule
`
`2013-07-08
`
`2016-12-31
`
`Amerincan
`Health
`Packaging
`
`Hydrochlorothiazide
`
`Tablet
`
`25 mg/1
`
`Oral
`
`Remedy Repack
`
`2013-03-01
`
`2016-11-01
`
`Hydrochlorothiazide
`
`Capsule
`
`12.5 mg/1 Oral
`
`Citron Pharma
`LLC
`
`2007-09-19 Not
`applicable
`
`Showing 1 to 10 of 231 entries
`
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`
`Company
`
`M & H
`
`Novartis
`
`Merck
`
`Merck
`
`Showing 1 to 4 of 4 entries
`
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`
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`
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`
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`
`Labeller
`
`Ingredients
`
`Approved Over the
`Counter Products
`
`Unapproved/Other
`
`Products
`
`Not Available
`
`Not Available
`
`International
`Brands
`
`Show 10
`
` entries
`
`Name
`
`Dichlotride
`
`Esidrex
`
`Hydrodiuril
`
`HydroDIURIL
`
`Brand mixtures
`
`Show 10
`
` entries
`
`Name
`
`Accuretic
`
`Accuretic 10/12.5 mg
`
`Pfizer
`
`Parke Davis Div Of Pfizer Inc
`
`Hydrochlorothiazide
`/ Quinapril
`
`Hydrochlorothiazide
`/ Quinapril
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 002
`
`

`

`Accuretic 20/12.5 mg
`
`Accuretic 20/25 mg
`
`Pfizer
`
`Pfizer
`
`Ach-telmisartan Hctz
`
`Accord Healthcare Limited
`
`Act Candesartan/hct
`
`Actavis Pharma Company
`
`Act Irbesartan/hct
`
`Act Losartan/hct
`
`Actavis Pharma Company
`
`Actavis Pharma Company
`
`Act Telmisartan/hct
`
`Actavis Pharma Company
`
`Actelsar Hct
`
`Actavis Group Hf
`
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`Next
`
`Hydrochlorothiazide
`/ Quinapril
`
`Hydrochlorothiazide
`/ Quinapril
`
`Hydrochlorothiazide
`/ Telmisartan
`
`Candesartan
`/ Hydrochlorothiazide
`
`Hydrochlorothiazide
`/ Irbesartan
`
`Hydrochlorothiazide
`/ Losartan
`
`Hydrochlorothiazide
`/ Telmisartan
`
`Hydrochlorothiazide
`/ Telmisartan
`
`Categories
`
`Agents Acting on the Renin-Angiotensin System
`Amides
`Antihypertensive Agents
`Benzothiadiazines
`Cardiovascular Agents
`Cardiovascular System
`Chlorothiazide
`Diuretics
`Hyperglycemia-Associated Agents
`Hypotensive Agents
`Membrane Transport Modulators
`Natriuretic Agents
`Renin-Inhibitors
`Sodium Chloride Symporter Inhibitors
`Sulfonamides
`Sulfones
`Sulfur Compounds
`Thiazides
`
`UNII
`
`0J48LPH2TH
`
`
`
`CAS number
`
`58-93-5
`
`Weight
`
`Average: 297.739
`Monoisotopic: 296.964474846
`
`Chemical Formula
`
`C H ClN O S
`7 8
`3 4 2
`
`InChI Key
`
`JZUFKLXOESDKRF-UHFFFAOYSA-N
`
`InChI
`
`IUPAC Name
`
`InChI=1S/C7H8ClN3O4S2/c8-4-1-5-7(2-6(4)16(9,12)13)17(14,15)11-3-10-5/h1-2,10-11H,3H2,(H2,9,12,13)
`6-chloro-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
`
`SMILES
`
`NS(=O)(=O)C1=C(Cl)C=C2NCNS(=O)(=O)C2=C1
`
`Pharmacology
`Pharmacology
`
`Indication
`
`For the treatment of high blood pressure and management of edema.
`
`Structured
`Indications
`
`
`
`Acidosis, Renal Tubular
`Calcium Nephrolithiasis
`Diabetes Insipidus
`Edema
`Hypertensive
`Premenstrual tension with edema
`Toxemia of pregnancy
`
`+
`-
`Pharmacodynamics Thiazides such as hydrochlorothiazide promote water loss from the body (diuretics). They inhibit Na /Cl reabsorption
`from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 003
`
`

`

`Mechanism of
`action
`
`acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their
`diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the
`mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels
`(large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.
`Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride
`symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption.
`Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining
`the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium
`ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral
`interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby
`establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter,
`hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.
`
`Target
`
`Pharmacological
`action
`
`Kind
`
`Actions
`
`Organism UniProt ID
`
`Solute carrier family 12 member 3
`
`Protein
`
`yes
`
`inhibitor
`
`Human
`
`P55017
`
`Carbonic anhydrase 1
`
`Protein
`
`unknown
`
`inhibitor
`
`Human
`
`P00915
`
`Carbonic anhydrase 2
`
`Protein
`
`unknown
`
`inhibitor
`
`Human
`
`P00918
`
`Carbonic anhydrase 4
`
`Protein
`
`unknown
`
`inhibitor
`
`Human
`
`P22748
`
`details
`
`details
`
`details
`
`details
`
`details
`
`details
`
`details
`
`      
`
`Carbonic anhydrase 9
`
`Protein
`
`unknown
`
`Carbonic anhydrase 12
`
`Protein
`
`unknown
`
`inhibitor
`
`inhibitor
`
`Human
`
`Human
`
`Calcium-activated potassium channel
`subunit alpha-1
`
`Protein
`
`unknown
`
`other/unknown Human
`
`Related Articles
`
`Absorption
`
`50-60%
`
`Volume of
`distribution
`
`Not Available
`
`Protein binding
`
`67.9%
`
`Metabolism
`
`Hydrochlorothiazide is not metabolized.
`
`Q16790
`
`O43570
`
`Q12791
`
`Route of
`elimination
`
`Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. Hydrochlorothiazide crosses the
`placental but not the blood-brain barrier and is excreted in breast milk.
`
`Half life
`
`5.6 and 14.8 hours
`
`Clearance
`
`Not Available
`
`Toxicity
`
`The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia,
`hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered,
`hypokalemia may accentuate cardiac arrhythmias. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the
`mouse and rat.
`
`Affected organisms
`
`Humans and other mammals
`
`Pathways
`
`Pathway
`
`Hydrochlorothiazide Action Pathway
`
`Not Available
`
`Not Available
`
`SNP Mediated
`Effects
`
`SNP Mediated
`Adverse Drug
`Reactions
`
`Interactions
`Interactions
`
`Drug Interactions
`
`Show 10
`
` entries
`
`Category
`
`Drug action
`
`SMPDB ID
`
`SMP00100
`
`Drug
`
`Interaction
`
`16-Bromoepiandrosterone
`
`16-Bromoepiandrosterone may increase the hypokalemic activities of
`Hydrochlorothiazide.
`
`Drug group
`
`Investigational
`
`Search
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 004
`
`

`

`19-norandrostenedione
`
`19-norandrostenedione may increase the hypokalemic activities of
`Hydrochlorothiazide.
`
`4-Androstenedione
`
`5-androstenedione
`
`4-Androstenedione may increase the hypokalemic activities of
`Hydrochlorothiazide.
`
`5-androstenedione may increase the hypokalemic activities of
`Hydrochlorothiazide.
`
`7,8-DICHLORO-1,2,3,4-
`TETRAHYDROISOQUINOLINE
`
`7,8-DICHLORO-1,2,3,4-TETRAHYDROISOQUINOLINE may increase
`the hypotensive activities of Hydrochlorothiazide.
`
`Experimental,
`Illicit
`
`Experimental,
`Illicit
`
`Experimental,
`Illicit
`
`Experimental
`
`Acarbose
`
`Acebutolol
`
`Aceclofenac
`
`Acetazolamide
`
`Acetohexamide
`
`The therapeutic efficacy of Acarbose can be decreased when used in
`combination with Hydrochlorothiazide.
`
`Approved,
`Investigational
`
`The risk or severity of adverse effects can be increased when
`Hydrochlorothiazide is combined with Acebutolol.
`
`Approved
`
`The therapeutic efficacy of Hydrochlorothiazide can be decreased when
`used in combination with Aceclofenac.
`
`Approved
`
`The risk or severity of adverse effects can be increased when
`Hydrochlorothiazide is combined with Acetazolamide.
`
`The therapeutic efficacy of Acetohexamide can be decreased when used
`in combination with Hydrochlorothiazide.
`
`Approved, Vet
`Approved
`
`Withdrawn
`
`Showing 1 to 10 of 646 entries
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`
`Avoid alcohol.
`Avoid excess salt/sodium unless otherwise instructed by your physician.
`Avoid natural licorice.
`Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
`Increase potassium intake; add a banana or orange juice; unless instructed otherwise.
`Take with food.
`
`Frederic J. Nugent, John K. C. Yen, “Process for preparing the combination products of triamterene and
`hydrochlorothiazide.” U.S. Patent US4804540, issued July, 1987.
`
`Food Interactions
`
`References
`References
`
`Synthesis
`Reference
`
`
`US4804540
`
`General References Not Available
`
`External Links
`
`Resource
`
`KEGG Drug
`
`PubChem Compound
`
`PubChem Substance
`
`BindingDB
`
`ChEMBL
`
`Therapeutic Targets Database
`
`DAP000750
`
`ATC Codes
`
`PharmGKB
`
`Drug Product Database
`
`PA449899
`
`
`
`10234
`
`
`
`RxList
`
`Drugs.com
`
`Wikipedia
`
`http://www.rxlist.com/cgi/generic/hctz.htm
`
`
`
`http://www.drugs.com/hctz.html
`
`
`
`Hydrochlorothiazide
`
`
`
`C09XA52
`C09XA — Renin-inhibitors
`C09X — OTHER AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C09 — AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C — CARDIOVASCULAR SYSTEM
`C09DX03
`C09DX — Angiotensin II antagonists, other combinations
`C09D — ANGIOTENSIN II ANTAGONISTS, COMBINATIONS
`C09 — AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C — CARDIOVASCULAR SYSTEM
`C03AB03
`
`Link
`
`D00340
`
`
`
`3639
`
`
`
`46504440
`
`
`
`13076
`
`
`
`CHEMBL435
`
` 
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 005
`
`

`

`C03AB — Thiazides and potassium in combination
`C03A — LOW-CEILING DIURETICS, THIAZIDES
`C03 — DIURETICS
`C — CARDIOVASCULAR SYSTEM
`C09DX01
`C09DX — Angiotensin II antagonists, other combinations
`C09D — ANGIOTENSIN II ANTAGONISTS, COMBINATIONS
`C09 — AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C — CARDIOVASCULAR SYSTEM
`C03EA01
`C03EA — Low-ceiling diuretics and potassium-sparing agents
`C03E — DIURETICS AND POTASSIUM-SPARING AGENTS IN COMBINATION
`C03 — DIURETICS
`C — CARDIOVASCULAR SYSTEM
`C03AX01
`C03AX — Thiazides, combinations with other drugs
`C03A — LOW-CEILING DIURETICS, THIAZIDES
`C03 — DIURETICS
`C — CARDIOVASCULAR SYSTEM
`C03AA03
`C03AA — Thiazides, plain
`C03A — LOW-CEILING DIURETICS, THIAZIDES
`C03 — DIURETICS
`C — CARDIOVASCULAR SYSTEM
`C09XA54
`C09XA — Renin-inhibitors
`C09X — OTHER AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C09 — AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
`C — CARDIOVASCULAR SYSTEM
`
`AHFS Codes
`
`40:28.20
`
`PDB Entries
`
`Not Available
`
`FDA label
`
`Not Available
`
`MSDS
`
`Download (72.7 KB)
`
`Clinical Trials
`Clinical Trials
`
`Clinical Trials
`
`
`
`Show 10
`
` entries
`
`Phase
`
`Status
`
`Purpose
`
`Conditions
`
`Count
`
`Search
`
`0
`
`0
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`1
`
`Pharmacoeconomics
`Pharmacoeconomics
`
`Completed Not
`Available
`
`Terminated Health
`Services
`Research
`
`Completed Not
`Available
`
`Completed Not
`Available
`
`Completed Not
`Available
`
`Healthy Volunteers
`
`Hypertensive / Proteinuria / Type 2 Diabetes Mellitus
`(T2D)
`
`Healthy Volunteers
`
`Hypertension, Essential
`
`Kidney Diseases
`
`Completed Treatment Fasting
`
`Completed Treatment Healthy Volunteers
`
`Completed Treatment Hypertensive
`
`Completed Treatment Type 2 Diabetes Mellitus (T2D)
`
`Unknown
`Status
`
`Treatment Healthy Volunteers
`
`Showing 1 to 10 of 109 entries
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`Next
`
`1
`
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`
`2
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`1
`
`1
`
`12
`
`5
`
`2
`
`1
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 006
`
`

`

`Manufacturers
`
`Packagers
`
`Apotex inc
`Aurobindo pharma ltd
`Cadista pharmaceuticals inc
`Ipca laboratories ltd
`Ivax pharmaceuticals inc sub teva pharmaceuticals usa
`Mylan pharmaceuticals inc
`Unichem laboratories ltd
`Vintage pharmaceuticals inc
`West ward pharmaceutical corp
`Watson laboratories inc
`Morton grove pharmaceuticals inc
`Roxane laboratories inc
`Novartis pharmaceuticals corp
`Abc holding corp
`Actavis elizabeth llc
`Alra laboratories inc
`Ascot hosp pharmaceuticals inc div travenol laboratories inc
`Barr laboratories inc
`Caraco pharmaceutical laboratories ltd
`Dava pharmaceuticals inc
`Elkins sinn div ah robins co inc
`Excellium pharmaceutical inc
`Heather drug co inc
`Heritage pharmaceuticals inc
`Impax laboratories inc
`Inwood laboratories inc sub forest laboratories inc
`Lannett holdings inc
`Mm mast and co
`Mutual pharmaceutical co inc
`Private formulations inc
`Sandoz inc
`Solvay pharmaceuticals
`Superpharm corp
`Teva pharmaceuticals usa inc
`Tg united labs llc
`Usl pharma inc
`Vangard laboratories inc div midway medical co
`Warner chilcott div warner lambert co
`Whiteworth towne paulsen inc
`Halsey drug co inc
`Merck and co inc
`Abbott laboratories pharmaceutical products div
`
`Abbott Laboratories Ltd.
`Actavis Group
`Advanced Pharmaceutical Services Inc.
`Aidarex Pharmacuticals LLC
`Amerisource Health Services Corp.
`Apotex Inc.
`Apotheca Inc.
`A-S Medication Solutions LLC
`AstraZeneca Inc.
`Atlantic Biologicals Corporation
`Aurobindo Pharma Ltd.
`Barr Pharmaceuticals
`Boehringer Ingelheim Ltd.
`Bristol-Myers Squibb Co.
`Bryant Ranch Prepack
`BTA Pharmaceuticals
`C.O. Truxton Inc.
`Cadista Pharmaceuticals Inc.
`Calvin Scott and Co. Inc.
`Caraco Pharmaceutical Labs
`Cardinal Health
`Carlisle Laboratories Inc.
`Central Texas Community Health Centers
`Ciba Geigy Ltd.
`Comprehensive Consultant Services Inc.
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 007
`
`

`

`Corepharma LLC
`Coupler Enterprises Inc.
`Darby Dental Supply Co. Inc.
`DAVA Pharmaceuticals
`Dee Stevens and Son Feeder
`DHHS Program Support Center Supply Service Center
`Direct Dispensing Inc.
`Dispensing Solutions
`Diversified Healthcare Services Inc.
`Doctor Reddys Laboratories Ltd.
`Duramed
`E.R. Squibb and Sons LLC
`Endo Pharmaceuticals Inc.
`Eon Labs
`Excellium Pharmaceutical Inc.
`Genpharm LP
`Glenmark Generics Ltd.
`Golden State Medical Supply Inc.
`Goldline Laboratories Inc.
`Greenstone LLC
`Group Health Cooperative
`H and H Laboratories
`H.J. Harkins Co. Inc.
`Heartland Repack Services LLC
`Heritage Pharmaceuticals
`International Laboratories Inc.
`Ipca Laboratories Ltd.
`Ivax Pharmaceuticals
`Kaiser Foundation Hospital
`Kraft Pharmaceutical Co. Inc.
`Lake Erie Medical and Surgical Supply
`Lannett Co. Inc.
`Liberty Pharmaceuticals
`Major Pharmaceuticals
`Mckesson Corp.
`Medisca Inc.
`Medvantx Inc.
`Merck & Co.
`Murfreesboro Pharmaceutical Nursing Supply
`Mylan
`Novartis AG
`Nucare Pharmaceuticals Inc.
`Ohm Laboratories Inc.
`Palmetto Pharmaceuticals Inc.
`Par Pharmaceuticals
`Patheon Inc.
`PCA LLC
`PD-Rx Pharmaceuticals Inc.
`Pharmaceutical Utilization Management Program VA Inc.
`Pharmedix
`Pharmpak Inc.
`Physicians Total Care Inc.
`Pliva Inc.
`Preferred Pharmaceuticals Inc.
`Prepackage Specialists
`Prepak Systems Inc.
`Qualitest
`Quality Research Pharmaceutical Inc.
`Ranbaxy Laboratories
`Rebel Distributors Corp.
`Remedy Repack
`Resource Optimization and Innovation LLC
`Roxane Labs
`Sandoz
`Solvay Pharmaceuticals
`Southwood Pharmaceuticals
`Stat Rx Usa
`Stat Scripts LLC
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 008
`
`

`

`Talbert Medical Management Corp.
`Taro Pharmaceuticals USA
`Teva Pharmaceutical Industries Ltd.
`UDL Laboratories
`Unichem Laboratories Ltd.
`United Research Laboratories Inc.
`Va Cmop Dallas
`Vangard Labs Inc.
`Vintage Pharmaceuticals Inc.
`Watson Pharmaceuticals
`West-Ward Pharmaceuticals
`
`Dosage forms
`
`Show 10
`
` entries
`
`Form
`
`Tablet
`
`Tablet, coated
`
`Capsule
`
`Capsule, gelatin coated
`
`Tablet
`
`Tablet
`
`Tablet
`
`Tablet
`
`Tablet
`
`Tablet, film coated
`
`Search
`
`Route
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Oral
`
`Strength
`
`12.5 mg
`
`12.5 mg/1
`
`12.5 mg/1
`
`12.5 mg/1
`
`25 mg/25mg
`
`25 mg/1
`
`50 mg/1
`
`50 mg/50mg
`
`Prices
`
`Show 10
`
` entries
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`Unit description
`
`Niferex-150 Forte 100 80-70 mg capsule Box
`
`Showing 1 to 10 of 15 entries
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`
`Cost
`
`109.86USD
`
`Unit
`
`box
`
`bottle
`
`Niferex 100 mg/5ml Elixir 236ml Bottle
`
`Niferex 100 40-20 mg capsule Box
`
`Capozide 50-25 mg tablet
`
`Ziac 10-6.25 mg tablet
`
`Ziac 2.5-6.25 mg tablet
`
`Ziac 5-6.25 mg tablet
`
`Capozide 50-15 tablet
`
`Capozide 50-25 tablet
`
`Capozide 50-15 mg tablet
`
`80.55USD
`
`77.99USD
`
`3.63USD
`
`3.6USD
`
`3.6USD
`
`3.6USD
`
`3.49USD
`
`3.49USD
`
`2.59USD
`
`box
`
`tablet
`
`tablet
`
`tablet
`
`tablet
`
`tablet
`
`tablet
`
`tablet
`
`Showing 1 to 10 of 40 entries
`
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`
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`
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`
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`
`
` DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
`
`Patents
`
`Show 10
`
` entries
`
`Search
`
`Pediatric Extension
`
`Approved
`
`Expires (estimated)
`
`No
`
`Yes
`
`1998-07-21
`
`2018-07-21
`
`1996-10-25
`
`2016-10-25
`
`Patent Number
`
` 
`
`US5559111
`
`US5616599
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 009
`
`

`

`Yes
`
`Yes
`
`No
`
`Yes
`
`No
`
`No
`
`Yes
`
`No
`
`1995-12-07
`
`2015-12-07
`
`1997-12-18
`
`2017-12-18
`
`2000-01-10
`
`2020-01-10
`
`2002-05-19
`
`2022-05-19
`
`2003-05-16
`
`2023-05-16
`
`2003-05-16
`
`2023-05-16
`
`2003-11-16
`
`2023-11-16
`
`2008-07-13
`
`2028-07-13
`
`Showing 1 to 10 of 11 entries
`
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`
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`
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`
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`
`       
`
`US5994348
`
`US6294197
`
`US6358986
`
`US6878703
`
`US8101599
`
`US8183295
`
`US8475839
`
`US8618172
`
`Properties
`Properties
`
`State
`
`Experimental
`Properties
`
`Solid
`
`Property
`
`melting point
`
`Value
`
`266-268
`
`Source
`
`U.S. Patent 3,163,645.
`
`water solubility
`
`722 mg/L (at 25 °C)
`
`YALKOWSKY,SH & DANNENFELSER,RM (1992)
`
`-0.07
`
`-2.62
`
`-6.06
`
`7.9
`
`logP
`
`logS
`
`Caco2 permeability
`
`pKa
`
`Property
`
`Water Solubility
`
`logP
`
`Predicted
`Properties
`
`HANSCH,C ET AL. (1995)
`
`ADME Research, USCD
`
`ADME Research, USCD
`
`SANGSTER (1994)
`
`Value
`
`2.24 mg/mL
`
`-0.16
`
`Source
`
`ALOGPS
`
`ALOGPS
`
`logP
`
`logS
`
`pKa (Strongest Acidic)
`
`pKa (Strongest Basic)
`
`Physiological Charge
`
`Hydrogen Acceptor Count
`
`Hydrogen Donor Count
`
`Polar Surface Area
`
`Rotatable Bond Count
`
`Refractivity
`
`Polarizability
`
`Number of Rings
`
`Bioavailability
`
`Rule of Five
`
`Ghose Filter
`
`Veber's Rule
`
`MDDR-like Rule
`
`Property
`
`Human Intestinal Absorption
`
`Blood Brain Barrier
`
`Caco-2 permeable
`
`P-glycoprotein substrate
`
`P-glycoprotein inhibitor I
`
`-0.58
`
`-2.1
`
`9.09
`
`-2.7
`
`0
`
`5
`
`3
`
`118.36 Å
`
`2
`
`1
`
`3
`63.11 m ·mol
`
`-1
`
`25.35 Å
`
`3
`
`2
`
`1
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Value
`
`+
`
`-
`
`-
`
`Non-substrate
`
`Non-inhibitor
`
`ChemAxon
`
`ALOGPS
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`ChemAxon
`
`Probability
`
`0.9202
`
`0.9659
`
`0.8956
`
`0.6533
`
`0.8624
`
`Predicted ADMET
`features
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 010
`
`

`

`P-glycoprotein inhibitor II
`Property
`Renal organic cation transporter
`
`CYP450 2C9 substrate
`
`CYP450 2D6 substrate
`
`CYP450 3A4 substrate
`
`CYP450 1A2 substrate
`
`CYP450 2C9 inhibitor
`
`CYP450 2D6 inhibitor
`
`CYP450 2C19 inhibitor
`
`CYP450 3A4 inhibitor
`
`Non-inhibitor
`Value
`Non-inhibitor
`
`Non-substrate
`
`Non-substrate
`
`Non-substrate
`
`Non-inhibitor
`
`Non-inhibitor
`
`Non-inhibitor
`
`Non-inhibitor
`
`Non-inhibitor
`
`CYP450 inhibitory promiscuity
`
`Low CYP Inhibitory Promiscuity
`
`Ames test
`
`Carcinogenicity
`
`Biodegradation
`
`Rat acute toxicity
`
`hERG inhibition (predictor I)
`
`hERG inhibition (predictor II)
`
`Non AMES toxic
`
`Non-carcinogens
`
`Not ready biodegradable
`
`2.0666 LD50, mol/kg
`
`Weak inhibitor
`
`Non-inhibitor
`
`0.8688
`Probability
`0.8416
`
`0.7664
`
`0.8333
`
`0.6217
`
`0.9401
`
`0.9071
`
`0.9252
`
`0.9025
`
`0.9569
`
`0.9036
`
`0.9133
`
`0.7986
`
`0.9964
`
`Not applicable
`
`0.9576
`
`0.9135
`
`
`
` ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. ( 23092397
`
`
`
`)
`
`Spectra
`Spectra
`
`Mass Spec (NIST)
`
`Download (11.5 KB)
`
`Spectra
`
`Spectrum
`Type
`
`LC-MS/MS
`
`Description
`
`Splash Key
`
`LC-MS/MS Spectrum - Quattro_QQQ 10V,
`Positive (Annotated)
`
`splash10-052b-0090000000-
`aaa48e4702874457ae26
`
`LC-MS/MS
`
`LC-MS/MS Spectrum - Quattro_QQQ 25V,
`Positive (Annotated)
`
`splash10-0r6r-0920000000-
`b129acf72e7dde12441e
`
`LC-MS/MS
`
`LC-MS/MS Spectrum - Quattro_QQQ 40V,
`Positive (Annotated)
`
`splash10-0a4i-1900000000-
`67f803f38aed0bd12ade
`
`MS
`
`Mass Spectrum (Electron Ionization)
`
`splash10-00r2-6490000000-
`3f5d9320308b823c6489
`
`1D NMR
`
`1H NMR Spectrum
`
`1D NMR
`
`1H NMR Spectrum
`
`1D NMR
`
`13C NMR Spectrum
`
`2D NMR
`
`[1H,13C] 2D NMR Spectrum
`
`Not Available
`
`Not Available
`
`Not Available
`
`Not Available
`
`View in MoNA
`
`
`
`View in MoNA
`
`
`
`View in MoNA
`
`
`
`View in MoNA
`
`
`
`Taxonomy
`Taxonomy
`
`Description
`
`This compound belongs to the class of organic compounds known as 1,2,4-benzothiadiazine-1,1-dioxides. These are
`aromatic heterocyclic compounds containing a 1,2,4-benzothiadiazine ring system with two S=O bonds at the 1-
`position.
`
`Kingdom
`
`Organic compounds
`
`
`
`Super Class
`
`Organoheterocyclic compounds
`
`
`
`Class
`
`Sub Class
`
`
`Thiadiazines
`
`Benzothiadiazines
`
`
`
`Direct Parent
`
`
`1,2,4-benzothiadiazine-1,1-dioxides
`
`Alternative Parents
`
`
`
`Secondary alkylarylamines
`
`Organosulfonamides
`
`Benzenoids
`
`Aryl chlorides
`Aminosulfonyl compounds
`
`Azacyclic compounds
`Organopnictogen compounds
`
`
`
`
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 011
`
`

`

`Substituents
`
`
`Organochlorides
`
`Organic oxides
`Hydrocarbon derivatives
`
`
`
`1,2,4-benzothiadiazine-1,1-dioxide
`Secondary aliphatic/aromatic amine
`Aryl chloride
`Aryl halide
`Organosulfonic acid amide
`Benzenoid
`Organic sulfonic acid or derivatives
`Organosulfonic acid or derivatives
`Aminosulfonyl compound
`Sulfonyl
`Secondary amine
`Azacycle
`Organic oxide
`Amine
`Organopnictogen compound
`Organosulfur compound
`Organonitrogen compound
`Organochloride
`Organohalogen compound
`Organic oxygen compound
`Organic nitrogen compound
`Hydrocarbon derivative
`Aromatic heteropolycyclic compound
`
`Molecular
`Framework
`
`External
`Descriptors
`
`Targets
`
`Aromatic heteropolycyclic compounds
`
`
`)
`sulfonamide (CHEBI:5778
`organochlorine compound (CHEBI:5778
`
`benzothiadiazine (CHEBI:5778
`)
`
`
`
`)
`
`1. Solute carrier family 12 member 3
`
`
`
` Details
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`yes
`Actions
`
`inhibitor
`
`General Function:
`Transporter activity
`Specific Function:
`Key mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium
`reabsorption.
`Gene Name:
`SLC12A3
`Uniprot ID:
`
`P55017
`Molecular Weight:
`113138.04 Da
`
`References
`
`
`]
`1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352
`2. Ran XW, Wang C, Dai F, Jiang JJ, Tong NW, Li XJ, Liang JZ: [A case of Gitelman's syndrome presenting with severe hypocalcaemia and
`
`hypokalemic periodic paralysis]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 Jul;36(4):583-7. [PubMed:16078592
`]
`3. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E: WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic.
`
`Hypertension. 2005 Oct;46(4):758-65. Epub 2005 Sep 19. [PubMed:16172412
`]
`4. Abuladze N, Yanagawa N, Lee I, Jo OD, Newman D, Hwang J, Uyemura K, Pushkin A, Modlin RL, Kurtz I: Peripheral blood mononuclear cells
`express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. J Am Soc Nephrol. 1998
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 012
`
`

`

`
`]
`May;9(5):819-26. [PubMed:9596079
`5. Barry EL, Gesek FA, Kaplan MR, Hebert SC, Friedman PA: Expression of the sodium-chloride cotransporter in osteoblast-like cells: effect of
`
`thiazide diuretics. Am J Physiol. 1997 Jan;272(1 Pt 1):C109-16. [PubMed:9038817
`]
`6. Kurschat C, Heering P, Grabensee B: [Gitelman's syndrome: an important differential diagnosis of hypokalemia]. Dtsch Med Wochenschr.
`
`2003 May 30;128(22):1225-8. [PubMed:12772080
`]
`7. Monroy A, Plata C, Hebert SC, Gamba G: Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and
`
`diuretics interaction. Am J Physiol Renal Physiol. 2000 Jul;279(1):F161-9. [PubMed:10894798
`]
`
`
`
` Details
`
`2. Carbonic anhydrase 1
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`General Function:
`Zinc ion binding
`Specific Function:
`Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
`Gene Name:
`CA1
`Uniprot ID:
`
`P00915
`Molecular Weight:
`28870.0 Da
`
`References
`
`1. Puscas I, Coltau M, Baican M, Domuta G, Hecht A: Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle
`
`carbonic anhydrase by a direct mechanism of action. Drugs Exp Clin Res. 1999;25(6):271-9. [PubMed:10713865
`]
`2. Couloigner V, Loiseau A, Sterkers O, Amiel C, Ferrary E: Effect of locally applied drugs on the endolymphatic sac potential. Laryngoscope.
`
`1998 Apr;108(4 Pt 1):592-8. [PubMed:9546276
`]
`3. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide,
`trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
`
`Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014
`]
`
`3. Carbonic anhydrase 2
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`
`
` Details
`
`General Function:
`Zinc ion binding
`Specific Function:
`Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate
`cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH
`regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate ex...
`Gene Name:
`CA2
`Uniprot ID:
`
`P00918
`Molecular Weight:
`29245.895 Da
`
`References
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 013
`
`

`

`1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
`[PubMed:17139284
`]
`2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34.
`[PubMed:17016423
`]
`3. Meyerson LR, Nesta D: [3H]acetazolamide binding to carbonic anhydrase in normal and transformed cells. Biochem Pharmacol. 1991 Mar 15-
`
`Apr 1;41(6-7):995-1000. [PubMed:1901209
`]
`4. Schaeffer P, Vigne P, Frelin C, Lazdunski M: Identification and pharmacological properties of binding sites for the atypical thiazide diuretic,
`
`indapamide. Eur J Pharmacol. 1990 Jul 17;182(3):503-8. [PubMed:2226620
`]
`5. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide,
`trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
`
`Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014
`]
`
` 
`
`4. Carbonic anhydrase 4
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`
`
` Details
`
`General Function:
`Zinc ion binding
`Specific Function:
`Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH
`homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the
`choroid.
`Gene Name:
`CA4
`Uniprot ID:
`
`P22748
`Molecular Weight:
`35032.075 Da
`
`References
`
`1. Puscas I, Coltau M, Baican M, Domuta G, Hecht A: Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle
`
`carbonic anhydrase by a direct mechanism of action. Drugs Exp Clin Res. 1999;25(6):271-9. [PubMed:10713865
`]
`2. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide,
`trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
`
`Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014
`]
`
`5. Carbonic anhydrase 9
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`
`
` Details
`
`General Function:
`Zinc ion binding
`Specific Function:
`Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and
`transformation. Appears to be a novel specific biomarker for a cervical neoplasia.
`Gene Name:
`CA9
`Uniprot ID:
`
`Q16790
`Molecular Weight:
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 014
`
`

`

`49697.36 Da
`
`References
`
`1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide,
`trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
`
`Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014
`]
`
`
`
` Details
`
`6. Carbonic anhydrase 12
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`General Function:
`Zinc ion binding
`Specific Function:
`Reversible hydration of carbon dioxide.
`Gene Name:
`CA12
`Uniprot ID:
`
`O43570
`Molecular Weight:
`39450.615 Da
`
`References
`
`1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide,
`trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
`
`Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [PubMed:19119014
`]
`
`7. Calcium-activated potassium channel subunit alpha-1
`
`
`
` Details
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`other/unknown
`
`General Function:
`Voltage-gated potassium channel activity
`Specific Function:
`Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also
`activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+)
`concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key ...
`Gene Name:
`KCNMA1
`Uniprot ID:
`
`Q12791
`Molecular Weight:
`137558.115 Da
`
`References
`
`1. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC: Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel
`
`of K+-deficient rats. FASEB J. 2004 Apr;18(6):760-1. Epub 2004 Feb 6. [PubMed:14766795
`]
`
`Par Pharm., Inc.
`Exhibit 1064
`Page 015
`
`

`

`Transporters
`
`1. Solute carrier family 22 member 6
`
`
`
` Details
`
`Kind
`Protein
`Organism
`Human
`Pharmacological action
`unknown
`Actions
`
`inhibitor
`
`General Function:
`Sodium-independent organic anion transmembrane transporter activity
`Specific Function:
`Involved in the renal elimination of endogenous and exogenous organic anions. F