BENZHYDROCODONE HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H25NO4.ClH
Molecular Weight	439.931
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of BENZHYDROCODONE HYDROCHLORIDE

Structure Search

SMILES

Cl.[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]15CCN(C)[C@]([H])(C4)[C@]5([H])CC=C2OC(=O)C6=CC=CC=C6

InChI

InChIKey=VVCUIDHKAHHSAN-RFIUKBLMSA-N

InChI=1S/C25H25NO4.ClH/c1-26-13-12-25-17-9-11-20(29-24(27)15-6-4-3-5-7-15)23(25)30-22-19(28-2)10-8-16(21(22)25)14-18(17)26;/h3-8,10-11,17-18,23H,9,12-14H2,1-2H3;1H/t17-,18+,23-,25-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	C25H25NO4
Molecular Weight	403.4703
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/books/NBK501225/ | https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208653s000lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/30140595 | https://www.ncbi.nlm.nih.gov/pubmed/29092079

Benzhydrocodone is a prodrug of hydrocodone. Benzhydrocodone is formed by covalently bonding hydrocodone to benzoic acid. Benzhydrocodone itself is not pharmacologically active, but must be metabolized to hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. Hydrocodone is a full agonist of the opioid receptors with a higher affinity for the mu-opioid receptor. Upon binding, hydrocodone produces an analgesic effect with no ceiling. APADAZ a combination of benzhydrocodone and acetaminophen is FDA approved and indicated for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. APADAZ, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.

CNS Activity

Approval Year

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 614 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1b89a045-d552-40b6-a717-09858b5e6239	Primary		Approved 8429	ZOHYDRO ER Approved Use ZOHYDRO ER is an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Launch Date 2013
Acute pain 17 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208653s000lbl.pdf	Primary		Approved 8429	APADAZ Approved Use APADAZ is a combination of benzhydrocodone, a prodrug of the opioid agonist hydrocodone, and acetaminophen, and is indicated for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Launch Date 2019

C_max

Value	Dose	Co-administered	Analyte	Population
10.1 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27138027/	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
23.6 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/005213s039lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
155 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27138027/	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
10.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27138027/	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/005213s039lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
55% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/005213s039lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROCODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
30 mg multiple, oral (total) Overdose Dose: 30 mg Route: oral Route: multiple Dose: 30 mg Co-administed with:: clarithromycin valproic acid(250 mg, 2 times per day) Sources: https://pubmed.ncbi.nlm.nih.gov/20837591	unhealthy, 5 years n = 1 Health Status: unhealthy Condition: cold Age Group: 5 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/20837591	Other AEs: Adverse event... Other AEs: Adverse event (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/20837591
160 mg 1 times / day multiple, oral Highest studied dose Dose: 160 mg, 1 times / day Route: oral Route: multiple Dose: 160 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf	Other AEs: Electrocardiogram QTc interval prolonged... Other AEs: Electrocardiogram QTc interval prolonged Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf
20 mg 1 times / day multiple, oral Recommended Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	Other AEs: Withdrawal syndrome neonatal... Other AEs: Withdrawal syndrome neonatal Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf
20 mg 1 times / day multiple, oral Recommended Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	Other AEs: Respiratory depression, Addiction... Other AEs: Respiratory depression (grade 5) Addiction Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf
20 mg 1 times / day multiple, oral Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	unhealthy, adult n = 296 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 296 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	Disc. AE: Vomiting, Nausea... AEs leading to discontinuation/dose reduction: Vomiting (1%) Nausea (1%) Headache (1%) Dizziness (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115

AEs

AE	Significance	Dose	Population
Adverse event	grade 5	30 mg multiple, oral (total) Overdose Dose: 30 mg Route: oral Route: multiple Dose: 30 mg Co-administed with:: clarithromycin valproic acid(250 mg, 2 times per day) Sources: https://pubmed.ncbi.nlm.nih.gov/20837591	unhealthy, 5 years n = 1 Health Status: unhealthy Condition: cold Age Group: 5 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/20837591
Electrocardiogram QTc interval prolonged		160 mg 1 times / day multiple, oral Highest studied dose Dose: 160 mg, 1 times / day Route: oral Route: multiple Dose: 160 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf
Withdrawal syndrome neonatal		20 mg 1 times / day multiple, oral Recommended Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	pregnant, adult Health Status: pregnant Age Group: adult Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf
Addiction		20 mg 1 times / day multiple, oral Recommended Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf
Respiratory depression	grade 5	20 mg 1 times / day multiple, oral Recommended Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206627s000lbl.pdf
Dizziness	1% Disc. AE	20 mg 1 times / day multiple, oral Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	unhealthy, adult n = 296 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 296 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115
Headache	1% Disc. AE	20 mg 1 times / day multiple, oral Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	unhealthy, adult n = 296 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 296 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115
Nausea	1% Disc. AE	20 mg 1 times / day multiple, oral Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	unhealthy, adult n = 296 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 296 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115
Vomiting	1% Disc. AE	20 mg 1 times / day multiple, oral Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115	unhealthy, adult n = 296 Health Status: unhealthy Age Group: adult Sex: M+F Population Size: 296 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000MedR.pdf Page: p. 115

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737		substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2B6 664 CYP2C19 991

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=29 Page: 29.0	minor
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=29 Page: 29.0	minor
CYP2D6 1217	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884456/; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=30	yes	yes (co-administration study) Comment: The 90% confidence interval (CI) of the geometric means for hydrocodone AUCinf (98 to 115%), AUCt (98 to 115%), and Cmax (93 to 121%) values were within the range of 80 to 125% when a single dose of HYSINGLA ER 20 mg was co-administered with CYP2D6 inhibitor paroxetine Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884456/; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=30
CYP3A4 1737	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884456/; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=30	yes	yes (co-administration study) Comment: Co-administration of HYSINGLA ER and CYP3A4 inhibitor ketoconazole increased mean hydrocodone AUC and Cmax by 135% and 78%, respectively; Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884456/; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=30

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206627Orig1s000PharmR.pdf#page=33 Page: 33.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5779	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5779
ZINC	ZINC000001280665	http://zinc15.docking.org/substances/ZINC000001280665
eMolecules	29539213	https://www.emolecules.com/cgi-bin/more?vid=29539213

PubMed

Title	Date	PubMed
Profound hearing loss associated with hydrocodone/acetaminophen abuse.	2000 Mar	10733182
Opioid formulations: tailoring to the needs in chronic pain.	2001	11798229
Harmonic Scalpel vs. electrocautery hemorrhoidectomy: a prospective evaluation.	2001 Apr	11330583
Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults.	2001 Feb	11293556
A retrospective study of the effect of postoperative indomethacin rectal suppositories on the need for narcotic analgesia in patients who had a cesarean delivery while they were under regional anesthesia.	2001 Jun	11408878
Who's feeling no pain?	2001 Mar 19	11276823
Evaluation of urinary dihydrocodeine excretion in human by gas chromatography-mass spectrometry.	2001 Mar 5	11254193
Important drugs for cough in advanced cancer.	2001 Nov	11762966
Cellulose granulomatosis presenting as centrilobular nodules: CT and histologic findings.	2001 Nov	11641191
Acetaminophen, aspirin, or Ibuprofen in combination analgesic products.	2001 Nov-Dec	11704782
Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.	2001 Sep	11589259
Synthesis and biological activity of 8beta-substituted hydrocodone indole and hydromorphone indole derivatives.	2002 Jan 21	11755345
A phase II study of hydrocodone for cough in advanced cancer.	2002 Jan-Feb	12171425
Exacerbation of panic disorder symptoms following Vicodin exposure.	2002 Nov-Dec	12490349
Rational use of analgesic combinations.	2002 Oct	12436825
Senate committee fights hydrocodone abuse.	2002 Sep	12380236
[Hypoxic brain damage in victims of fatal road traffic accident: prevalence, distribution and association with survival time and other head and extracranial injuries].	2002 Sep	12364952
Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers.	2003 Aug	12920424
Quantification of the O- and N-demethylated metabolites of hydrocodone and oxycodone in human liver microsomes using liquid chromatography with ultraviolet absorbance detection.	2003 Feb 25	12535841
I am following a health care professional who, I think, has a drug problem.	2003 Jan	12652834
Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers.	2003 Jan	12404072
[Maternal and fetal morbidity in patients with premature rupture of the membrane after 27-week gestation. Causes and costs].	2003 Jul	14515665
Rapid communication: laparoscopic Anderson-Hynes dismembered pyeloplasty using the da Vinci robot: technical considerations.	2003 Mar	12689399
Misuse of prescribed controlled substances defined by urinalysis.	2003 Mar-Apr	12874916
Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study.	2003 Nov	14636819
Evaluation of postoperative bupivacaine infusion for pain management after anterior cruciate ligament reconstruction.	2003 Oct	14551548
Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor.	2004 Feb	14742366
Office visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs. 2000.	2004 Jun	15157714
Local anesthetic infusion pumps improve postoperative pain after inguinal hernia repair: a randomized trial.	2004 Nov	15586515
6-oxo-morphinane oximes: pharmacology, chemistry and analytical application.	2004 Oct	15544463
Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid requirements and opioid-related adverse effects.	2004 Oct	15352969
Metaxalone (Skelaxin)-related death.	2004 Sep	15516312
Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial.	2004 Sep	15333854
The GC-MS detection and characterization of neopine resulting from opium use and codeine metabolism and its potential as an opiate-product-use marker.	2005 Jun	15782326

Patents

Sample Use Guides

In Vivo Use Guide

APADAZ Immediate-release tablets: 6.12 mg benzhydrocodone (equivalent to 6.67 mg benzhydrocodone hydrochloride) and 325 mg acetaminophen. Initiate treatment with APADAZ at 1 or 2 tablets every 4 to 6 hours as needed for pain. Dosage should not exceed 12 tablets in a 24 hour period.

Route of Administration: Oral

Substance Class	Chemical Created by `admin` on `Sat Dec 16 02:11:00 GMT 2023` Edited by `admin` on `Sat Dec 16 02:11:00 GMT 2023`
Record UNII	I894QAU7FJ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BENZHYDROCODONE HYDROCHLORIDE

Official Name

English

BENZHYDROCODONE HYDROCHLORIDE [USAN]

Common Name

English

Hydrochloride of 6,7-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6-yl benzoate

Common Name

English

MORPHINAN-6-OL, 6,7-DIDEHYDRO-4,5-EPOXY-3-METHOXY-17-METHYL-, 6-BENZOATE, HYDROCHLORIDE (1:1), (5.ALPHA.)-

Systematic Name

English

Benzhydrocodone hydrochloride [WHO-DD]

Common Name

English

KP201

Code

English

BENZHYDROCODONE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

KP-201

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C67413