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

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
[Longitudinal study of parameters of respiratory function tests and blood gas analysis in patients with progressive systemic scleroderma].	2001	12001574
Opioid formulations: tailoring to the needs in chronic pain.	2001	11798229
Harmonic Scalpel vs. electrocautery hemorrhoidectomy: a prospective evaluation.	2001 Apr	11330583
Do gender and race affect decisions about pain management?	2001 Apr	11318921
Persistently elevated acetaminophen concentrations for two days after an initial four-hour non-toxic concentration.	2001 Aug	11474737
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
Psychosis after ultrarapid opiate detoxification.	2001 Jun	11384923
[Does the inhalation of a 1% L-menthol solution in the premedication of fiberoptic bronchoscopy affect coughing and the sensation of dyspnea?].	2001 Mar	11303537
Evaluation of urinary dihydrocodeine excretion in human by gas chromatography-mass spectrometry.	2001 Mar 5	11254193
Complications of intranasal prescription narcotic abuse.	2002 Feb	11860072
Esophageal cancer and the esophagus: challenges and potential strategies for selective cytoprotection of the tumor-bearing organ during cancer treatment.	2002 Jan	11917287
Combination hydrocodone and ibuprofen versus combination oxycodone and acetaminophen in the treatment of moderate or severe acute low back pain.	2002 Jan	11833838
Photodynamic therapy for Barrett's esophagus and high grade dysplasia: results of a patient satisfaction survey.	2002 Jul-Aug	12195146
Gender differences in narcotic-induced emesis in the ED.	2002 May	11992331
Exacerbation of panic disorder symptoms following Vicodin exposure.	2002 Nov-Dec	12490349
Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers.	2003 Jan	12404072
Hair analysis for opiates: evaluation of washing and incubation procedures.	2003 Jun 5	12726847
Rapid communication: laparoscopic Anderson-Hynes dismembered pyeloplasty using the da Vinci robot: technical considerations.	2003 Mar	12689399
Postmortem oxycodone and hydrocodone blood concentrations.	2003 Mar	12665006
Current concepts in acute pain management.	2003 May	12839235
[Spanish scientific production in anesthesiology and resuscitation 1983-1995].	2003 Nov	14753139
The influence of gender and race on physicians' pain management decisions.	2003 Nov	14636818
Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.	2003 Nov-Dec	14597688
Evaluation of postoperative bupivacaine infusion for pain management after anterior cruciate ligament reconstruction.	2003 Oct	14551548
Carisoprodol withdrawal syndrome.	2004 Dec	15585447
A message of hope.	2004 Fall	15503937
Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors.	2004 Feb	14600248
Postoperative pain management after anterior cruciate ligament reconstruction.	2004 Jan	14971669
Loss prevention case of the month. Monitoring remains critical.	2004 Jan	14968682
Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches.	2004 Jun	15166776
Persistent nonmalignant pain and analgesic prescribing patterns in elderly nursing home residents.	2004 Jun	15161448
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.	2004 Mar	14998425
[Origin and growth of the National Program of Continuous Academic Development for the General Physician].	2004 May-Jun	15646146
Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs.	2005 Apr 8	15804436

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

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