Benzhydrocodone

Identification

Brand Names
Apadaz
Generic Name
Benzhydrocodone
DrugBank Accession Number
DB15465
Background

Benzhydrocodone is a benzylic prodrug of hydrocodone.5 It was developed in an effort to reduce parenteral bioavailability of the active metabolite as a deterrent to abuse.4 Benzhydrocodone is indicated for use in the short-term management of pain. It was first approved by the FDA in February 2018 in combination with acetaminophen under the trade name Apadaz, marketed by KVK Tech and developed by KemPharm.6,7

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 403.478
Monoisotopic: 403.178358289
Chemical Formula
C25H25NO4
Synonyms
  • Benzhydrocodone

Pharmacology

Indication

Benzyhydrocodone is indicated, in combination with acetaminophen, for the short-term management of acute pain requiring opioid therapy.5

Pharmacology
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Associated Conditions
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Contraindications
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Pharmacodynamics

Benzhydrocodone is rapidly metabolized to hydrocodone which acts on the central nervous system to produce analgesia. The action of hydrocodone in the brain can also produce euphoria, leading to addiction.

Mechanism of action

Benzyhydrocodone is not reported to have pharmacological activity of its own and it not present in the plasma at detectable concentrations. Its active metabolite, hydrocodone is a mu-opioid receptor agonist.

Absorption

The absorption profile of benzhydrocodone meets the FDA bioequivalence requirements for similar hydrocodone immediate-release products.5 Benzhydrocodone itself is rapidly metabolized by intestinal enzymes to the active metabolite, hydrocodone, with no detectable benzhydrocodone reaching circulation. Single oral doses of 6.67 mg benzhydrocodone produces a Cmax of 19.18 ng/mL with a Tmax of 1.25 h and an AUC of 125.73 h*ng/mL. Administration with food may slightly delay absorption but has no significant effect on AUC.

Volume of distribution

The hydrocodone metabolite of benzhydrocodone has an apparent volume of distribution of 714 L.1

Protein binding

Not Available

Metabolism

Benzhydrocodone is rapidly metabolized to hydrocodone by intestinal enzymes.5 Hydrocodone undergoes oxidative metabolism by CYP3A4 and CYP2D6 which contribute to N-demethylation and O-demethylation respectively.5,3 The dealkylated metabolites undergo further 6-ketoreduction to the 6-α- and 6-β-hydroxy metabolites as well as glucuronide conjugation.2

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Route of elimination

The hydrocodone metabolite is eliminated through a mix of metabolism and renal excretion.5,1

Half-life

The hydrocodone metabolite has a half life of elimination of 4.5 h.5

Clearance

The apparent clearance of the hydrocodone metabolite is 64.4 L/h.1

Adverse Effects
Adverseeffects
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Toxicity

Overdosage with benzhydrocodone presents as opioid intoxication including respiratory depression, somnolence, coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.5

In case of oversdosage the foremost priority is the maintenance of a patent and protected airway with the provision of assisted ventilation if necessary. Supportive measures such as IV fluids, supplemental oxygen, and vasopressors may be used to manage circulatory shock.5 Advanced life support may be necessary in the case of cardiac arrest or arrhythmias. Opioid antagonists such as naloxone may be used to reverse the respiratory and circulatory effects of hydrocodone. Emergency monitoring is still required after naloxone administration as the opioid effects may reappear. Additionally, if used in an opioid tolerant patient, naloxone may produce opioid withdrawal symptoms.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Benzhydrocodone is combined with 1,2-Benzodiazepine.
AcetazolamideThe therapeutic efficacy of Acetazolamide can be decreased when used in combination with Benzhydrocodone.
AcetophenazineThe risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Benzhydrocodone.
AclidiniumThe risk or severity of adverse effects can be increased when Aclidinium is combined with Benzhydrocodone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Benzhydrocodone.
AlimemazineThe risk or severity of hypotension and CNS depression can be increased when Alimemazine is combined with Benzhydrocodone.
AlloinThe therapeutic efficacy of Alloin can be decreased when used in combination with Benzhydrocodone.
AlprazolamThe risk or severity of adverse effects can be increased when Benzhydrocodone is combined with Alprazolam.
AlvimopanThe risk or severity of adverse effects can be increased when Benzhydrocodone is combined with Alvimopan.
AmantadineThe risk or severity of adverse effects can be increased when Amantadine is combined with Benzhydrocodone.
Interactions
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Food Interactions
  • Avoid alcohol. Ingesting alcohol may increase the CNS depressive effects of benzhydrocodone. Apadaz also contains acetaminophen, which, when combined with alcohol, may increase the risk of hepatotoxicity.
  • Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Benzhydrocodone hydrochlorideI894QAU7FJ1379679-42-1VVCUIDHKAHHSAN-JJHQWJQCSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ApadazBenzhydrocodone hydrochloride (6.12 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag
ApadazBenzhydrocodone hydrochloride (6.12 mg/1) + Acetaminophen (325 mg/1)TabletOralKemPharm, Inc.2019-06-282019-06-28US flag
ApadazBenzhydrocodone hydrochloride (8.16 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag
ApadazBenzhydrocodone hydrochloride (8.16 mg/1) + Acetaminophen (325 mg/1)TabletOralKemPharm, Inc.2019-06-282019-06-28US flag
ApadazBenzhydrocodone hydrochloride (4.08 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag
ApadazBenzhydrocodone hydrochloride (4.08 mg/1) + Acetaminophen (325 mg/1)TabletOralKemPharm, Inc.2019-06-282019-06-28US flag
Benzhydrocodone and AcetaminophenBenzhydrocodone hydrochloride (6.12 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag
Benzhydrocodone and AcetaminophenBenzhydrocodone hydrochloride (8.16 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag
Benzhydrocodone and AcetaminophenBenzhydrocodone hydrochloride (4.08 mg/1) + Acetaminophen (325 mg/1)TabletOralKVK-Tech, Inc.2019-06-28Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
75MS0AAZ9I
CAS number
1259440-61-3
InChI Key
VPMRSLWWUXNYRY-NDOYXKHWSA-N
InChI
InChI=1S/C25H25NO4/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/t17-,18-,23+,25+/m1/s1
IUPAC Name
(1S,5R,13R,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10,14-tetraen-14-yl benzoate
SMILES
[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1([H])CC=C2OC(=O)C1=CC=CC=C1

References

Synthesis Reference

U.S. Patent 2018 / 0055836 A1.

General References
  1. Melhem MR, Rubino CM, Farr SJ, Robinson CY: Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules. Clin Pharmacokinet. 2013 Oct;52(10):907-17. doi: 10.1007/s40262-013-0081-6. [Article]
  2. Cone EJ, Darwin WD, Gorodetzky CW, Tan T: Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog. Drug Metab Dispos. 1978 Jul-Aug;6(4):488-93. [Article]
  3. Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA: CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004 Mar;57(3):287-97. [Article]
  4. Guenther SM, Mickle TC, Barrett AC, Roupe KA, Zhou J, Lam V: Relative Bioavailability, Intranasal Abuse Potential, and Safety of Benzhydrocodone/Acetaminophen Compared with Hydrocodone Bitartrate/Acetaminophen in Recreational Drug Abusers. Pain Med. 2018 May 1;19(5):955-966. doi: 10.1093/pm/pnx195. [Article]
  5. FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
  6. KemPharm: Apadaz approval announcement [Link]
  7. FDA Approved Drug Products: Apadaz (benzhydrocodone/acetaminophen) oral tablets [Link]
ChemSpider
34222482
RxNav
2001352
ChEMBL
CHEMBL3137321
ZINC
ZINC000103297957
Wikipedia
Benzhydrocodone
FDA label
Download (784 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9132125No2015-09-152030-07-01US flag
US8828978No2014-09-092030-07-01US flag
US9549923No2017-01-242030-07-01US flag
US8748413No2014-06-102030-07-01US flag
US8461137No2013-06-112031-02-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP3.71ChemAxon
pKa (Strongest Basic)9.36ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area48 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity114.96 m3·mol-1ChemAxon
Polarizability43.74 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Drug created on July 31, 2019 16:53 / Updated on February 21, 2021 18:55