Brand Names
Generic Name
DrugBank Accession Number

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

Small Molecule
Average: 403.478
Monoisotopic: 403.178358289
Chemical Formula
  • Benzhydrocodone



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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofAcute pain••••••••••••
Contraindications & Blackbox Warnings
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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.


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


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


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


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

Adverse Effects
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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.

Not Available
Pharmacogenomic Effects/ADRs
Not Available


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.
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.
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.


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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


Drug Categories
Not classified
Affected organisms
Not Available

Chemical Identifiers

CAS number
InChI Key
(1S,5R,13R,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10,14-tetraen-14-yl benzoate


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]
  8. FDA Approved Drug Products: APADAZ (benzhydrocodone and acetaminophen) tablets, for oral use, CII (December 2023) [Link]
FDA label
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Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns


Not Available
Not Available
Dosage Forms
Not Available
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


Experimental Properties
Not Available
Predicted Properties
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
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available


Mass Spec (NIST)
Not Available
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0000900000-40c8706281a26e60e8a3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0010900000-1b88c45253da214b6d07
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udj-0009800000-2b2330fc1d9fd1536281
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fr2-2190500000-3eb60a00674f0d9fed7f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0pb9-4693200000-b9f1f8e492e7c3aa9f04
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9203200000-882896ef5bae231af42d
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Drug created at July 31, 2019 16:53 / Updated at January 25, 2024 05:59