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
Structure for Benzhydrocodone (DB15465)
- 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Acute pain •••••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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
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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.
- 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of adverse effects can be increased when Benzhydrocodone is combined with 1,2-Benzodiazepine. Acetazolamide The therapeutic efficacy of Acetazolamide can be decreased when used in combination with Benzhydrocodone. Acetophenazine The risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Benzhydrocodone. Aclidinium The risk or severity of adverse effects can be increased when Aclidinium is combined with Benzhydrocodone. Alfentanil The 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.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Benzhydrocodone hydrochloride I894QAU7FJ 1379679-42-1 VVCUIDHKAHHSAN-JJHQWJQCSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Apadaz Benzhydrocodone hydrochloride (4.08 mg/1) + Acetaminophen (325 mg/1) Tablet Oral KemPharm, Inc. 2019-06-28 2019-06-28 US 
Apadaz Benzhydrocodone hydrochloride (6.12 mg/1) + Acetaminophen (325 mg/1) Tablet Oral KVK-Tech, Inc. 2019-06-28 Not applicable US Apadaz Benzhydrocodone hydrochloride (6.12 mg/1) + Acetaminophen (325 mg/1) Tablet Oral KemPharm, Inc. 2019-06-28 2019-06-28 US Apadaz Benzhydrocodone hydrochloride (8.16 mg/1) + Acetaminophen (325 mg/1) Tablet Oral KemPharm, Inc. 2019-06-28 2019-06-28 US Apadaz Benzhydrocodone hydrochloride (8.16 mg/1) + Acetaminophen (325 mg/1) Tablet Oral KVK-Tech, Inc. 2019-06-28 Not applicable US
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
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
- KemPharm: Apadaz approval announcement [Link]
- FDA Approved Drug Products: Apadaz (benzhydrocodone/acetaminophen) oral tablets [Link]
- FDA Approved Drug Products: APADAZ (benzhydrocodone and acetaminophen) tablets, for oral use, CII (December 2023) [Link]
- External Links
- ChemSpider
- 34222482
- 2001352
- ChEMBL
- CHEMBL3137321
- ZINC
- ZINC000103297957
- Wikipedia
- Benzhydrocodone
- FDA label
- Download (784 KB)
Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9132125 No 2015-09-15 2030-07-01 US US8828978 No 2014-09-09 2030-07-01 US US9549923 No 2017-01-24 2030-07-01 US US8748413 No 2014-06-10 2030-07-01 US US8461137 No 2013-06-11 2031-02-22 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source logP 3.71 Chemaxon pKa (Strongest Basic) 9.36 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 48 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 114.96 m3·mol-1 Chemaxon Polarizability 43.74 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0udi-0000900000-40c8706281a26e60e8a3 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-0010900000-1b88c45253da214b6d07 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0udj-0009800000-2b2330fc1d9fd1536281 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0fr2-2190500000-3eb60a00674f0d9fed7f Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pb9-4693200000-b9f1f8e492e7c3aa9f04 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-9203200000-882896ef5bae231af42d Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Drug created at July 31, 2019 16:53 / Updated at January 25, 2024 05:59