HY-PHEN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for HY-PHEN (HY-PHEN).

How it works

HY-PHEN is a combination of hydrocodone (a mu-opioid receptor agonist) and acetaminophen (an analgesic and antipyretic). Hydrocodone binds to mu-opioid receptors in the CNS, altering pain perception and emotional response to pain. Acetaminophen inhibits cyclooxygenase (COX) enzymes, particularly in the CNS, reducing prostaglandin synthesis.

What the body does with it

Metabolism	Hydrocodone is metabolized via CYP3A4 to hydromorphone (active) and via CYP2D6 to norhydrocodone. Acetaminophen is primarily metabolized via glucuronidation and sulfation; a minor pathway via CYP2E1 produces a hepatotoxic metabolite (NAPQI) that is normally detoxified by glutathione.
Excretion	Renal (primarily as glucuronide conjugates and unchanged drug). Approximately 90-95% eliminated in urine within 24 hours; fecal excretion <5%.
Half-life	2-3 hours (terminal elimination half-life). Clinical context: Short half-life requires frequent dosing (every 4-6 hours) for sustained analgesic effect.
Protein binding	25-35% bound to plasma proteins (mainly albumin).
Volume of Distribution	0.9-1.5 L/kg. Clinical meaning: Moderate Vd indicates distribution into total body water; does not extensively accumulate in tissues.
Bioavailability	Oral: 60-90% (first-pass metabolism reduces systemic availability); Rectal: 70-80%; IV/IM: 100%.
Onset of Action	Oral: 30-60 minutes; Rectal: 30-90 minutes; IV: 5-10 minutes; IM: 10-20 minutes.
Duration of Action	Oral/Rectal: 4-6 hours; IV/IM: 3-4 hours. Clinical note: Duration is dose-dependent; higher doses may extend duration but increase risk of hepatotoxicity.

Classification & Brands

Dosing & administration

1-2 tablets (acetaminophen 500 mg/hydrocodone 5-10 mg) orally every 4-6 hours as needed for pain; maximum 8 tablets per day.

Dosage form	TABLET
Renal impairment	GFR 30-50 mL/min: administer at 75% of usual dose every 6 hours; GFR <30 mL/min: administer at 50% of usual dose every 8 hours. Avoid in severe renal impairment.
Liver impairment	Child-Pugh Class A: no adjustment; Class B: reduce dose by 50% and extend interval to every 8 hours; Class C: contraindicated.
Pediatric use	Not recommended for children under 18 years due to risk of opioid-related adverse effects; alternative analgesics preferred.
Geriatric use	Initiate with lowest effective dose (e.g., acetaminophen 500 mg/hydrocodone 5 mg) every 6 hours; monitor for respiratory depression, constipation, and falls; may require dose reduction by 25-50% compared to younger adults.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for HY-PHEN (HY-PHEN).

Breastfeeding	HY-PHEN (hydrocodone/acetaminophen) is excreted into breast milk in low concentrations. M/P ratio for hydrocodone is approximately 2.0, for acetaminophen ~1.0. Use caution; monitor infant for sedation, respiratory depression, and poor feeding. Consider risk of neonatal withdrawal if maternal use is chronic.
Teratogenic Risk	Pregnancy Category C. First trimester: No well-controlled studies; potential for fetal harm based on animal studies (cleft palate, skeletal anomalies). Second and third trimesters: Prolonged use may cause neonatal withdrawal syndrome (irritability, hypertonia, respiratory depression) if used near term. Avoid use in pregnancy unless benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion of acetaminophen (especially in children) can cause hepatotoxicity; neonatal opioid withdrawal syndrome with prolonged use during pregnancy; risks from concomitant use with benzodiazepines or other CNS depressants (additive respiratory depression).

Side Effect Profile

Serious Effects

Absolute Contraindications

Significant respiratory depression; acute or severe bronchial asthma; known or suspected gastrointestinal obstruction (e.g., paralytic ileus); severe hepatic impairment; hypersensitivity to hydrocodone, acetaminophen, or any component; use of MAO inhibitors within 14 days (hypertensive crisis).

Clinical Precautions

Precautions

Hepatotoxicity due to acetaminophen (dose-dependent); respiratory depression (especially in elderly, debilitated, or COPD); opioid-induced hyperalgesia; adrenal insufficiency; severe hypotension; seizures; serotonin syndrome with serotonergic drugs; urinary retention; bile duct spasm; use in patients with head injury or increased intracranial pressure (risk of masking neurological signs); neonatal withdrawal syndrome.

Clinical Tips & Counseling

Drug interactions

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HY-PHEN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for HY-PHEN (HY-PHEN).

How it works

What the body does with it

Metabolism	Hydrocodone is metabolized via CYP3A4 to hydromorphone (active) and via CYP2D6 to norhydrocodone. Acetaminophen is primarily metabolized via glucuronidation and sulfation; a minor pathway via CYP2E1 produces a hepatotoxic metabolite (NAPQI) that is normally detoxified by glutathione.
Excretion	Renal (primarily as glucuronide conjugates and unchanged drug). Approximately 90-95% eliminated in urine within 24 hours; fecal excretion <5%.
Half-life	2-3 hours (terminal elimination half-life). Clinical context: Short half-life requires frequent dosing (every 4-6 hours) for sustained analgesic effect.
Protein binding	25-35% bound to plasma proteins (mainly albumin).
Volume of Distribution	0.9-1.5 L/kg. Clinical meaning: Moderate Vd indicates distribution into total body water; does not extensively accumulate in tissues.
Bioavailability	Oral: 60-90% (first-pass metabolism reduces systemic availability); Rectal: 70-80%; IV/IM: 100%.
Onset of Action	Oral: 30-60 minutes; Rectal: 30-90 minutes; IV: 5-10 minutes; IM: 10-20 minutes.
Duration of Action	Oral/Rectal: 4-6 hours; IV/IM: 3-4 hours. Clinical note: Duration is dose-dependent; higher doses may extend duration but increase risk of hepatotoxicity.

Classification & Brands

Dosing & administration

1-2 tablets (acetaminophen 500 mg/hydrocodone 5-10 mg) orally every 4-6 hours as needed for pain; maximum 8 tablets per day.

Dosage form	TABLET
Renal impairment	GFR 30-50 mL/min: administer at 75% of usual dose every 6 hours; GFR <30 mL/min: administer at 50% of usual dose every 8 hours. Avoid in severe renal impairment.
Liver impairment	Child-Pugh Class A: no adjustment; Class B: reduce dose by 50% and extend interval to every 8 hours; Class C: contraindicated.
Pediatric use	Not recommended for children under 18 years due to risk of opioid-related adverse effects; alternative analgesics preferred.
Geriatric use	Initiate with lowest effective dose (e.g., acetaminophen 500 mg/hydrocodone 5 mg) every 6 hours; monitor for respiratory depression, constipation, and falls; may require dose reduction by 25-50% compared to younger adults.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for HY-PHEN (HY-PHEN).

Breastfeeding	HY-PHEN (hydrocodone/acetaminophen) is excreted into breast milk in low concentrations. M/P ratio for hydrocodone is approximately 2.0, for acetaminophen ~1.0. Use caution; monitor infant for sedation, respiratory depression, and poor feeding. Consider risk of neonatal withdrawal if maternal use is chronic.
Teratogenic Risk	Pregnancy Category C. First trimester: No well-controlled studies; potential for fetal harm based on animal studies (cleft palate, skeletal anomalies). Second and third trimesters: Prolonged use may cause neonatal withdrawal syndrome (irritability, hypertonia, respiratory depression) if used near term. Avoid use in pregnancy unless benefit outweighs risk.