Hydrocodone and Acetaminophen

Pronunciation

(hye droe KOE done & a seet a MIN oh fen)

U.S. Brand Names

Anexsia®; Bancap HC®; Ceta-Plus®; Co-Gesic®; hycet™; Lorcet® 10/650; Lorcet®-HD; Lorcet® Plus; Lortab®; Margesic® H; Maxidone™; Norco®; Stagesic®; Vicodin®; Vicodin® ES; Vicodin® HP; Zydone®

Synonyms

Acetaminophen and Hydrocodone

Generic Available

Yes

Use

Relief of moderate to severe pain

Use - Dental

Treatment of postoperative pain

Restrictions

C-III

Pregnancy Risk Factor

C/D (prolonged use or high doses near term)

Pregnancy Implications

Animal reproduction studies have not been conducted with this combination product. Opioid analgesics are considered FDA risk category D if used for prolonged periods or in large doses near term. Withdrawal symptoms may be observed in babies born to mothers taking opioids regularly during pregnancy. Respiratory depression may be observed in the newborn if opioids are given close to delivery.

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to hydrocodone, acetaminophen, or any component of the formulation; CNS depression; severe respiratory depression

Warnings/Precautions

Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (morphine, hydromorphone, levorphanol, oxycodone, oxymorphone); tolerance or drug dependence may result from extended use.

Respiratory depressant effects may be increased with head injuries. Use caution with acute abdominal conditions; clinical course may be obscured. Use caution with thyroid dysfunction, prostatic hyperplasia, hepatic or renal disease, and in the elderly. Causes sedation; caution must be used in performing tasks which require alertness (eg, operating machinery or driving).

Limit acetaminophen to <4 g/day. May cause severe hepatic toxicity in acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Use with caution in patients with alcoholic liver disease; consuming 3 alcoholic drinks/day may increase the risk of liver damage. Use caution in patients with known G6PD deficiency.

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, cardiac arrest, circulatory collapse, coma, hypotension

Central nervous system: anxiety, dizziness, drowsiness, dysphoria, euphoria, fear, lethargy, lightheadedness, malaise, mental clouding, mental impairment, mood changes, physiological dependence, sedation, somnolence, stupor

Dermatologic: Pruritus, rash

Endocrine & metabolic: Hypoglycemic coma

Gastrointestinal: Abdominal pain, constipation, gastric distress, heartburn, nausea, peptic ulcer, vomiting

Genitourinary: Ureteral spasm, urinary retention, vesical sphincter spasm

Hematologic: Agranulocytosis, bleeding time prolonged, hemolytic anemia, iron deficiency anemia, occult blood loss, thrombocytopenia

Hepatic: Hepatic necrosis, hepatitis

Neuromuscular & skeletal: Skeletal muscle rigidity

Otic: Hearing impairment or loss (chronic overdose)

Renal: Renal toxicity, renal tubular necrosis

Respiratory: Acute airway obstruction, apnea, dyspnea, respiratory depression (dose related)

Miscellaneous: Allergic reactions, clamminess, diaphoresis

Overdosage/Toxicology

Symptoms of overdose include hepatic necrosis, blood dyscrasias, and respiratory depression. Treatment consists of acetylcysteine 140 mg/kg orally (loading) followed by 70 mg/kg every 4 hours for 17 doses; therapy should be initiated based upon laboratory analysis suggesting a high probability for hepatotoxic potential. Naloxone, 2 mg I.V. with repeat administration as necessary up to a total of 10 mg, can also be used to reverse toxic effects of the opiate. Activated charcoal is effective at binding certain chemicals, and this is especially true for acetaminophen.

Drug Interactions

Hydrocodone: Substrate of CYP2D6 (major)

Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C8/9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Acetaminophen component: Refer to Acetaminophen monograph.

Hydrocodone component:

CYP2D6 inhibitors may decrease the effects of hydrocodone. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CNS depressants (including antianxiety agents, antihistamines, antipsychotics, narcotics): CNS depression is additive; dose adjustment may be needed

MAO inhibitors: May see increased effects of MAO inhibitor and hydrocodone.

Tricyclic antidepressants (TCAs): May see increased effects of TCA and hydrocodone.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression); consuming 3 alcoholic drinks/day may increase the risk of liver damage

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of excessive sedation).

Mechanism of Action

Hydrocodone, as with other narcotic (opiate) analgesics, blocks pain perception in the cerebral cortex by binding to specific receptor molecules (opiate receptors) within the neuronal membranes of synapses. This binding results in a decreased synaptic chemical transmission throughout the CNS thus inhibiting the flow of pain sensations into the higher centers. Mu and kappa are the two subtypes of the opiate receptor which hydrocodone binds to cause analgesia.

Acetaminophen inhibits the synthesis of prostaglandins in the CNS and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center.

Pharmacodynamics/Kinetics

Acetaminophen: See Acetaminophen monograph.

Hydrocodone:

Onset of action: Narcotic analgesic: 10-20 minutes

Duration: 4-8 hours

Distribution: Crosses placenta

Metabolism: Hepatic; O-demethylation; N-demethylation and 6-ketosteroid reduction

Half-life elimination: 3.3-4.4 hours

Excretion: Urine

Dosage

Oral (doses should be titrated to appropriate analgesic effect): Analgesic:

Children 2-13 years or <50 kg: Hydrocodone 0.135 mg/kg/dose every 4-6 hours; do not exceed 6 doses/day or the maximum recommended dose of acetaminophen

Children and Adults 50 kg: Average starting dose in opioid naive patients: Hydrocodone 5-10 mg 4 times/day; the dosage of acetaminophen should be limited to 4 g/day (and possibly less in patients with hepatic impairment or ethanol use).

Dosage ranges (based on specific product labeling): Hydrocodone 2.5-10 mg every 4-6 hours; maximum: 60 mg hydrocodone/day (maximum dose of hydrocodone may be limited by the acetaminophen content of specific product)

Elderly: Doses should be titrated to appropriate analgesic effect; 2.5-5 mg of the hydrocodone component every 4-6 hours. Do not exceed 4 g/day of acetaminophen.

Dosage adjustment in hepatic impairment: Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure

Patient Education

If self-administered, use exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. Take with food or milk. While using this medication, do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause dizziness, lightheadedness, confusion, or drowsiness (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); or nausea or vomiting (frequent mouth care, frequent sips of fluids, chewing gum, or sucking lozenges may help). Report chest pain or palpitations; persistent dizziness, shortness of breath, or respiratory difficulty; unusual bleeding or bruising; or unusual fatigue and weakness. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Nursing Implications

Observe patient for excessive sedation, respiratory depression

Anesthesia and Critical Care Concerns/Other Considerations

Doses of agent must be individualized according to degree of pain; commonly used in place of Tylenol® with Codeine; patients on this drug chronically should have liver function monitored secondary to acetaminophen in the product. Keep acetaminophen dose

4 g/day. Patients with chronic alcoholism, liver disease, or those who are fasting can develop severe hepatic disease even at therapeutic doses.

Cardiovascular Considerations

May cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dental Comment

Neither hydrocodone nor acetaminophen elicit anti-inflammatory effects. Because of addiction liability of opiate analgesics, the use of hydrocodone should be limited to 2-3 days postoperatively for treatment of dental pain. Nausea is the most common adverse effect seen after use in dental patients; sedation and constipation are second. Nausea elicited by narcotic analgesics is centrally mediated and the presence or absence of food will not affect the degree nor incidence of nausea.

Acetaminophen:

A study by Hylek, et al, suggested that the combination of acetaminophen with warfarin (Coumadin®) may cause enhanced anticoagulation. The following recommendations have been made by Hylek, et al, and supported by an editorial in JAMA by Bell.

Dose and duration of acetaminophen should be as low as possible, individualized and monitored

The study by Hylek reported the following:

For patients who reported taking the equivalent of at least 4 regular strength (325 mg) tablets for longer than a week, the odds of having an INR >6.0 were increased 10-fold above those not taking acetaminophen. Risk decreased with lower intakes of acetaminophen reaching a background level of risk at a dose of 6 or fewer 325 mg tablets per week.

Mental Health: Effects on Mental Status

Sedation is common; may cause confusion; may rarely cause hallucinations

Mental Health: Effects on Psychiatric Treatment

May result in loss of pain control when used in combination with SSRIs (especially paroxetine and fluoxetine); concurrent use with psychotropics may produce additive sedation

Dosage Forms

Capsule (Bancap HC®, Ceta-Plus®, Lorcet®-HD, Margesic® H, Stagesic®): Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

Elixir: Hydrocodone bitartrate 7.5 mg and acetaminophen 500 mg per 15 mL (480 mL)

Lortab®: Hydrocodone bitartrate 7.5 mg and acetaminophen 500 mg per 15 mL (480 mL) [contains alcohol 7%; tropical fruit punch flavor]

Solution, oral (hycet™): Hydrocodone bitartrate 7.5 mg and acetaminophen 325 mg per 15 mL (480 mL) [contains alcohol 7%; tropical fruit punch flavor]

Tablet:

Hydrocodone bitartrate 2.5 mg and acetaminophen 500 mg

Hydrocodone bitartrate 5 mg and acetaminophen 325 mg

Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 325 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 500 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 650 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 750 mg

Hydrocodone bitartrate 10 mg and acetaminophen 325 mg

Hydrocodone bitartrate 10 mg and acetaminophen 500 mg

Hydrocodone bitartrate 10 mg and acetaminophen 650 mg

Hydrocodone bitartrate 10 mg and acetaminophen 660 mg

Anexsia®:

5/500: Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

7.5/650: Hydrocodone bitartrate 7.5 mg and acetaminophen 650 mg

Co-Gesic® 5/500: Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

Lorcet® 10/650: Hydrocodone bitartrate 10 mg and acetaminophen 650 mg

Lorcet® Plus: Hydrocodone bitartrate 7.5 mg and acetaminophen 650 mg

Lortab®:

2.5/500: Hydrocodone bitartrate 2.5 mg and acetaminophen 500 mg

5/500: Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

7.5/500: Hydrocodone bitartrate 7.5 mg and acetaminophen 500 mg

10/500: Hydrocodone bitartrate 10 mg and acetaminophen 500 mg

Maxidone™: Hydrocodone bitartrate 10 mg and acetaminophen 750 mg

Norco®:

Hydrocodone bitartrate 5 mg and acetaminophen 325 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 325 mg

Hydrocodone bitartrate 10 mg and acetaminophen 325 mg

Vicodin®: Hydrocodone bitartrate 5 mg and acetaminophen 500 mg

Vicodin® ES: Hydrocodone bitartrate 7.5 mg and acetaminophen 750 mg

Vicodin® HP: Hydrocodone bitartrate 10 mg and acetaminophen 660 mg

Zydone®:

Hydrocodone bitartrate 5 mg and acetaminophen 400 mg

Hydrocodone bitartrate 7.5 mg and acetaminophen 400 mg

Hydrocodone bitartrate 10 mg and acetaminophen 400 mg

References

"Acute Pain Management in Infants, Children, and Adolescents: Operative or Medical Procedures and Trauma (Quick Reference Guide for Clinicians)," Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 92-0020. February 1992.

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Carpenter, RL, "Optimizing Postoperative Pain Management," Am Fam Physician , 1997, 56(3):835-44, 847-50. Available at http://www.aafp.org/afp/970901ap/painmgmt.html. Accessed May 4, 2004.

Dionne RA, "New Approaches to Preventing and Treating Postoperative Pain," J Am Dent Assoc , 1992, 123(6):26-34.

Gobetti JP, "Controlling Dental Pain," J Am Dent Assoc , 1992, 123(6):47-52.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

"Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain," 5th ed, Glenview, IL: American Pain Society, 2003.

Rathmell JP, Viscomi CM, and Ashburn MA, "Management of Nonobstetric Pain During Pregnancy and Lactation," Anesth Analg , 1997, 85(5):1074-87.

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