hydrocodone/acetaminophen (Rx)

Frequency Not Defined

Biliary tract spasm

Hallucinations

Circulatory collapse

Histamine release

Physical and psychological dependence with prolonged use

Urinary tract spasm

Bradycardia

Cardiac arrest

Confusion

Decreased urination

Dizziness

Drowsiness

Dyspnea

Fatigue

Hypotension

Coma

Dysphoria

Euphoria

Lethargy

Lightheadedness

Mood changes

Stupor

Mental clouding

Nausea

Sedation

Vomiting

Weakness

Peptic ulcer

Agranulocytosis

Hemolytic anemia

Hepatic necrosis

Respiratory depression

Contraindications

Hypersensitivity

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to hydrocodone, ibuprofen, or any components of the drug product

Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity

Cautions

Do not prescribe for acute pain or as needed (prn) pain relief; only for severe chronic pain requiring continuous, around-the-clock opioid analgesia

Hydrocodone is an opioid agonist and a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone

Coadministration with other CNS depressants may cause profound sedation, respiratory depression, and death; if coadministration is required, consider dose reduction of 1 or both drugs

Monitor carefully in elderly, cachectic, debilitated patients, and those with chronic pulmonary disease because of increased risk for life-threatening respiratory depression

Monitor patients with head injury or increased ICP for sedation and respiratory depression; avoid use in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention

May cause severe hypotension, including orthostatic hypotension and syncope; added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone

Coadministration with CYP3A4 inhibitors may increase hydrocodone systemic exposure and result in toxicity; if co-administration with CYP3A4 necessary, monitor patients closely who are currently taking, or discontinuing, CYP3A4 inhibitors or inducers; evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved

Caution must be used with potentially hazardous activities

Avoid use of mixed agonist/antagonist analgesics (ie, pentazocine, nalbuphine, butorphanol) when taking full opioid agonist analgesics

Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

May cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

Use caution in debilitated patients, drug abuse history, elderly patients, G6PD deficiency, head injury, hepatic dysfunction, hypothyroidism, impaired pulmonary function, increased intracranial pressure, toxic psychosis, renal dysfunction

Hydrocodone may obscure diagnosis or clinical symptoms of acute abdominal conditions

Acetaminophen associated with cases of acute liver failure, at times resulting in liver transplantation or death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)

Acetaminophen associated with rare, but serious skin reactions that can be fatal; these reactions include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP); symptoms may include skin redness, blisters and rash

Caution and awareness are necessary regarding misuse, abuse, or diversion

Constipation may occur; take measures to prevent constipation, such as, administering stool softener and increasing fiber

Chronic alcoholics should limit acetaminophen intake to <2 g/day

Use caution in morbidly obese patients

Use hydrocodone with caution in patients with prostatic hyperplasia and/or urinary stricture

Use caution in patients with seizure disorders

Pregnancy

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome; there are no available data in pregnant women to inform a drug associated risk for major birth defects and miscarriage; published studies with morphine use during pregnancy have not reported a clear association with opioids and major birth defects

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

Lactation

Drug is present in breast milk; published lactation studies report variable concentrations of drug in breast milk with administration of immediate-release formulation to nursing mothers in early postpartum period

The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy; capsules and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Monitor infants exposed to drug through breast milk for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast- feeding is stopped

Mechanism of Action

Acetaminophen: Acts on the hypothalamus to produce antipyresis; inhibits prostaglandin synthetase

Hydrocodone: Opioid analgesic agonist; blocks pain perception in the cerebral cortex; decreases synaptic chemical transmission throughout the CNS, which in turn inhibits pain sensation into higher centers

Metabolism

Acetaminophen: Primarily undergoes glucuronidation and sulfate conjugation; however, a small percentage is metabolized via CYP2E1 and CYP1A2 to a hepatotoxic metabolite

Hydrocodone: Metabolized in the liver to the active opioid hydromorphone via CYP2D6; also by O-demethylation, N-demethylation, and 6 ketosteroid reduction

CYP2D6 poor metabolizers may not achieve adequate analgesia

Ultrarapid metabolizers (up to 7% of whites and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion

Metabolites (acetaminophen): N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI; further metabolized via conjugation with glutathione

Elimination