hydrocodone (Rx)

>10%

Zohydro ER

• Constipation (8-11%)

1-10%

Zohydro ER

• Nausea (7-10%)
• Vomiting (3-5%)
• Somnolence (1-5%)
• UTI (1-5%)
• Headache (4%)
• Fatigue (1-4%)
• Back pain (1-4%)
• Dry mouth (3%)
• Pruritus (3%)
• Tremor (3%)
• Dizziness (2-3%)
• Peripheral edema (1-3%)
• URI infection (1-3%)
• Muscle spasms (1-3%)

1-10% (Hysingla ER)

• Nausea (8%)
• Constipation (3%)
• Vomiting (6%)
• Dizziness (3%)
• Insomnia (3%)
• Influenza (3%)
• Decreased appetite (2%)
• Headache (2%)
• Tinnitus (2%)
• Somnolence (1%)
• Fatigue (1%)

Contraindications

Hypersensitivity

Significant respiratory depression

Acute or severe bronchial asthma or hypercarbia

Suspected paralytic ileus

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

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

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

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

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

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

Do not abruptly discontinue therapy in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

Hydrocodone ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings; monitor patients with a history of seizure disorders for worsened seizure control during hydrocodone ER therapy

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

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

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

Labor or delivery

• Opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in neonate; drug is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions that temporarily reduce strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Mu opioid receptor agonist; interacts with other opioid receptors at higher doses; activates opioid receptors at sites in the peri-aquaductal and peri-ventricular gray matter, the ventro-medial medulla and the spinal cord to produce analgesia

Also elicits euphoric, respiratory depressant, and physiologic dependence properties of mu receptors within the CNS

Absorption

Zohydro ER

• Extended-release provided by spheroidal oral drug absorption system (SODAS) technology (ie, multi-particulate formulation of coated carrier beads in hard gelatin capsules); contains rate-controlling polymers and drug release by diffusion
• Peak plasma time: 5 hr
• Peak plasma concentration increased by 27% when administered with a high fat meal

Hysingla ER

• Peak plasma time (mean): 14-16 hr (range 6-30 hr)
• AUC and peak plasma concentration increase linearly with doses
• Peak plasma concentration (median): 14.6-110 ng/mL
• AUC (median): 284-1787 ng•hr/mL
• Peak plasma concentration increased by 20% when administered with a high fat meal

Vantrela ER

• Peak plasma time: 8 hr (single dose); 5 hr (steady-state)
• Peak plasma concentration (single doses): 12.6-62.5 ng/mL
• AUC (single doses): 199-1189 ng•hr/mL

Distribution

Protein bound: ~19% (Zohydro ER); 36% (Hysingla ER); 19-45% (Vantrela ER)

Vd: 402 L (Hysingla ER); 1300-1400 L (Vantrela ER)

Metabolism

Metabolized in liver by CYP2D6 (minor) via O-demethylation, CYP3A4 (major) via N-demethylation, and 6-keto reduction

Metabolites: CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway; CYP2D6 to hydromorphone (active metabolite with higher binding capacity to mu opioid receptor)

Elimination

Half-life: 8 hr (Zohydro ER); 7-9 hr (Hysingla ER); 11-12 hr (Vantrela ER)

Excretion: Primarily by kidneys

Oral Administration

Swallow capsule/tablet whole; crushing, chewing, or dissolving the extended-release dosage form will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

Must be taken whole, 1 capsule/tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth