Dosing & Uses
Dosage Forms & Strengths
capsule, extended-release (Zohydro ER): Schedule II
- Abuse-deterrent product (BeadTek technology)
- 10mg
- 15mg
- 20mg
- 30mg
- 40mg
- 50mg
tablet, extended-release (Hysingla ER): Schedule II
- Abuse-deterrent product (RESISTEC)
- 20mg
- 30mg
- 40mg
- 60mg
- 80mg
- 100mg
- 120mg
tablet, extended-release (Vantrela ER): Schedule II
- Abuse-deterrent product
- 15mg
- 30mg
- 45mg
- 60mg
- 90mg
Chronic Pain
Indicated for the management of pain severe enough to require daily, around-the-clock, long-term treatment and for which alternative treatment options are inadequate
Initial dosing
- Should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain
- Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse
- Monitor patients closely for respiratory depression, especially within the first 24-72 hr of initiating therapy
Opioid naïve or first opioid analgesic
- Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
- Zohydro ER
- Zohydro ER: 10 mg PO q12hr initially
- A single dose of Zohydro ER >40 mg, Zohydro ER 50 mg capsules, or a total daily dose greater than 80 mg are only for patients in whom tolerance to an opioid of comparable potency is established
- Hysingla ER
- Hysingla ER: Administer once daily as 20 mg PO q24h initially
- Daily doses of Hysingla ER ≥80 mg/day are only for use in opioid tolerant patients
- Vantrela ER
- Vantrela ER: 15 mg PO q12hr initially
- 90-mg tablets, a single dose >60 mg, or a total daily dose >120 mg are only for use in opioid tolerant patients
Opioid tolerant
- See prescribing information for conversion table from existing opioid analgesic to hydrocodone extended-release
- Opioid tolerance definition
- Defined as patients who are receiving the following opioids (or an equianalgesic dose of another opioid) for 1 week or longer
- morphine 60 mg/day PO
- transdermal fentanyl 25 mcg/hr
- oxycodone 30 mg/day
- hydromorphone 8 mg/day PO
- oxymorphone 25 mg/day PO
Titration, maintenance, discontinuation
- Zohydro ER: Increase by increments of 10 mg q12hr q3-7d as needed to achieve adequate analgesia
- Hysingla ER: Increase by increments of 10-20 mg/day q3-5d as needed to achieve adequate analgesia
- Vantrela ER: May increase to the next higher dose q3-7d as needed to achieve adequate analgesia
- Assess pain frequently for toxicity, breakthrough pain, or need for short-acting rescue analgesia
- Discontinue by a gradual downward titration every 2-4 days; do not withdraw abruptly
Dosage Modifications
Hepatic impairment
- Mild-to-moderate (Vantrela ER): Initiate therapy with one-half of the recommended initial dose and titrate carefully; use alternative analgesia for patients requiring <15 mg
- Severe: Initiate with lowest dose, 10 mg (Zohydro ER) or 50% of initial dose (Hysingla ER) and monitor closely for signs of respiratory depression and excessive sedation
Renal impairment
- Patients with renal impairment may have higher plasma concentrations than those with normal function
- Moderate-to-severe and ESRD: Initiate therapy with a low initial dose (Zohydro ER) or 50% of initial dose (Hysingla ER, Vantrela ER) and monitor closely for respiratory depression and sedation
Dosing Considerations
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve use for patients for whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
Not indicated for acute pain or as an as-needed (prn) analgesic
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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%)
Warnings
Black Box Warnings
Addiction, abuse, and misuse
- Long-acting hydrocodone exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death
- Assess each patient’s risk prior to prescribing, and monitor all patients regularly for the development of these behaviors or conditions
Life-threatening respiratory depression
- Serious, life-threatening, or fatal respiratory depression may occur
- Monitor for respiratory depression, especially during initiation or following a dose increase
- Instruct patients to swallow capsules/tablets whole; crushing, chewing, or dissolving the extended-release dosage forms can cause rapid release and absorption of a potentially fatal dose of hydrocodone
Accidental exposure
- Accidental consumption of even 1 dose of hydrocodone, especially by children, can result in a fatal overdose of hydrocodone
Neonatal opioid withdrawal syndrome
- For patients who require opioid therapy while pregnant, be aware that infants may require treatment for neonatal opioid withdrawal syndrome
- Prolonged maternal use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening and requires management according to protocols developed by neonatology experts
Interaction with CNS depressants
- Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
- Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate
- Limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation
- Coingestion of Zohydro ER with alcohol may increase hydrocodone plasma levels and result in a potentially fatal overdose (alters release of drug from capsule)
Interaction with CYP3A4 inhibitors
- Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone from hydrocodone ER
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
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
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 & Lactation
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.
Pharmacology
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
Administration
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
Images
Patient Handout
Formulary
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