Dosing and uses of Zohydro ER, Hysingla ER (hydrocodone)
Adult dosage forms and 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
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: 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: 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
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
- Assess pain frequently for toxicity, breakthrough pain, or need for rescue analgesia
- Discontinue by a gradual downward titration every 2-4 days; do not withdraw abruptly
Dosage modifications
Hepatic impairment
- Mild-to-moderate: No adjustment to starting dose required
- 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
- Initiate therapy with a low initial dose (Zohydro ER) or 50% of initial dose (Hysingla 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
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Zohydro ER, Hysingla ER (hydrocodone) adverse (side) 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 alcohoL
- Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking hydrocodone (increased CNS depression)
- 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
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
Prolonged gastric obstruction may occur
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
Pregnancy and lactation
Pregnancy category: C
Fetuses of rabbits administered oral doses of 75 mg/kg/day hydrocodone bitartrate (15 times an adult human dose of 100 mg/day on a mg/m² basis) during the period of organogenesis exhibited an increased number of malformations consisting of umbilical hernia, and irregularly shaped bones (ulna, femur, tibia and/or fibula)
Lactation: Low concentrations of hydrocodone and hydromorphone in human breast milk of nursing mothers using hydrocodone for postpartum pain control have been reported in published literature
Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrocodone, taking into account the importance of the drug to the mother
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 of Zohydro ER, Hysingla ER (hydrocodone)
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
Distribution
Protein bound: ~19% (Zohydro ER); 36% (Hysingla ER)
Vd: 402 L (Hysingla 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)
Excretion: Primarily by kidneys
