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Zohydro ER

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Zohydro ER

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Addiction, Abuse, and Misuse

Zohydro ER contains hydrocodone, a Schedule II controlled substance. As an opioid, Zohydro ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. As modified-release products such as Zohydro ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Zohydro ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Zohydro ER, and monitor all patients receiving Zohydro ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Zohydro ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Zohydro ER, but use in such patients necessitates intensive counseling about the risks and proper use of Zohydro ER along within intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Zohydro ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see OVERDOSAGE].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Zohydro ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with Zohydro ER and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of Zohydro ER are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the Zohydro ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental consumption of even one dose of Zohydro ER, especially by children, can result in respiratory depression and death due to an 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 of Zohydro ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and requires management according to protocols developed by neonatology experts.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Interactions with CNS Depressants

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on Zohydro ER therapy. The co-ingestion of alcohol with Zohydro ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see CLINICAL PHARMACOLOGY].

Hypotension, profound sedation, coma, respiratory depression, and death may result if Zohydro ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

When considering the use of Zohydro ER in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Zohydro ER is made, start with a lower Zohydro ER dose than usual (ie, 20-30% less), monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant. [see DRUG INTERACTIONS].

Use in Elderly, Cachectic, and Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating Zohydro ER and when Zohydro ER is given concomitantly with other drugs that depress respiration.

Use in Patients with Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with Zohydro ER, as in these patients, even usual therapeutic doses of Zohydro ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

Use in Patients with Head Injury and Increased Intracranial Pressure

In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on papillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury.

Avoid the use of Zohydro ER in patients with impaired consciousness or coma.

Hypotensive Effect

Zohydro ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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. Monitor these patients for signs of hypotension after initiating or titrating the dose of Zohydro ER. In patients with circulatory shock, Zohydro ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Zohydro ER in patients with circulatory shock.

Gastrointestinal Effects

Zohydro ER is contraindicated in patients with known or suspected paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of Zohydro ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the Sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.

Cytochrome P450 CYP3A4 Inhibitors and Inducers

Since the CYP3A4 isoenzyme plays a major role in the metabolism of Zohydro ER, drugs that alter CYP3A4 activity may cause changes in clearance of hydrocodone which could lead to changes in hydrocodone plasma concentrations.

The expected clinical results with CYP3A4 inhibitors is an increase in hydrocodone plasma concentrations and possibly increased or prolonged opioid effects, which could be more pronounced with concomitant use of CYP CYP3A4 inhibitors. The expected clinical results with CYP3A4 inducers is a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone.

If co-administration is necessary, monitor patients closely who are currently taking, or discontinuing, CYP3A4 inhibitors or CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see DRUG INTERACTIONS].

Driving and Operating Machinery

Zohydro ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Zohydro ER and know how they will react to the medication.

Interaction with Mixed Agonist/Antagonist Opioid Analgesics

Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including Zohydro ER. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Information for Patients and Caregivers

Addiction, Abuse, and Misuse

Inform patients that the use of Zohydro ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share Zohydro ER with others and to take steps to protect Zohydro ER from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Zohydro ER or when the dose is increased, and that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.

Accidental Consumption

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store Zohydro ER securely and to dispose of unused Zohydro ER by flushing the Capsules down the toilet.

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that chronic use of Zohydro ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening [see WARNINGS AND PRECAUTIONS].

Interaction with Alcohol and other CNS Depressants

Inform patients that the concomitant use of alcohol with Zohydro ER can increase the risk of life-threatening respiratory depression. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the counter products that contain alcohol, during treatment with Zohydro ER. The co-ingestion of alcohol with Zohydro ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Inform patients that potentially serious additive effects may occur if Zohydro ER is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.

Important Administration Instructions

Instruct patients how to properly take Zohydro ER, including the following:

  • The capsules must be swallowed whole and must not be chewed, crushed, or dissolved. Taking chewed, crushed or dissolved Zohydro ER capsules or contents can lead to rapid release and absorption of a potentially fatal dose of hydrocodone.
  • Use Zohydro ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
  • Contact prescriber if pain control is not adequate or if there are adverse reactions occurring during therapy
  • Do not discontinue Zohydro ER without first discussing the need for a tapering regimen with the prescriber
Hypotension

Inform patients that Zohydro ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Driving or Operating Heavy Machinery

Inform patients that Zohydro ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Zohydro ER. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that Zohydro ER can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of hydrocodone have not been conducted.

Mutagenesis

Hydrocodone bitartrate was genotoxic in an in vitro chromosomal aberration assay in the presence of metabolic activation. No evidence of clastogenicity was observed in this assay in the absence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Impairment of Fertility

In a fertility study, rats were administered once daily by oral gavage the vehicle or hydrocodone bitartrate at doses of 25, 75, and 100 mg/kg/day (equivalent to approximately 2, 7, and 10 times an adult human dose of 100 mg/day, on a mg/m² basis). Male and female rats were dosed before cohabitation (up to 28 days), during the cohabitation and until gestation day 7 (females) or necropsy (males; 2-3 weeks post-cohabitation). Hydrocodone bitartrate did not affect reproductive function in males, although the weights of male reproductive organs were decreases at all doses. Doses of 25 mg/kg/day and greater in females reduced the rate at which females became pregnant which correlated with suppression of estrous cyclicity, thought to be due to increases in prolactin. In hydrocodone bitartrate-treated rats that became pregnant, at 25 mg/kg early embryonic development was unaffected (approximately 2 times the adult human daily dose of 100 mg/day on a mg/m² basis). In rats, prolactin plays a unique role in the estrous cycle and the clinical relevance of the female rat reproductive findings is uncertain.

Use In Specific Populations

Pregnancy

The safety of using Zohydro ER in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of Zohydro ER in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child.

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS].

Teratogenic Effects - Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Zohydro ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral doses of hydrocodone bitartrate up to 25 mg/kg/day in rats and 50 mg/kg/day in rabbits, equivalent to 2 and 10 times an adult human dose of 100 mg/day, respectively on a mg/m² basis, did not result in any fetal malformations. 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). In addition, oral hydrocodone bitartrate reduced fetal weights at doses greater than or equal to 25 mg/kg/day (equivalent to approximately 2 times an adult human dose of 100 mg/day on a mg/m² basis). Delays in fetal skeletal maturation (reduced ossification of hyoid bodies and xiphoid bones) were seen following dosing with 75 mg/kg/day (a dose equivalent to 15 times an adult human dose of 100 mg/day on a mg/m² basis).

Hydrocodone bitartrate administered orally to female rats at oral doses of 10 and 25 mg/kg/day during gestation and lactation resulted in pups which were noted as cold to touch and caused a reduction in fetal viability (increases in the number of stillborn pups and/or pups dying postpartum), and pup weight. The doses causing these effects were equivalent to approximately 1 and 2.4 times an adult human dose of 100 mg/day, on a mg/m² basis. Nursing was reduced in pups of mothers administered 25 mg/kg/day. Decreased body weight/body weight gain and food consumption were seen in male pups delivered by mothers given 25 mg/kg/day.

Labor and Delivery

Opioids cross the placenta and may produce respiratory depression in neonates. Zohydro ER is not for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions which temporarily reduce the 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.

Nursing Mothers

Low concentrations of hydrocodone and hydromorphone in breast milk of nursing mothers using hydrocodone for postpartum pain control have been reported in published literature.a Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue Zohydro ER, taking into account the importance of the drug to the mother. Infants exposed to Zohydro ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.a

Pediatric Use

The safety and effectiveness of Zohydro ER in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Clinical studies of Zohydro ER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of the concomitant disease or other drug therapy.

Hydrocodone is known to be substantially secreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and observed closely for adverse events such as respiratory depression.

Hepatic Impairment

Patients with hepatic impairment may have higher plasma concentrations than those with normal function. No adjustment in starting dose with Zohydro ER is required in patients with mild or moderate hepatic impairment; however, in patients with severe hepatic impairment, start with the lowest dose, 10 mg. Monitor these patients closely for adverse events such as respiratory depression. [see CLINICAL PHARMACOLOGY].

Renal Impairment

Patients with renal impairment have higher plasma concentrations than those with normal function. Use a low initial dose of Zohydro ER in patients with renal impairment and monitor closely for adverse events such as respiratory depression [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 11/7/2013
This monograph has been modified to include the generic and brand name in many instances.

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