March 23, 2017
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Zohydro ER

"The FDA is spelling out this and other precautions in class-wide boxed warnings on the labels of opioid painkillers such as oxycodone, prescription cough medicine containing opioids, benzodiazepines, which include alprazolam (Xanax, Pharma"...

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Zohydro ER

Warnings
Precautions

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. Because extended-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 [see Drug Abuse And Dependence].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ZOHYDRO ER. 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 and 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 opioids such as ZOHYDRO ER, but use in such patients necessitates intensive counseling about the risks and proper use of ZOHYDRO ER along with 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 Drug Abuse And Dependence, OVERDOSE].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ZOHYDRO ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PATIENT INFORMATION]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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 OVERDOSE]. 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 dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ZOHYDRO ER.

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 ingestion 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

Prolonged use of ZOHYDRO ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and mange accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. [see Use In Specific Populations, PATIENT INFORMATION].

Risks From Concomitant Use Or Discontinuation Of Cytochrome P450 3A4 Inhibitors And Inducers

Concomitant use of ZOHYDRO ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Life-Threatening Respiratory Depression], particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ZOHYDRO ER-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using ZOHYDRO ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ZOHYDRO ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved [see DRUG INTERACTIONS].

Concomitant use of ZOHYDRO ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using ZOHYDRO ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see DRUG INTERACTIONS].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ZOHYDRO ER 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.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see DRUG INTERACTIONS].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum duration of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when ZOHYDRO ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see DRUG INTERACTIONS and Patient Counseling Information].

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].

Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients.

The use of ZOHYDRO ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients With Chronic Pulmonary Disease

ZOHYDRO ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ZOHYDRO ER.

Elderly, Cachectic, Or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particular when initiating and titrating ZOHYDRO ER and when ZOHYDRO ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the 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. The information available does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

ZOHYDRO ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see DRUG INTERACTIONS]. Monitor these patients for signs of hypotension after initiating or titrating the dosage 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.

Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ZOHYDRO ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ZOHYDRO ER.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ZOHYDRO ER in patients with impaired consciousness or coma.

Risks Of Use In Patients With Gastrointestinal Conditions

ZOHYDRO ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Hydrocodone in ZOHYDRO ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening of symptoms.

Increased Risk Of Seizures In Patients With Seizure Disorders

The hydrocodone in ZOHYDRO ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ZOHYDRO ER therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ZOHYDRO ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see DRUG INTERACTIONS].

When discontinuing ZOHYDRO ER, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue ZOHYDRO ER [see Drug Abuse And Dependence].

Risks Of 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. [see CLINICAL PHARMACOLOGY, PATIENT INFORMATION].

Patient Counseling Information

Advise the patient to read the FDA approved patient labeling (Medication Guide).

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 dosage is increased, and that it can occur even at recommended dosages [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by 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.

Interaction With Benzodiazepines And Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if ZOHYDRO ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with ZOHYDRO ER [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see DRUG INTERACTIONS].

MAOI Interaction

Inform patients to avoid taking ZOHYDRO ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking HYSINGLA ER [see DRUG INTERACTIONS].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS AND PRECAUTIONS].

Important Administration Instructions

[see DOSAGE AND ADMINISTRATION]

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

  • Use ZOHYDRO ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see WARNINGS AND PRECAUTIONS].
  • Swallow ZOHYDRO ER capsules whole.
  • Do not crush, chew, or dissolve the capsule or its contents.
  • 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 [see WARNINGS AND PRECAUTIONS]).

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 [see CONTRAINDICATIONS, ADVERSE REACTIONS].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that ZOHYDRO ER can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use In Specific Populations].

Lactation

Advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER [see Use In Specific Populations].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS, Use In Specific Populations].

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. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated dose administration. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS AND PRECAUTIONS].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Instruct patients to monitor their analgesic response following the use of strong laxatives and to contact the prescriber if changes are noted [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].

Disposal of Unused ZOHYDRO ER

Advise patients to flush the unused capsules down the toilet when ZOHYDRO ER is no longer needed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Hydrocodone was evaluated for carcinogenic potential in rats and mice. In a two-year bioassay in rats, doses up to 30 mg/kg in males and 100 mg/kg in females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.1 times and 0.6 times for males and females, respectively, the human hydrocodone dose of 100 mg/day based on AUC exposure comparisons). In a two-year bioassay in mice, doses up to 100 mg/kg in males and females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.8 times and 1.5 times, respectively, the human hydrocodone dose of 100 mg/day based on AUC exposure comparisons.

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. No evidence of DNA damage was found in an in vivo comet assay in mouse liver. 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 decreased 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

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS]. There are no studies of ZOHYDRO ER use in pregnant women. Rats administered oral hydrocodone during gestation and lactation showed increases in stillborn pups and decreases in pup survival at doses equivalent to the human dose of 100 mg/day. Reduced nursing behavior and decreased body weights were observed at 2 times the human dose. Reduced fetal weights were observed in rabbits administered hydrocodone during the period of organogenesis at doses equivalent to 5 times the human dose of 100 mg/day. In this study, increases in the number of umbilical hernias, irregularly shaped bones, and delays in fetal skeletal maturation were observed at doses 15 times the human dose of 100 mg/day. No fetal malformations were observed in animal reproduction studies with oral administration of hydrocodone bitartrate during organogenesis in rats and rabbits at doses approximately 2 and 10 times a human dose of 100 mg/day, respectively [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the newborn and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see WARNINGS AND PRECAUTIONS].

Labor or Delivery

Opioids cross the 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 the neonate. ZOHYDRO ER is not recommended for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including ZOHYDRO ER, 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.

Data

Animal Data

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). Maternal toxicity was evident at this dose (decreased body weight). In addition, oral hydrocodone bitartrate reduced fetal weights at doses greater than or equal to 25 mg/kg/day (equivalent to approximately 5 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). 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 which correlated with decreased body weight/body weight gain and food consumption in male pups. Minimal maternal toxicity was evident at 25 mg/kg (decreased body weight).

Lactation

Risk Summary

Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with extended-release hydrocodone, including ZOHYDRO ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER.

Clinical Considerations

Monitor infants exposed to ZOHYDRO ER 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.

Females And Males Of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

In rat fertility studies, no effects on male fertility were observed with hydrocodone at doses equivalent to 10 times the human dose of 100 mg/day, however, decreases in the weight of male reproductive organs were observed in all treated groups at doses equivalent to 2.4 times the human dose of 100 mg/day and above. Reductions in female fertility indices were observed at doses of hydrocodone equivalent to 2 times the human dose of 100 mg/day and above. These changes are attributed to a hydrocodone-mediated decrease in prolactin levels in the rat. Unique to rodents, prolactin is required for normal estrous cycling and the effects on fertility observed in this study are most likely rodent-specific and not believed to be clinically relevant [see Nonclinical Toxicology].

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. Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ZOHYDRO ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see WARNINGS AND PRECAUTIONS].

Hydrocodone is known to be substantially secreted by the kidney and the risk adverse reactions to this drug may be greater in patients with impaired renal function. 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.

Hepatic Impairment

No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see CLINICAL PHARMACOLOGY]. Therefore, a dosage reduction is recommended for patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION]. Monitor patients with severe hepatic impairment closely for respiratory depression, sedation, and hypotension [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 respiratory depression, sedation, and hypotension [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/6/2017

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Precautions

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