2.1 Initial Dosing 

ZOHYDRO ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

ZOHYDRO ER 50 mg capsules, a single dose of ZOHYDRO ER greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.    

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 [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with ZOHYDRO ER [see Warnings and Precautions (5.2)].

ZOHYDRO ER must be taken whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving the pellets in ZOHYDRO ER capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions (5.1)]. 

Use of ZOHYDRO ER as the First Opioid Analgesic
Initiate treatment with ZOHYDRO ER with one 10 mg capsule every 12 hours. 

Use of ZOHYDRO ER in Patients Who Are Not Opioid Tolerant 
The starting dose for patients who are not opioid tolerant is ZOHYDRO ER 10 mg orally every 12 hours.  Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. 

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression. 

Conversion from Other Oral Opioids to ZOHYDRO ER
Discontinue all other around-the-clock opioid drugs when ZOHYDRO ER therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24‑hour oral hydrocodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone requirements which could result in adverse reactions. In a ZOHYDRO ER clinical trial with an open label titration period, patients were converted from their prior opioid to ZOHYDRO ER using Table 1 as a guide for the initial ZOHYDRO ER dose.

Consider the following when using the information in Table 1:

• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to ZOHYDRO ER.  
• The table cannot be used to convert from ZOHYDRO ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.

To calculate the estimated daily ZOHYDRO ER dose using Table 1: 

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours.
• For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain approximate total hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. 

Always round the dose down, if necessary, to the appropriate ZOHYDRO ER strength(s) available.

Example conversion from a single opioid to ZOHYDRO ER

Step 1: Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone.

Step 2: Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone x 2 = 60 mg of oral hydrocodone daily. The daily dose should then be divided in half for administration every 12 hours. 

Step 3: Calculate the approximate starting dose which is 30 mg ZOHYDRO ER every 12 hours. Round down, if necessary, to the appropriate ZOHYDRO ER capsule strengths available. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to ZOHYDRO ER.

The dose of ZOHYDRO ER can be gradually adjusted preferably at increments of 10 mg every 12 hours every 3 to 7 days, until adequate pain relief and acceptable adverse reactions have been achieved.

Conversion from Methadone to ZOHYDRO ER
Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.

Conversion from Transdermal Fentanyl to ZOHYDRO ER
ZOHYDRO ER treatment can be initiated 18 hours following the removal of the transdermal fentanyl patch. Although there has been no systematic assessment of such conversion, a conservative hydrocodone dose, approximately 10 mg every 12 hours of ZOHYDRO ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to ZOHYDRO ER, as there is limited documented experience with this conversion.

2.2 Titration and Maintenance of Therapy

Individually titrate ZOHYDRO ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving ZOHYDRO ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics. Patients who experience breakthrough pain may require a dose increase of ZOHYDRO ER, or may need a rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain while adjusting the ZOHYDRO ER dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, ZOHYDRO ER dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days. If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of ZOHYDRO ER

When a patient no longer requires therapy with ZOHYDRO ER, use a gradual downward titration of the dose every 2 to 4 days to prevent signs and symptoms of withdrawal in the physically-dependent patient. During the Phase 3 study, the following taper schedule was utilized for patients assigned to placebo in the treatment phase of the study (Table 2):

*q12h = every 12 hours

Doses above 100 mg every 12 hours (q12h) were not studied in the Phase 3 trial. For patients exceeding 100 mg q12h use a gradual downward titration of the dose every 2 to 4 days. Patients should be monitored closely for signs and symptoms of opioid withdrawal which may indicate a need to taper more slowly. Do not abruptly discontinue ZOHYDRO ER.

2.4 Administration of ZOHYDRO ER

Instruct patients to swallow ZOHYDRO ER capsules whole. The pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.1)].

2.5 Hepatic Impairment

Patients with hepatic impairment may have higher plasma concentrations of hydrocodone 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 every 12 hours. Monitor these patients closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)].

2.6 Renal Impairment

Patients with renal impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with a low initial dose of ZOHYDRO ER in patients with renal impairment and monitor closely for respiratory depression and sedation [see Clinical Pharmacology (12.3)].

5.1 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 (9)]. 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 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 Overdosage (10)].

Opioid agonists such as ZOHYDRO ER 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 Counseling Information (17)]. 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.

5.2 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 (10)]. 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 (2)]. 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.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged 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 if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available 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.

5.4 Interactions with Central Nervous System 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 (12.3)].

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 of 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 (i.e., 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 (7.2)].

5.5 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 [see Warnings and Precautions (5.2)].

5.6 Use in Patients with Chronic Pulmonary Disease

Monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting 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 [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible.

5.7 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.

5.8 Use in Patients with Head Injury and Increased Intracranial Pressure

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

5.9 Use in Patients with Gastrointestinal Conditions

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.

5.10 Use in Patients with Convulsive or Seizure Disorders

The hydrocodone in ZOHYDRO 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 ZOHYDRO ER therapy.

5.11 Avoidance of Withdrawal

Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agoinist (buprenorphine) analgesics 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 and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4)]

5.12 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.

5.13 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. 

Inhibition of CYP3A4 activity by its inhibitors 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 effects. 

CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to 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 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZOHYDRO ER was evaluated in a total of 1,148 subjects in Phase 3 clinical trials.

Table 3 lists the most frequently occurring adverse reactions occurring at a greater frequency than placebo from the placebo-controlled trial in subjects with moderate-to-severe chronic lower back pain.

The common (≥1% to <10%) adverse drug reactions reported at least once by subjects treated with ZOHYDRO ER in the Phase 3 clinical trials and not represented in Table 3 were:

Gastrointestinal Disorders: abdominal discomfort, abdominal pain, gastroesophageal reflux disease
General Disorders and Administration Site Conditions: non-cardiac chest pain, pain, peripheral edema, pyrexia
Injury, Poisoning and Procedural Complications: contusion, fall, foot fracture, joint injury, joint sprain, muscle strain, skin laceration
Investigations: increased blood cholesterol, increased gamma-glutamyltransferase
Metabolism and Nutrition Disorders: dehydration, hypokalemia
Musculoskeletal and Connective Tissue Disorders: arthralgia, musculoskeletal pain, myalgia, neck pain, osteoarthritis, pain in extremity
Nervous System Disorders: lethargy, migraine, paresthesia
Psychiatric Disorders: anxiety, depression, insomnia
Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea
Skin and Subcutaneous Tissue Disorders: hyperhidrosis, night sweats, rash
Vascular Disorders: hot flush

7.1 Alcohol

Concomitant use of alcohol with ZOHYDRO ER can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on ZOHYDRO ER therapy [see Clinical Pharmacology (12.3)].

7.2 CNS Depressants

The concomitant use of ZOHYDRO ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, can increase the risk of respiratory depression, profound sedation, coma, or death. Monitor patients receiving CNS depressants and ZOHYDRO ER for signs of respiratory depression, sedation, and hypotension.

When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.1) and Warnings and Precautions (5.4)].

7.3 Drugs Affecting Cytochrome P450 Isoenzymes

Inhibitors of CYP3A4 and 2D6
Because the CYP3A4 isoenzyme plays a major role in the metabolism of hydrocodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of hydrocodone which could lead to an increase in hydrocodone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with ZOHYDRO ER is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].

Inducers of CYP3A4
Cytochrome P450 3A4 inducers may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration with ZOHYDRO ER is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].

After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see Clinical Pharmacology (12.3)].

7.4 Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of hydrocodone or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving ZOHYDRO ER.

7.5 Monoamine Oxidase Inhibitors (MAOI)

The effects of opioid analgesics may be potentiated by MAOIs. ZOHYDRO ER is not recommended for use in patients who have received MAO inhibitors within 14 days as severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. No specific interaction between hydrocodone and MAO inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.

7.6 Anticholinergics

Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may increase the risk of urinary retention or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention and constipation in addition to respiratory and central nervous system depression when ZOHYDRO ER is used concurrently with anticholinergic drugs.

8.1 Pregnancy

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 neonate 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 (5.3)].

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. 

8.2 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.

8.3 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 

8.4 Pediatric Use

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

8.5 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.

8.6 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 (12.3)].

8.7 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 (12.3)].

9.1 Controlled Substance

ZOHYDRO ER contains hydrocodone bitartrate, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse.

9.2 Abuse

All patients treated with opioids require careful monitoring for signs of abuse and addiction as use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common to addicts and drug abusers. Drug seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people with untreated addiction, and criminals seeking drugs to sell. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

ZOHYDRO ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing, storage, and disposal are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of ZOHYDRO ER

ZOHYDRO ER is for oral use only. Abuse of ZOHYDRO ER poses a risk of overdose and death. The risk is increased with concurrent use of ZOHYDRO ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved ZOHYDRO ER enhances drug release and increases the risk of overdose and death.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

ZOHYDRO ER should not be abruptly discontinued [see Dosage and Administration (2.3)]. If ZOHYDRO ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2, 8.3)].

12.1 Mechanism of Action

Hydrocodone is a semi-synthetic opioid agonist with relative selectivity for the mu-opioid (µ) receptor, although it can interact with other opioid receptors at higher doses. Hydrocodone acts as a full agonist, binding to and activating opioid receptors at sites in the peri-aquaductal and peri-ventricular gray matter, the ventro-medial medulla and the spinal cord to produce analgesia. The analgesia, as well as the euphoriant, respiratory depressant and physiologic dependence properties of μ agonist opioids like hydrocodone, result principally from agonist action at the μ receptors.

12.2 Pharmacodynamics

Effects on the Central Nervous System
The principal therapeutic action of hydrocodone is analgesia. In common with other opioids, hydrocodone causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Opioids depress the cough reflex by direct effect on the cough center in the medulla.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)]. In addition to analgesia, the widely diverse effects of hydrocodone include drowsiness, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system [see Clinical Pharmacology (12.1)].

Effects on the Gastrointestinal Tract and Other Smooth Muscle
Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System
Hydrocodone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System
Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may manifest from these hormonal changes.

Effects on the Immune System
In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.

Concentration—Efficacy Relationships
The minimum effective plasma concentration of hydrocodone for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. As a result, individually titrate patients to achieve a balance between therapeutic and adverse effects. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, progression of disease, development of a new pain syndrome and/or potential development of analgesic tolerance.

Concentration—Adverse Experience Relationships
There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression.

The dose of ZOHYDRO ER must be individualized [see Dosage and Administration (2.1)]. The effective analgesic dose for some patients will be too high to be tolerated by other patients.

12.3 Pharmacokinetics

As compared to immediate-release hydrocodone combination products, ZOHYDRO ER at similar daily doses results in similar overall exposure but with lower maximum concentrations. The half-life is also longer due to the prolonged duration of absorption. Based on the half-life of hydrocodone, steady-state should be obtained after 3 days of dosing. Following 7 days of dosing, AUC and Cmax increase approximately two-fold as compared to the first day of dosing. The pharmacokinetics of ZOHYDRO ER has been shown to be independent of dose up to a dose of 50 mg.

Absorption
ZOHYDRO ER capsules exhibit peak plasma concentrations occurring approximately 5 hours after dose administration.

Food Effects
Food has no significant effect on the extent of absorption of hydrocodone from ZOHYDRO ER. Although there was no evidence of dose dumping associated with this formulation under fasted and fed conditions, peak plasma concentration of hydrocodone increased by 27% when a ZOHYDRO ER 20 mg capsule was administered with a high-fat meal.

Distribution
Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% [hydromorphone] to 45% [oxycodone]), hydrocodone is expected to fall within this range.

Metabolism
Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7.3)]. Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.

Excretion
Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean apparent plasma half-life after ZOHYDRO ER administration of approximately 8 hours.

Interactions with Alcohol
The rate of absorption of ZOHYDRO ER 50 mg was affected by co-administration with 40% alcohol in the fasted state, as exhibited by an increase in peak hydrocodone concentrations (on average 2.4-fold increase with maximum increase of 3.9-fold in one subject) and a decrease in the time to peak concentrations. The extent of absorption was increased on average 1.2-fold with maximum increase of 1.7-fold in one subject with 40% alcohol [see Warnings and Precautions (5.4)].

Special Populations
Elderly (≥ 65 years)
No significant pharmacokinetic differences by age were observed based on population pharmacokinetic analysis.

Gender
No significant pharmacokinetic differences by gender were observed based on population pharmacokinetic analysis.

Hepatic Impairment
After a single dose of 20 mg ZOHYDRO ER in 20 patients with mild to moderate hepatic impairment based on Child-Pugh classifications, mean hydrocodone Cmax values were 25 ± 5, 24 ± 5, and 22 ± 3.3 ng/mL for moderate and mild impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 509 ± 157, 440 ± 124, and 391 ± 74 ng×h/mL for moderate and mild impairment, and normal subjects, respectively. Hydrocodone Cmax values were 8-10% higher in patients with hepatic impairment while AUC values were 10% and 26% higher in patients with mild and moderate hepatic impairment, respectively. Severely impaired subjects were not studied [see Use in Specific Populations (8.6)].

Renal Impairment
After a single dose of 20 mg ZOHYDRO ER in 28 patients with mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria, mean hydrocodone Cmax values were 26 ± 6.0, 28 ± 7.5, 21 ± 5.1 and 19 ± 4.4 ng/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 487 ± 123, 547 ± 184, 391 ± 122 and 343 ± 105 ng×h/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Hydrocodone Cmax values were 15%, 48%, and 41% higher and AUC values were 15%, 57% and 44% higher in patients with mild, moderate, and severe renal impairment, respectively [see Use in Specific Populations (8.7)].

Drug-Drug Interactions
While comprehensive PK drug-drug interaction studies (other than alcohol) have not been performed in humans receiving hydrocodone, published in vitro and human PK studies indicate that conversion of hydrocodone to its primary metabolite, norhydrocodone and lesser metabolite, hydromorphone, is mediated by the cytochrome P450 enzyme system. N-demethylation of hydrocodone to form norhydrocodone is attributed to CYP3A4 and O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.

CYP3A4 Inhibitors and Inducers
An increase in CYP3A4 activity by initiation of CYP3A4 inhibiting drugs or discontinuation of CYP3A4 inducing drugs could alter the metabolic profile of hydrocodone causing a slowing of hydrocodone clearance, and lead to elevated hydrocodone concentrations and effects, which could be more pronounced with concomitant use of cytochrome P450 CYP3A4 inhibitors. Initiation of a CYP3A4 inducing drug can lower hydrocodone plasma levels and may induce an opioid-withdrawal syndrome [see Warnings and Precautions (5.13) and Drug Interactions (7.3)].

13.1 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 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.

14.1 Placebo-Controlled Study in Opioid-Experienced Subjects with Moderate to Severe Chronic Lower Back Pain

A total of 510 subjects currently on chronic opioid therapy entered an open-label conversion and titration phase (up to 6 weeks) with ZOHYDRO ER dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication. For inadequately controlled pain, ZOHYDRO ER was increased by 10 mg per 12-hour dose, once every 3–7 days until a stabilized dose was identified, or a maximum dosage of 100 mg every 12 hours. There were 302 subjects (59%) randomized at a ratio of 1:1 into a 12-week double-blind treatment phase with their fixed stabilized dose of ZOHYDRO ER (40–200 mg daily taken as 20–100 mg, every 12 hours) or a matching placebo. Subjects randomized to placebo were given a blinded taper of ZOHYDRO ER according to a pre-specified tapering schedule. During the treatment phase, subjects were allowed to use rescue medication (hydrocodone 5 mg/500 mg acetaminophen) up to 2 doses (2 tablets) per day. There were 124 treated subjects (82%) that completed the 12-week treatment with ZOHYDRO ER and 59 subjects (39%) with placebo.

ZOHYDRO ER provided greater analgesia compared to placebo. There was a significant difference in the mean changes from Baseline to Week 12 in average weekly pain intensity Numeric Rating Scale (NRS) scores between the two groups. 

The percentage of subjects in each group who demonstrated improvement in their NRS pain score at End-of-Study, as compared to Screening is shown in the figure below. The figure is cumulative, so subjects whose change from Screening is, for example, 30%, are also included at every level of improvement below 30%. Subjects who did not complete the study were classified as non-responders. Treatment with ZOHYDRO ER produced a greater number of responders, defined as subjects with at least a 30% improvement, as compared to placebo (67.5% vs. 31.1%).

17.1 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 (5.1)]. 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 (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.

Accidental Ingestion
Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. 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 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 (5.3)].

Interaction with Alcohol and other CNS Depressants
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 healthcare provider.

Important Administration Instructions

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

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

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

ZOHYDRO® ER is a trademark of Zogenix®, Inc.

Manufactured for Zogenix®, Inc. by Alkermes Gainesville LLC under license from Alkermes Pharma Ireland Limited (APIL), Ireland.

U.S. Patent Nos.: US 6,228,398 and US 6,902,742