Zohydro

Overdose

Acute overdosage with Zohydro can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdosage. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydrocodone overdose.

Because the duration of reversal is expected to be less than the duration of action of hydrocodone in Zohydro, carefully monitor the patient until spontaneous respiration is reliably reestablished. Zohydro will continue to release hydrocodone and add to the hydrocodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Contraindications

Zohydro is contraindicated in patients with:

• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestional obstruction, including paralytic ileus
• Hypersensitivity (e.g., anaphylaxis) to hydrocodone or any other ingredients in Zohydro

Pharmaceutical form

Undesirable effects

The following serious adverse reactions are discussed elsewhere in the labeling:

• Addiction, Abuse, and Misuse
• Life-Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Benzodiazepines and Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal

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 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.

Table 3. Treatment-Emergent Adverse Events in ≥2% of Subjects During the Open-Label Titration Period and/or the Double-Blind Treatment Period, by Preferred Term — Number (%) of Treated Subjects (Placebo-Controlled Study in Opioid-Experienced 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 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

The following adverse reactions have been identified during post approval use of hydrocodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis has been reported with ingredients contained in Zohydro.

Cases of androgen deficiency have occurred with chronic use of opioids.

Therapeutic indications

ZOHYDRO® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations , reserve Zohydro for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Zohydro is not indicated as an as-needed (prn) analgesic.

Pharmacodynamic properties

Hydrocodone produces respiratory depression by direct action on brain stem 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. 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.

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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in gastric, in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Hydrocodone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

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. Overall, the effects of opioids appear to be modestly immunosuppressive.

The minimum effective analgesic concentration will vary widely among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or potential development of analgesic tolerance..

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

Pharmacokinetic properties

As compared to immediate-release hydrocodone combination products, Zohydro 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 have been shown to be independent of dose up to a dose of 50 mg.

Zohydro capsules exhibit peak plasma concentrations approximately 5 hours after dose administration.

Food Effects

Food has no significant effect on the extent of absorption of hydrocodone from Zohydro. 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 20 mg capsule was administered with a high-fat meal.

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 6keto 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. 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 administration of approximately 8 hours.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Zohydro contains hydrocodone, a Schedule II controlled substance. As an opioid, Zohydro exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as Zohydro 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. 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, and monitor all patients receiving Zohydro 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 for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Zohydro, but use in such patients necessitates intensive counseling about the risks and proper use of Zohydro along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Zohydro 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.

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. 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. 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.

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. 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, 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.

To reduce the risk of respiratory depression, proper dosing and titration of Zohydro are essential. Overestimating the Zohydro 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, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

Prolonged use of Zohydro 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..

Concomitant use of Zohydro 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 , particularly when an inhibitor is added after a stable dose of Zohydro is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Zohydro-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using Zohydro with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Zohydro-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Zohydro until stable drug effects are achieved.

Concomitant use of Zohydro 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 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.

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

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 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.

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

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

Zohydro-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.

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 and when Zohydro is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

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.

Zohydro 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). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Zohydro. In patients with circulatory shock, Zohydro may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Zohydro in patients with circulatory shock.

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 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.

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

Zohydro is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Hydrocodone in Zohydro 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.

The hydrocodone in Zohydro 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 therapy.

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. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing Zohydro, gradually taper the dosage. Do not abruptly discontinue Zohydro.

Zohydro 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 and know how they will react to the medication..

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

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

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Zohydro or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death. Instruct patients to take steps to store Zohydro securely and to dispose of unused Zohydro by flushing the capsules down the toilet.

Inform patients and caregivers that potentially fatal additive effects may occur if Zohydro 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.

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..

Inform patients to avoid taking Zohydro while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking HYSINGLA ER.

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.

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

• Use Zohydro exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression).
• Swallow Zohydro capsules whole.
• Do not crush, chew, or dissolve the capsule or its contents.
• Do not discontinue Zohydro without first discussing the need for a tapering regimen with the prescriber.

Inform patients that Zohydro 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 ).

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

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Zohydro during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Zohydro can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Advise patients that breastfeeding is not recommended during treatment with Zohydro.

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Inform patients that Zohydro 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.

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.

Disposal of Unused Zohydro

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

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.

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).

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.

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. There are no studies of Zohydro 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. 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.

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.

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 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, 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.

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).

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, 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.

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.

Monitor infants exposed to Zohydro 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.

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.

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

Clinical studies of Zohydro 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 slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

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.

No adjustment in starting dose with Zohydro 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. Therefore, a dosage reduction is recommended for patients with severe hepatic impairment. Monitor patients with severe hepatic impairment closely for respiratory depression, sedation, and hypotension.

Patients with renal impairment have higher plasma concentrations than those with normal function. Use a low initial dose of Zohydro in patients with renal impairment and monitor closely for respiratory depression, sedation, and hypotension.

Dosage (Posology) and method of administration

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

Daily doses of Zohydro, a single dose of greater than 40 mg, or a total daily dose of 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, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Zohydro and adjust the dosage accordingly.

Instruct patients to swallow Zohydro capsules whole. Crushing, chewing, or dissolving the beads in Zohydro capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death.

Zohydro is administered orally twice daily (every 12 hours)

Initiate therapy with Zohydro with one 10 mg capsule every 12 hours.

The starting dose for patients who are not opioid tolerant is Zohydro 10 mg orally every 12 hours.

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

Patients receiving other oral hydrocodone-containing formulations may be converted to Zohydro by dividing the patient’s total daily oral hydrocodone dose in half and administrating as Zohydro every 12 hours.

Discontinue all other around-the-clock opioid drugs when Zohydro therapy is initiated.

There is inter-patient variability in the relative potency of different opioid drugs and products. Therefore, a conservative approach is advised when determining the total daily dosage of Zohydro. It is safer to underestimate a patient’s 24-hour oral hydrocodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone dosage and manage an adverse reaction due to an overdose.

In a Zohydro clinical trial with an open label titration period, patients were converted from their prior opioid to Zohydro using Table 1 as a guide for the initial Zohydro dose. To obtain the initial ZOHDYRO ER dose, first use Table 1 to convert the prior oral opioids to a total hydrocodone daily dose and then reduce the calculated daily hydrocodone dose by 25% to account for interpatient variability in relative potency of different opioids.

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.
• The table cannot be used to convert from Zohydro to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.

Table 1. Conversion Factors to Zohydro (Not Equianalgesic Doses)

To calculate the estimated daily Zohydro 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 approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose. Divide the daily dose 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.
• Reduce the calculated daily oral hydrocodone dose by 25%

Always round the dose down, if necessary, to the nearest Zohydro strength(s) available and initiate therapy with that dose.

Example conversion from a single opioid to Zohydro

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 every 12 hours. Round down, if necessary, to the appropriate Zohydro 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.

The dose of Zohydro 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.

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.

Zohydro 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, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to Zohydro, as there is limited documented experience with this conversion.

Individually titrate Zohydro to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Zohydro 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 dosage adjustment of Zohydro, 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 before increasing the Zohydro dosage. Because steady-state plasma concentrations are approximated within 3 days, Zohydro 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, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. Therefore, initiate therapy with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension. No adjustment in starting dose with Zohydro is required in patients with mild or moderate hepatic impairment.

Do not abruptly discontinue Zohydro. When a patient no longer requires therapy with Zohydro, taper the dose gradually, according to the schedule in Table 2, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these sign or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

Table 2. Zohydro Taper Schedule Used in Phase 3 Study

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.