Benzhydrocodone and Acetaminophen for Pain

INDICATIONS AND USAGE APADAZ is indicated for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.1 ) ] reserve APADAZ for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. APADAZ should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. APADAZ is a combination of benzhydrocodone, a prodrug of the opioid agonist hydrocodone, and acetaminophen, and is indicated for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve APADAZ for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia APADAZ should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

DOSAGE AND ADMINISTRATION APADAZ should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of APADAZ for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy especially when initiating and following dosage increases with APADAZ. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with APADAZ. Consider prescribing naloxone based on the patient’s risk factors for overdose ( 2.2 , 5.1 , 5.3 , 5.7 ). Initiate treatment with APADAZ at 1 or 2 tablets every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of APADAZ. Dosage should not exceed 12 tablets in a 24- hour period. ( 2.5 ) See full prescribing information for conversion from hydrocodone bitartrate/acetaminophen. ( 2.4 ) Do not abruptly discontinue APADAZ in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 , 5.16 ) 2.1 Important Dosage and Administration Instructions APADAZ should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of APADAZ for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. The total dosage of APADAZ and any concomitant acetaminophen-containing products should not exceed 4000 mg of acetaminophen in a 24-hour period. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with APADAZ. Consider this risk when selecting an initial dose and when making dose adjustments [ see Warnings and Precautions ( 5.2) ] . 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with APADAZ [see Warnings and Precautions ( 5.3 )]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.2, 5.3 )] . Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Use of APADAZ as the First Opioid Analgesic Initiate treatment with APADAZ at 1 to 2 tablets every 4 to 6 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of APADAZ. Dosage should not exceed 12 tablets in a 24-hour period. 2.4 Conversion from Other Opioids to APADAZ There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of APADAZ. It is safer to underestimate a patient's 24-hour APADAZ dosage than to overestimate the 24-hour APADAZ dosage and manage an adverse reaction due to overdose. Conversion from Hydrocodone Bitartrate/Acetaminophen to APADAZ Patients can be converted from immediate-release hydrocodone bitartrate/acetaminophen to a dosing regimen of APADAZ as shown in Table 1 . Table 1. Conversion from Hydrocodone bitartrate/Acetaminophen to APADAZ. Hydrocodone bitartrate doses (mg) APADAZ equivalent (mg benzhydrocodone) 5 4.08 7.5 6.12 10 8.16 2.5 Titration and Maintenance of Therapy Individually titrate APADAZ to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving APADAZ to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [ see Warnings and Precautions ( 5.1 , 5.16 ) ] . 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. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the APADAZ dosage. If after increasing the dosage unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Total dosage of APADAZ and any concomitant acetaminophen-containing products should not exceed 4000 mg of acetaminophen in a 24-hour period. 2.6 Safe Reduction or Discontinuation of APADAZ Do not abruptly discontinue APADAZ in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other s

WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of APADAZ in patients with circulatory shock. ( 5.10 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of APADAZ in patients with impaired consciousness or coma. ( 5.12 ) Serious Skin Reactions : Discontinue APADAZ immediately at the first appearance of skin rash and if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy. ( 5.18 ) 5.1 Addiction, Abuse, and Misuse APADAZ contains benzhydrocodone, a Schedule II controlled substance. As an opioid, APADAZ exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 ) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed APADAZ. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing APADAZ, and reassess all patients receiving APADAZ 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as APADAZ, but use in such patients necessitates intensive counseling about the risks and proper use of APADAZ along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing APADAZ. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and 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. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) 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 APADAZ, the risk is greatest during the initiation of therapy or following a dosage increase of APADAZ. To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential [see Dosage and Administration ( 2 )] . Overestimating the APADAZ dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of APADAZ, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.6 )] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with APADAZ. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions ( 5.1 , 5.7 ), Overdosage ( 10 )]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of APADAZ with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] . 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 durations 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (in

DRUG INTERACTIONS Table 2. Clinically Significant Drug Interactions with APADAZ. CYP3A4 and 2D6 Inhibitors Clinical Impact: The concomitant use of APADAZ and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of APADAZ and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of APADAZ is achieved [see Warnings and Precautions ( 5.5 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone. Intervention: If concomitant use is necessary, consider dosage reduction of APADAZ until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation at. If a CYP3A4 inhibitor is discontinued, consider increasing the APADAZ dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) etc. CYP3A4 Inducers Clinical Impact: The concomitant use of APADAZ and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions ( 5.16 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the APADAZ dosage until stable drug effects are achieved [see Dosage and Administration ( 2 )] . Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider APADAZ dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin etc. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 , 5.7 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue APADAZ if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.3 )] . If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of APADAZ is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of APADAZ and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of APADAZ and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions ( 5.3 , 5.7 )] . Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when APADAZ is used concomitantly with anticholinergic drugs. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue APADAZ if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with APADAZ because they may reduce analgesic effect of APADAZ or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.10 )] Severe Hypotension [see Warnings and Precautions ( 5.11 )] Serious Skin Reactions [see Warnings and Precautions ( 5.18 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 )] Anaphylaxis and Other Hypersensitivity Reactions [see Warnings and Precautions ( 5.14 )] Seizures [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 )] Most common adverse reactions (>5%) are nausea, somnolence, vomiting, constipation, pruritus, dizziness, and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zevra Therapeutics, Inc. at 1-888-958-1253 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice. The safety of APADAZ was evaluated in six Phase 1 studies in which a total of 200 healthy adult subjects receive at least one oral dose of APADAZ. The most common AEs (>5%) reported across these studies were: nausea (21.5%), somnolence (18.5%), vomiting (13.0%), constipation (12.0%), pruritus (11.5%), dizziness (7.5%), and headache (6.0%). The following adverse reactions occurred with an incidence of 1% to 5% in single-dose or repeated-dose clinical trials of APADAZ. Gastrointestinal disorder: abdominal distension, abdominal pain, flatulence General disorders and administration site conditions: asthenia Nervous system disorders: presyncope, tremor Respiratory, thoracic and mediastinal disorders: dyspnea Vascular disorders: hot flush, hypotension Adverse reactions occurring at less than 1% : the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in APADAZ clinical trials. Eye disorders: eye pruritus Gastrointestinal disorders: diarrhea, gastroesophageal reflux disease, haematemesis General disorders and administration site conditions: chest discomfort Infections and infestations: rhinitis Nervous system disorders: hypoesthesia, syncope Psychiatric disorders: agitation, euphoric mood, nightmare 6.2 Postmarketing Experience 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. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in APADAZ. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).