Apadaz

(Benzhydrocodone And Acetaminophen)

Check Drug InteractionsCheck known drug interactions.

Apadaz Prescribing Information

Addiction, Abuse, and Misuse

Because the use of APADAZ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions

[see Warnings and Precautions (

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

]

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 , Warnings and Precautions ]

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.

)]

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of APADAZ, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential

[see Warnings and Precautions (

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 ]

. 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 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 ]

. 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 ]

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 , Overdosage ].

)]

Accidental Ingestion

Accidental ingestion of even one dose of APADAZ, especially by children, can result in a fatal overdose of hydrocodone

[see Warnings and Precautions (

5.2 Life-Threatening Respiratory Depression

[see Overdosage ]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of APADAZ are essential

[see Dosage and Administration ]

. 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.

[see

Dosage and Administration ]

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions , Overdosage ].

)]

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of APADAZ and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate

[see Warnings and Precautions (

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 , Warnings and Precautions , Overdosage ]

Advise both patients and caregivers about the risks of respiratory depression and sedation when APADAZ 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 for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

[see Drug Interactions ].

), Drug Interactions (

7 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 ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology ] , 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 ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology ] , 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 ] . 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 , Warnings and Precautions ] .
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 ] . 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 ] .
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.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
: Avoid use with APADAZ because they may reduce analgesic effect of APADAZ or precipitate withdrawal symptoms.
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.

)]

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery

[see Warnings and Precautions (

5.4 Neonatal Opioid Withdrawal Syndrome

Use of APADAZ for an extended period of time 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 manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

[see Use in Specific Populations ].

)]

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription

[see Warnings and Precautions (

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

Complete a
REMS-compliant education program
offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

)]

Cytochrome P450 3A4 Interaction

The concomitant use of APADAZ with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Regularly evaluate patients receiving APADAZ and any CYP3A4 inhibitor or inducer

[see Warnings and Precautions (

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Complete a
REMS-compliant education program
offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

), Drug Interactions (

7 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 ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology ] , 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 ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology ] , 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 ] . 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 , Warnings and Precautions ] .
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 ] . 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 ] .
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.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
: Avoid use with APADAZ because they may reduce analgesic effect of APADAZ or precipitate withdrawal symptoms.
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.

), Clinical Pharmacology (

12.3 Pharmacokinetics

APADAZ has met the bioequivalence criteria for hydrocodone AUC and C_maxto other immediate-release hydrocodone combination products. Benzhydrocodone was not detectable in plasma after oral administration in clinical studies, indicating that exposure to benzhydrocodone was minimal and transient. Steady state with APADAZ is attained within 24 to 36 hours of dosing. The systemic exposure to hydrocodone from APADAZ increases linearly after administration of single and multiple doses of 2 tablets of APADAZ.

Absorption

Single-Dose Studies

In 2 comparative bioavailability studies following oral administration of single dose to healthy subjects under fasted conditions, 6.12 mg/325 mg APADAZ tablet met the bioequivalence criteria for hydrocodone AUC and C_maxto immediate-release tablet of 7.5 mg hydrocodone/200 mg ibuprofen (N = 28); and the bioequivalence criteria for acetaminophen AUC and C_maxto immediate-release tablet of 37.5 mg tramadol/325 mg acetaminophen (N = 27).

In a comparative bioavailability study following oral administration of single dose under fasted conditions in 24 healthy subjects comparing 6.12 mg/325 mg APADAZ to immediate-release tablet of 7.5 mg hydrocodone/325 mg acetaminophen, APADAZ met the bioequivalence criteria for hydrocodone C_maxand AUC; and met the bioequivalence criteria for acetaminophen AUC, with comparable acetaminophen C_max.

In a study to assess the effect of food on the bioavailability and pharmacokinetics of APADAZ in 38 healthy subjects compared to fasted conditions, co-administration of APADAZ with a high-fat, high-calorie meal showed a slight decrease in the rate but no change in the extent of hydrocodone absorption; and no difference in rate and extent of acetaminophen absorption. The effect of a high-fat, high-calorie meal on pharmacokinetics is similar between APADAZ and immediate-release tablet of 7.5 mg hydrocodone/325 mg acetaminophen. APADAZ can be administered without regard to food. The PK parameters for hydrocodone and acetaminophen after oral administration of APADAZ tablet,

6.12 mg /325 mg under fasted and fed conditions are shown in Table 4 below.

Table 4. PK parameters of hydrocodone and acetaminophen after oral administration of APADAZ tablet, 6.12 mg /325 mg under fasted and fed conditions.
Parameter*	Fed	Fasted
Hydrocodone	Fed	Fasted
C_max(ng/mL)	16.04 ± 3.60 (40)	19.18 ± 4.84 (38)
T_max(h)	2.50 (40) [0.50–4.00]	1.25 (38) [0.50–3.00]
AUC_inf(h•ng/mL)	130.91 ± 29.45 (40)	125.73 ± 36.78 (38)
t_½(h)	4.53 ± 0.70 (40)	4.33 ± 0.67 (38)
Acetaminophen
C_max(μg/mL)	3.34 ± 1.01 (39)	4.05 ± 1.30 (38)
T_max(h)	1.50 (39) [0.50–4.00]	1.00 (38) [0.50–3.00]
AUC_inf(h•μg/mL)	15.0 ± 3.53 (36)	14.7 ± 3.87 (36)
t_½(h)	5.64 ± 1.58 (36)	4.78 ± 1.30 (36)

* Arithmetic mean ± standard deviation (N) except T_maxfor which the median (N) [Range] is reported

Multiple-Dose Study

A multiple-dose study in 24 healthy subjects showed no measurable exposure to benzhydrocodone, when 2 tablets of APADAZ, 6.12 /325 mg, was administered orally every 4 hours for a total of 13 doses. Steady state for hydrocodone and acetaminophen was achieved after 24 hours and between 24 and 36 hours, respectively. The accumulation ratios for hydrocodone C_maxand AUC values were 1.85-fold and 2.03-fold, respectively. The accumulation ratios for acetaminophen C_maxand AUC values were 1.38-fold and 1.80-fold, respectively.

Elimination

Hydrocodone is eliminated primarily from the kidneys. Elimination of acetaminophen is principally by liver metabolism and subsequent renal excretion of metabolites.

Metabolism

Benzhydrocodone is a prodrug of hydrocodone and is converted to active hydrocodone by enzymes in the intestinal tract.

Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. Hydromorphone, a potent opioid, is formed from the O-demethylation of hydrocodone and contributes to the total analgesic effect of hydrocodone. The O- and N- demethylation processes are mediated by separate P-450 isoenzymes: CYP2D6 and CYP3A4, respectively

[see Drug Interactions ]

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

a) conjugation with glucuronide;

b) conjugation with sulfate; and

c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours.

The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine.

Specific Populations

Age

For hydrocodone, no significant pharmacokinetic differences based on age have been demonstrated. For APAP, a population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with immediate-release tablets of 7.5 mg hydrocodone/325 mg acetaminophen, which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in the pharmacokinetics of acetaminophen in elderly patients with normal renal and hepatic function

[see Use in Specific Populations ]

Sex

For hydrocodone, no significant pharmacokinetic differences based on gender have been demonstrated.

Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of APADAZ has not been determined

[see Use in Specific Populations ]

Hepatic Impairment

Because acetaminophen is extensively metabolized by the liver, the use of APADAZ in patients with severe hepatic impairment or severe active liver disease is contraindicated. The pharmacokinetics and tolerability of APADAZ in patients with impaired hepatic function have not been studied

[see Contraindications , Use in Specific Populations ]

)]

Hepatotoxicity

APADAZ contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product

[see Warnings and Precautions (

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 CYP3A4 Inhibitors and Inducers

Concomitant use of APADAZ with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression

[see Warnings and Precautions ]

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

[see Drug Interactions ]

Concomitant use of APADAZ 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 APADAZ with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur

[see Drug Interactions ]

)]

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 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

]

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.

[see Dosage and Administration , Warnings and Precautions ]

)

]

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.

Immediate-release tablet.

Capsule-shaped white tablet debossed with “KP201” on one side and “445” on the opposite side contains 4.08 mg benzhydrocodone (equivalent to 4.45 mg benzhydrocodone hydrochloride) and 325 mg acetaminophen.
Capsule-shaped white tablet debossed with “KP201” on one side and blank on the opposite side contains 6.12 mg benzhydrocodone (equivalent to 6.67 mg benzhydrocodone hydrochloride) and 325 mg acetaminophen.
Capsule-shaped white tablet debossed with “KP201” on one side and “890” on the opposite side contains 8.16 mg benzhydrocodone (equivalent to 8.90 mg benzhydrocodone hydrochloride) and 325 mg acetaminophen.

APADAZ is contraindicated in patients with:

Significant respiratory depression

[see Warnings and Precautions (

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 , Warnings and Precautions , Overdosage ]
.
Advise both patients and caregivers about the risks of respiratory depression and sedation when APADAZ 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 for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
[see Drug Interactions ].
)]
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

[see Warnings and Precautions (

5.8 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect
[see Dependence ]
. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety)
[see Dosage and Administration , Warnings and Precautions ]
.
)]
Known or suspected gastrointestinal obstruction, including paralytic ileus

[see Warnings and Precautions (

5.14 Hypersensitivity/Anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue APADAZ tablets immediately and seek medical care if they experience these symptoms. Do not prescribe APADAZ tablets for patients with acetaminophen allergy.
)]
Hypersensitivity to hydrocodone or acetaminophen, or any other component of this product (e.g., anaphylaxis)
[see Warnings and Precautions (

5.13 Risks of Use in Patients with Gastrointestinal Conditions
APADAZ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The hydrocodone from APADAZ may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
), Adverse Reactions (
6 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 ]
Life-Threatening Respiratory Depression
[see Warnings and Precautions ]
Interactions with Benzodiazepines and other CNS Depressants
[see Warnings and Precautions ]
Neonatal Opioid Withdrawal Syndrome
[see Warnings and Precautions ]
Hepatotoxicity
[see Warnings and Precautions ]
Opioid-Induced Hyperalgesia and Allodynia
[see Warnings and Precautions ]
Adrenal Insufficiency
[see Warnings and Precautions ]
Severe Hypotension
[see Warnings and Precautions ]
Serious Skin Reactions
[see Warnings and Precautions ]
Gastrointestinal Adverse Reactions
[see Warnings and Precautions ]
Anaphylaxis and Other Hypersensitivity Reactions
[see Warnings and Precautions ]
Seizures
[see Warnings and Precautions ]
Withdrawal
[see Warnings and Precautions ]
Most common adverse reactions (>5%) are nausea, somnolence, vomiting, constipation, pruritus, dizziness, and headache.
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 ].
Hyperalgesia and Allodynia
: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration
[see Warnings and Precautions ]
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).
)]

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 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
]
.
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 , Warnings and Precautions ]
.
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.
)]
Life-Threatening Respiratory Depression

[see Warnings and Precautions (

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 ]
. 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 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 ]
. 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 ]
.
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 , Overdosage ].
)]
Interactions with Benzodiazepines and other CNS Depressants

[see Warnings and Precautions (

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 , Warnings and Precautions , Overdosage ]
.
Advise both patients and caregivers about the risks of respiratory depression and sedation when APADAZ 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 for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
[see Drug Interactions ].
)]
Neonatal Opioid Withdrawal Syndrome

[see Warnings and Precautions (

5.4 Neonatal Opioid Withdrawal Syndrome
Use of APADAZ for an extended period of time 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 manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations ].
)]
Hepatotoxicity

[see Warnings and Precautions (

5.7 Acetaminophen Hepatotoxicity
APADAZ contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product
[see Overdosage ]
. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
Instruct patients to look for “acetaminophen” or “APAP” on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.
)]
Opioid-Induced Hyperalgesia and Allodynia

[see Warnings and Precautions (

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of APADAZ in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease:
APADAZ-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 APADAZ
[see Warnings and Precautions ]
.
Elderly, Cachectic, or Debilitated Patients:
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
[see Warnings and Precautions ]
.
Regularly evaluate such patients, particularly when initiating and titrating APADAZ and when APADAZ is given concomitantly with other drugs that depress respiration
[see Warnings and Precautions ]
. Alternatively, consider the use of non-opioid analgesics in these patients.
)]
Adrenal Insufficiency

[see Warnings and Precautions (

5.10 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the 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 opioids as being more likely to be associated with adrenal insufficiency.
)]
Severe Hypotension

[see Warnings and Precautions (

5.11 Severe Hypotension
APADAZ may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)
[see Drug Interactions ]
. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of APADAZ.
In patients with circulatory shock, APADAZ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of APADAZ in patients with circulatory shock.
)]
Serious Skin Reactions

[see Warnings and Precautions (

5.18 Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Inform patients about the signs of serious skin reactions and discontinue use at the first appearance of skin rash or any other sign of hypersensitivity.
)]
Gastrointestinal Adverse Reactions

[see Warnings and Precautions (

5.13 Risks of Use in Patients with Gastrointestinal Conditions
APADAZ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The hydrocodone from APADAZ may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
)]
Anaphylaxis and Other Hypersensitivity Reactions

[see Warnings and Precautions (

5.14 Hypersensitivity/Anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue APADAZ tablets immediately and seek medical care if they experience these symptoms. Do not prescribe APADAZ tablets for patients with acetaminophen allergy.
)]
Seizures

[see Warnings and Precautions (

5.15 Increased Risk of Seizures in Patients with Seizure Disorders
The hydrocodone from APADAZ may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during APADAZ therapy.
)]
Withdrawal

[see Warnings and Precautions (

5.16 Withdrawal
Do not abruptly discontinue APADAZ in a patient physically dependent on opioids. When discontinuing APADAZ in a physically dependent patient, gradually taper the dosage. Rapid tapering of APADAZ in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
[see Dosage and Administration , Drug Abuse and Dependence ].
Additionally, 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 APADAZ. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
[see Drug Interactions ].
)]

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 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Complete a
REMS-compliant education program
offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

)]

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease

[see Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

Single-Dose Studies

Table 4. PK parameters of hydrocodone and acetaminophen after oral administration of APADAZ tablet, 6.12 mg /325 mg under fasted and fed conditions.
Parameter*	Fed	Fasted
Hydrocodone	Fed	Fasted
C_max(ng/mL)	16.04 ± 3.60 (40)	19.18 ± 4.84 (38)
T_max(h)	2.50 (40) [0.50–4.00]	1.25 (38) [0.50–3.00]
AUC_inf(h•ng/mL)	130.91 ± 29.45 (40)	125.73 ± 36.78 (38)
t_½(h)	4.53 ± 0.70 (40)	4.33 ± 0.67 (38)
Acetaminophen
C_max(μg/mL)	3.34 ± 1.01 (39)	4.05 ± 1.30 (38)
T_max(h)	1.50 (39) [0.50–4.00]	1.00 (38) [0.50–3.00]
AUC_inf(h•μg/mL)	15.0 ± 3.53 (36)	14.7 ± 3.87 (36)
t_½(h)	5.64 ± 1.58 (36)	4.78 ± 1.30 (36)

* Arithmetic mean ± standard deviation (N) except T_maxfor which the median (N) [Range] is reported

Multiple-Dose Study

Elimination

Hydrocodone is eliminated primarily from the kidneys. Elimination of acetaminophen is principally by liver metabolism and subsequent renal excretion of metabolites.

Metabolism

Benzhydrocodone is a prodrug of hydrocodone and is converted to active hydrocodone by enzymes in the intestinal tract.

[see Drug Interactions ]

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours.

Specific Populations

Age

[see Use in Specific Populations ]

Sex

For hydrocodone, no significant pharmacokinetic differences based on gender have been demonstrated.

Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of APADAZ has not been determined

[see Use in Specific Populations ]

Hepatic Impairment

[see Contraindications , Use in Specific Populations ]

)]

, 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 Pharmacokinetics

Absorption

Single-Dose Studies

Table 4. PK parameters of hydrocodone and acetaminophen after oral administration of APADAZ tablet, 6.12 mg /325 mg under fasted and fed conditions.
Parameter*	Fed	Fasted
Hydrocodone	Fed	Fasted
C_max(ng/mL)	16.04 ± 3.60 (40)	19.18 ± 4.84 (38)
T_max(h)	2.50 (40) [0.50–4.00]	1.25 (38) [0.50–3.00]
AUC_inf(h•ng/mL)	130.91 ± 29.45 (40)	125.73 ± 36.78 (38)
t_½(h)	4.53 ± 0.70 (40)	4.33 ± 0.67 (38)
Acetaminophen
C_max(μg/mL)	3.34 ± 1.01 (39)	4.05 ± 1.30 (38)
T_max(h)	1.50 (39) [0.50–4.00]	1.00 (38) [0.50–3.00]
AUC_inf(h•μg/mL)	15.0 ± 3.53 (36)	14.7 ± 3.87 (36)
t_½(h)	5.64 ± 1.58 (36)	4.78 ± 1.30 (36)

* Arithmetic mean ± standard deviation (N) except T_maxfor which the median (N) [Range] is reported

Multiple-Dose Study

Elimination

Hydrocodone is eliminated primarily from the kidneys. Elimination of acetaminophen is principally by liver metabolism and subsequent renal excretion of metabolites.

Metabolism

Benzhydrocodone is a prodrug of hydrocodone and is converted to active hydrocodone by enzymes in the intestinal tract.

[see Drug Interactions ]

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours.

Specific Populations

Age

[see Use in Specific Populations ]

Sex

For hydrocodone, no significant pharmacokinetic differences based on gender have been demonstrated.

Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of APADAZ has not been determined

[see Use in Specific Populations ]

Hepatic Impairment

[see Contraindications , Use in Specific Populations ]

)]

, 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 Withdrawal

Do not abruptly discontinue APADAZ in a patient physically dependent on opioids. When discontinuing APADAZ in a physically dependent patient, gradually taper the dosage. Rapid tapering of APADAZ in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

[see Dosage and Administration , Drug Abuse and Dependence ].

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

[see Drug Interactions ].

)]

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase

[see Clinical Pharmacology (

12.3 Pharmacokinetics

Absorption

Single-Dose Studies

Table 4. PK parameters of hydrocodone and acetaminophen after oral administration of APADAZ tablet, 6.12 mg /325 mg under fasted and fed conditions.
Parameter*	Fed	Fasted
Hydrocodone	Fed	Fasted
C_max(ng/mL)	16.04 ± 3.60 (40)	19.18 ± 4.84 (38)
T_max(h)	2.50 (40) [0.50–4.00]	1.25 (38) [0.50–3.00]
AUC_inf(h•ng/mL)	130.91 ± 29.45 (40)	125.73 ± 36.78 (38)
t_½(h)	4.53 ± 0.70 (40)	4.33 ± 0.67 (38)
Acetaminophen
C_max(μg/mL)	3.34 ± 1.01 (39)	4.05 ± 1.30 (38)
T_max(h)	1.50 (39) [0.50–4.00]	1.00 (38) [0.50–3.00]
AUC_inf(h•μg/mL)	15.0 ± 3.53 (36)	14.7 ± 3.87 (36)
t_½(h)	5.64 ± 1.58 (36)	4.78 ± 1.30 (36)

* Arithmetic mean ± standard deviation (N) except T_maxfor which the median (N) [Range] is reported

Multiple-Dose Study

Elimination

Hydrocodone is eliminated primarily from the kidneys. Elimination of acetaminophen is principally by liver metabolism and subsequent renal excretion of metabolites.

Metabolism

Benzhydrocodone is a prodrug of hydrocodone and is converted to active hydrocodone by enzymes in the intestinal tract.

[see Drug Interactions ]

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean plasma half-life of 4.5 hours.

Specific Populations

Age

[see Use in Specific Populations ]

Sex

For hydrocodone, no significant pharmacokinetic differences based on gender have been demonstrated.

Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of APADAZ has not been determined

[see Use in Specific Populations ]

Hepatic Impairment

[see Contraindications , Use in Specific Populations ]

)]

, 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 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.
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.
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.
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.
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.
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 .
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.
See full prescribing information for conversion from hydrocodone bitartrate/acetaminophen.
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.

2.1 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 ]
. 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
].
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 ].
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 ]
.
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

]

. 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 ]. 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 substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking APADAZ, there are a variety of factors that should be considered, including the total daily dose of opioid (including APADAZ) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on APADAZ who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

[see Warnings and Precautions , Drug Abuse and Dependence

]

)]

. 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 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions ].

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).

[see Warnings and Precautions ]

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

), Warnings and Precautions (

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

]

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.

[see Dosage and Administration , Warnings and Precautions ]

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions , Warnings and Precautions , Overdosage ]

[see Drug Interactions ].

5.7 Acetaminophen Hepatotoxicity

[see Overdosage ]

. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for “acetaminophen” or “APAP” on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

)]

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 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions , Warnings and Precautions , Overdosage ]

[see Drug Interactions ].

)]

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

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions ].

[see Warnings and Precautions ]

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

, Warnings and Precautions (

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions , Warnings and Precautions , Overdosage ]

[see Drug Interactions ].

5.7 Acetaminophen Hepatotoxicity

[see Overdosage ]

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

)]

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.

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