Hydrocodone Bitartrate Capsule, Extended Release
FDA Label NDC 47781-410

Addiction, Abuse, and Misuse

Hydrocodone Bitartrate Extended-Release Capsules 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 Hydrocodone Bitartrate Extended-Release Capsules and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Hydrocodone Bitartrate Extended-Release Capsules. Monitor for respiratory depression, especially during initiation of Hydrocodone Bitartrate Extended-Release Capsules or following a dose increase. Instruct patients to swallow Hydrocodone Bitartrate Extended-Release Capsules whole; crushing, chewing, or dissolving Hydrocodone Bitartrate Extended-Release Capsules can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.3)].

Accidental Ingestion

Accidental ingestion of even one dose of Hydrocodone Bitartrate Extended-Release Capsules, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.3)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hydrocodone Bitartrate Extended-Release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].

Cytochrome P450 3A4 Interaction

The concomitant use of Hydrocodone Bitartrate Extended-Release Capsules with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects 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. Monitor patients receiving Hydrocodone Bitartrate Extended-Release Capsules and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.6), Drug Interactions (7)].

• Reserve concomitant prescribing of Hydrocodone Bitartrate Extended-Release Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking Hydrocodone Bitartrate Extended-Release Capsules. The co-ingestion of alcohol with Hydrocodone Bitartrate Extended-Release Capsules may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve Hydrocodone Bitartrate Extended-Release Capsules for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Hydrocodone Bitartrate Extended-Release Capsules are not indicated as an as-needed (prn) analgesic.

Use of Hydrocodone Bitartrate Extended-Release Capsules as the First Opioid Analgesic (opioid-naïve patients)

Initiate therapy with Hydrocodone Bitartrate Extended-Release Capsules with one 10 mg capsule every 12 hours.

Use of Hydrocodone Bitartrate Extended-Release Capsules in Patients Who Are Not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is Hydrocodone Bitartrate Extended-Release Capsules 10 mg orally every 12 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.3)].

Conversion from Oral Hydrocodone Formulations to Hydrocodone Bitartrate Extended-Release Capsules

Patients receiving other oral hydrocodone-containing formulations may be converted to Hydrocodone Bitartrate Extended-Release Capsules by dividing the patient's total daily oral hydrocodone dose in half and administrating as Hydrocodone Bitartrate Extended-Release Capsules every 12 hours.

Conversion from Other Oral Opioid to Hydrocodone Bitartrate Extended-Release Capsules

Discontinue all other around-the-clock opioid drugs when Hydrocodone Bitartrate Extended-Release Capsules therapy is initiated.

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

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

Consider the following when using the information in Table 1:

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

Table 1. Conversion Factors to Hydrocodone Bitartrate Extended-Release Capsules (Not Equianalgesic Doses)

Prior Oral Opioid	Oral Dose (mg)	Approximate Oral Conversion Factor
The conversion ratios in this table are only to be used for the conversion from current opioid therapy to Hydrocodone Bitartrate Extended-Release Capsules.
Hydrocodone	10	1
Oxycodone	10	1
Methadone	10	1
Oxymorphone	5	2
Hydromorphone	3.75	2.67
Morphine	15	0.67
Codeine	100	0.10

To calculate the estimated daily Hydrocodone Bitartrate Extended-Release Capsules dose using Table 1:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose. Divide the daily dose in half for administration every 12 hours.
• For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain approximate total hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
• Reduce the calculated daily oral hydrocodone dose by 25%.

Always round the dose down, if necessary, to the nearest Hydrocodone Bitartrate Extended-Release Capsule strength(s) available and initiate therapy with that dose.

Example conversion from a single opioid to Hydrocodone Bitartrate Extended-Release Capsules

Step 1:	Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone.
Step 2:	Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone × 2 = 60 mg of oral hydrocodone daily. The daily dose should then be divided in half for administration every 12 hours.
Step 3:	Calculate the approximate starting dose which is 30 mg Hydrocodone Bitartrate Extended-Release Capsules every 12 hours. Round down, if necessary, to the appropriate Hydrocodone Bitartrate Extended-Release Capsule strengths available. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Hydrocodone Bitartrate Extended-Release Capsules.

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

Conversion from Methadone to Hydrocodone Bitartrate Extended-Release Capsules

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

Conversion from Transdermal Fentanyl to Hydrocodone Bitartrate Extended-Release Capsules

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

Patients with Chronic Pulmonary Disease: Hydrocodone Bitartrate Extended-Release Capsule-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 Hydrocodone Bitartrate Extended-Release Capsules.

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

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

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no studies of Hydrocodone Bitartrate Extended-Release Capsules use in pregnant women. Rats administered oral hydrocodone during gestation and lactation showed increases in stillborn pups and decreases in pup survival at doses equivalent to the human dose of 100 mg/day. Reduced nursing behavior and decreased body weights were observed at 2 times the human dose. Reduced fetal weights were observed in rabbits administered hydrocodone during the period of organogenesis at doses equivalent to 5 times the human dose of 100 mg/day. In this study, increases in the number of umbilical hernias, irregularly shaped bones, and delays in fetal skeletal maturation were observed at doses 15 times the human dose of 100 mg/day. No fetal malformations were observed in animal reproduction studies with oral administration of hydrocodone bitartrate during organogenesis in rats and rabbits at doses approximately 2 and 10 times a human dose of 100 mg/day, respectively [see Data ]. Based on animal data, advise pregnant women of the potential risks to a fetus.

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

Clinical Considerations

Fetal/neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the newborn and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.4)].

Data

Animal Data

Oral doses of hydrocodone bitartrate up to 25 mg/kg/day in rats and 50 mg/kg/day in rabbits, equivalent to 2 and 10 times an adult human dose of 100 mg/day, respectively on a mg/m² basis, did not result in any fetal malformations. Fetuses of rabbits administered oral doses of 75 mg/kg/day hydrocodone bitartrate (15 times an adult human dose of 100 mg/day on a mg/m² basis) during the period of organogenesis exhibited an increased number of malformations consisting of umbilical hernia, and irregularly shaped bones (ulna, femur, tibia and/or fibula). Maternal toxicity was evident at this dose (decreased body weight). In addition, oral hydrocodone bitartrate reduced fetal weights at doses greater than or equal to 25 mg/kg/day (equivalent to approximately 5 times an adult human dose of 100 mg/day on a mg/m² basis). Delays in fetal skeletal maturation (reduced ossification of hyoid bodies and xiphoid bones) were seen following dosing with 75 mg/kg/day (a dose equivalent to 15 times an adult human dose of 100 mg/day on a mg/m² basis).

Hydrocodone bitartrate administered orally to female rats at oral doses of 10 mg/kg/day and 25 mg/kg/day during gestation and lactation resulted in pups which were noted as cold to touch and caused a reduction in fetal viability (increases in the number of stillborn pups and/or pups dying postpartum). The doses causing these effects were equivalent to approximately 1 and 2.4 times an adult human dose of 100 mg/day, on a mg/m² basis. Nursing was reduced in pups of mothers administered 25 mg/kg/day which correlated with decreased body weight/body weight gain and food consumption in male pups. Minimal maternal toxicity was evident at 25 mg/kg (decreased body weight).

Risk Summary

Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with extended-release hydrocodone, including Hydrocodone Bitartrate Extended-Release Capsules, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Hydrocodone Bitartrate Extended-Release Capsules.

Clinical Considerations

Monitor infants exposed to hydrocodone bitartrate through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Infertility

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

In rat fertility studies, no effects on male fertility were observed with hydrocodone at doses equivalent to 10 times the human dose of 100 mg/day, however, decreases in the weight of male reproductive organs were observed in all treated groups at doses equivalent to 2.4 times the human dose of 100 mg/day and above. Reductions in female fertility indices were observed at doses of hydrocodone equivalent to 2 times the human dose of 100 mg/day and above. These changes are attributed to a hydrocodone-mediated decrease in prolactin levels in the rat. Unique to rodents, prolactin is required for normal estrous cycling and the effects on fertility observed in this study are most likely rodent-specific and not believed to be clinically relevant [see Nonclinical Toxicology (13)].

Risks Specific to Abuse of Hydrocodone Bitartrate Extended-Release Capsules

Hydrocodone Bitartrate Extended-Release Capsules are for oral use only. Abuse of Hydrocodone Bitartrate Extended-Release Capsules pose a risk of overdose and death. The risk is increased with concurrent use of Hydrocodone Bitartrate Extended-Release Capsules with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved Hydrocodone Bitartrate Extended-Release Capsules enhances drug release and increases the risk of overdose and death.

With intravenous abuse, the inactive ingredients in Hydrocodone Bitartrate Extended-Release Capsules can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis and valvular heart injury, embolism, and death. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Clinical Presentation

Acute overdosage with Hydrocodone Bitartrate Extended-Release Capsules can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

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

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

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

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

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

Effects on the Central Nervous System

Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)].

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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

Effects on the Cardiovascular System

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

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration—Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or potential development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].

Concentration—Adverse Experience Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Absorption

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

Hydrocodone Bitartrate Extended-Release Capsules exhibit peak plasma concentrations approximately 5 hours after dose administration.

Food Effects

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

Distribution

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

Elimination

Metabolism

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

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys, with a mean apparent plasma half-life after Hydrocodone Bitartrate Extended-Release Capsules administration of approximately 8 hours.

Special Populations

Age: Geriatric Patients

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

Sex: No significant pharmacokinetic differences by sex were observed based on population pharmacokinetic analysis.

Hepatic Impairment

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

Renal Impairment

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

Drug Interaction Studies

Interactions with Alcohol

The rate of absorption of Hydrocodone Bitartrate Extended-Release Capsules 50 mg was affected by co-administration with 40% alcohol in the fasted state, as exhibited by an increase in peak hydrocodone concentrations (on average 2.4-fold increase with maximum increase of 3.9-fold in one subject) and a decrease in the time to peak concentrations. The extent of absorption was increased on average 1.2-fold with maximum increase of 1.7-fold in one subject with 40% alcohol [see Warnings and Precautions (5.6)].

Cytochrome P450 Enzymes

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

CYP3A4 Inhibitors and Inducers

An increase in CYP3A4 activity by initiation of CYP3A4 inhibiting drugs or discontinuation of CYP3A4 inducing drugs could alter the metabolic profile of hydrocodone causing a slowing of hydrocodone clearance, and lead to elevated hydrocodone concentrations and effects, which could be more pronounced with concomitant use of cytochrome P450 CYP3A4 inhibitors. Initiation of a CYP3A4 inducing drug can lower hydrocodone plasma levels and may induce an opioid-withdrawal syndrome [see Warnings and Precautions (5.5) and Drug Interactions (7)].

Carcinogenesis

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

Mutagenesis

Hydrocodone bitartrate was genotoxic in an in vitro chromosomal aberration assay in the presence of metabolic activation. No evidence of clastogenicity was observed in this assay in the absence of metabolic activation. No evidence of DNA damage was found in an in vivo comet assay in mouse liver. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Impairment of Fertility

In a fertility study, rats were administered once daily by oral gavage the vehicle or hydrocodone bitartrate at doses of 25 mg/kg/day, 75 mg/kg/day, and 100 mg/kg/day (equivalent to approximately 2, 7, and 10 times an adult human dose of 100 mg/day, on a mg/m² basis). Male and female rats were dosed before cohabitation (up to 28 days), during the cohabitation and until gestation day 7 (females) or necropsy (males; 2 to 3 weeks post-cohabitation). Hydrocodone bitartrate did not affect reproductive function in males, although the weights of male reproductive organs were decreased at all doses. Doses of 25 mg/kg/day and greater in females reduced the rate at which females became pregnant which correlated with suppression of estrous cyclicity, thought to be due to increases in prolactin. In hydrocodone bitartrate-treated rats that became pregnant, at 25 mg/kg early embryonic development was unaffected (approximately 2 times the adult human daily dose of 100 mg/day on a mg/m² basis). In rats, prolactin plays a unique role in the estrous cycle and the clinical relevance of the female rat reproductive findings is uncertain.

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

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

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

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




Figure (Figure)

Addiction, Abuse, and Misuse

Inform patients that the use of Hydrocodone Bitartrate Extended-Release Capsules, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share Hydrocodone Bitartrate Extended-Release Capsules with others and to take steps to protect Hydrocodone Bitartrate Extended-Release Capsules from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydrocodone Bitartrate Extended-Release Capsules or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

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

Interaction with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Hydrocodone Bitartrate Extended-Release Capsules is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider. Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with Hydrocodone Bitartrate Extended-Release Capsules [see Warnings and Precautions (5.6), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].

MAOI Interaction

Inform patients to avoid taking Hydrocodone Bitartrate Extended-Release Capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydrocodone Bitartrate Extended-Release [see Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.8)].

Important Administration Instructions [see Dosage and Administration (2)]

Instruct patients how to properly take Hydrocodone Bitartrate Extended-Release Capsules, including the following:

• Use Hydrocodone Bitartrate Extended-Release Capsules exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.3)].
• Swallow Hydrocodone Bitartrate Extended-Release Capsules whole.
• Do not crush, chew, or dissolve the capsule or its contents.

Hypotension

Inform patients that Hydrocodone Bitartrate Extended-Release Capsules may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position [see Warnings and Precautions (5.9)]).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate Extended-Release Capsules. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Hydrocodone Bitartrate Extended-Release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Hydrocodone Bitartrate Extended-Release Capsules can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with Hydrocodone Bitartrate Extended-Release Capsules [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that Hydrocodone Bitartrate Extended-Release Capsules may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated dose administration. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.14)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Instruct patients to monitor their analgesic response following the use of strong laxatives and to contact the prescriber if changes are noted [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Disposal of Unused Hydrocodone Bitartrate Extended-Release Capsules

Advise patients to flush the unused capsules down the toilet when Hydrocodone Bitartrate Extended-Release Capsules are no longer needed.

Distributed by:
Alvogen, Inc.
Morristown, NJ 07960 USA

PI409-01

Rev. 10/2019

Hydrocodone Bitartrate Extended-Release Capsules are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Hydrocodone Bitartrate Extended-Release Capsules should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

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

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Hydrocodone Bitartrate Extended-Release Capsules and adjust the dosage accordingly [see Warnings and Precautions (5.3)].

Instruct patients to swallow Hydrocodone Bitartrate Extended-Release Capsules whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving the beads in Hydrocodone Bitartrate Extended-Release Capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions (5.1)].

Hydrocodone Bitartrate Extended-Release Capsules is administered orally twice daily (every 12 hours).

Individually titrate Hydrocodone Bitartrate Extended-Release Capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydrocodone Bitartrate Extended-Release Capsules to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of Hydrocodone Bitartrate Extended-Release Capsules, or may need a rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Hydrocodone Bitartrate Extended-Release Capsules dosage. Because steady-state plasma concentrations are approximated within 3 days, Hydrocodone Bitartrate Extended-Release Capsules dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. Therefore, initiate therapy with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension. No adjustment in starting dose with Hydrocodone Bitartrate Extended-Release Capsules is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

Do not abruptly discontinue Hydrocodone Bitartrate Extended-Release Capsules 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 Hydrocodone Bitartrate Extended-Release Capsules, there are a variety of factors that should be considered, including the dose of Hydrocodone Bitartrate Extended-Release Capsules 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 co- morbid 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 Hydrocodone Bitartrate Extended-Release Capsules 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, monitor 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 a long duration 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 (5.13), Drug Abuse and Dependence (9.3)].

Hydrocodone Bitartrate Extended-Release Capsules are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.3)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)]
• Hypersensitivity (e.g., anaphylaxis) to hydrocodone or any other ingredients in Hydrocodone Bitartrate Extended-Release Capsules

Hydrocodone Bitartrate Extended-Release Capsules contain hydrocodone, a Schedule II controlled substance. As an opioid, Hydrocodone Bitartrate Extended-Release Capsules exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as Hydrocodone Bitartrate Extended-Release Capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present [see Drug Abuse and Dependence (9.1)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydrocodone Bitartrate Extended-Release Capsules. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Hydrocodone Bitartrate Extended-Release Capsules, and monitor all patients receiving Hydrocodone Bitartrate Extended-Release Capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Hydrocodone Bitartrate Extended-Release Capsules for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydrocodone Bitartrate Extended-Release Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate Extended-Release Capsules along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Hydrocodone Bitartrate Extended-Release Capsules by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see Drug Abuse and Dependence (9.1), Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydrocodone Bitartrate Extended-Release Capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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.

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 (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 Hydrocodone Bitartrate Extended-Release Capsules, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Hydrocodone Bitartrate Extended-Release Capsules.

To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate Extended-Release Capsules are essential [see Dosage and Administration (2.3)]. Overestimating the Hydrocodone Bitartrate Extended-Release Capsules dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Hydrocodone Bitartrate Extended-Release Capsules, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

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 (2.5)].

Prolonged use of Hydrocodone Bitartrate Extended-Release Capsules during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and mange accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

Concomitant use of Hydrocodone Bitartrate Extended-Release Capsules 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 (5.3)], particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate Extended-Release Capsules is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hydrocodone Bitartrate Extended-Release Capsule-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using Hydrocodone Bitartrate Extended-Release Capsules with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Hydrocodone Bitartrate Extended-Release Capsule-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Hydrocodone Bitartrate Extended-Release Capsules until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of Hydrocodone Bitartrate Extended-Release Capsules 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 Hydrocodone Bitartrate Extended-Release Capsules with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydrocodone Bitartrate Extended-Release Capsules with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (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 duration of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydrocodone Bitartrate Extended-Release Capsules is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on Hydrocodone Bitartrate Extended-Release Capsules therapy. The co-ingestion of alcohol with Hydrocodone Bitartrate Extended-Release Capsules may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Clinical Pharmacology (12.3)].

The use of Hydrocodone Bitartrate Extended-Release Capsules in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.

Hydrocodone Bitartrate Extended-Release Capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydrocodone Bitartrate Extended-Release Capsules. In patients with circulatory shock, Hydrocodone Bitartrate Extended-Release Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate Extended-Release Capsules in patients with circulatory shock.

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

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydrocodone Bitartrate Extended-Release Capsules in patients with impaired consciousness or coma.

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

The hydrocodone in Hydrocodone Bitartrate Extended-Release Capsules may increase the frequency of seizures in patients with seizure disorders, and may increase the risk occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hydrocodone Bitartrate Extended-Release Capsules therapy.

Do not abruptly discontinue Hydrocodone Bitartrate Extended-Release Capsules in a patient physically dependent on opioids. When discontinuing Hydrocodone Bitartrate Extended-Release Capsules in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].

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 Hydrocodone Bitartrate Extended-Release Capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

Hydrocodone Bitartrate Extended-Release Capsules may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydrocodone Bitartrate Extended-Release Capsules and know how they will react to the medication [see Clinical Pharmacology (12.3), Patient Counseling Information (17)].

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.6)]
• Adrenal Insufficiency [see Warnings and Precautions (5.8)]
• Severe Hypotension [see Warnings and Precautions (5.9)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.12)]
• Withdrawal [see Warnings and Precautions (5.13)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of Hydrocodone Bitartrate Extended-Release Capsules was evaluated in a total of 1,148 subjects in Phase 3 clinical trials.

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

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

Gastrointestinal Disorders: abdominal discomfort, abdominal pain, gastroesophageal reflux disease

General Disorders and Administration Site Conditions: non-cardiac chest pain, pain, peripheral edema, pyrexia

Injury, Poisoning and Procedural Complications: contusion, fall, foot fracture, joint injury, joint sprain, muscle strain, skin laceration

Investigations: increased blood cholesterol, increased gamma-glutamyltransferase

Metabolism and Nutrition Disorders: dehydration, hypokalemia

Musculoskeletal and Connective Tissue Disorders: arthralgia, musculoskeletal pain, myalgia, neck pain, osteoarthritis, pain in extremity

Nervous System Disorders: lethargy, migraine, paresthesia

Psychiatric Disorders: anxiety, depression, insomnia

Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, night sweats, rash

Vascular Disorders: hot flush

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

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 Hydrocodone Bitartrate Extended-Release Capsules.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid induced respiratory depression in the neonate. Hydrocodone Bitartrate Extended-Release Capsules are not recommended for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Hydrocodone Bitartrate Extended-Release Capsules, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

The safety and effectiveness of Hydrocodone Bitartrate Extended-Release Capsules in pediatric patients below the age of 18 years have not been established.

Clinical studies of Hydrocodone Bitartrate Extended-Release Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of the concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydrocodone Bitartrate Extended-Release Capsules slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

Hydrocodone is known to be substantially secreted by the kidney and the risk adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

No adjustment in starting dose with Hydrocodone Bitartrate Extended-Release Capsules is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, a dosage reduction is recommended for patients with severe hepatic impairment [see Dosage and Administration (2.4)]. Monitor patients with severe hepatic impairment closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Patients with renal impairment have higher plasma concentrations than those with normal function. Use a low initial dose of Hydrocodone Bitartrate Extended-Release Capsules in patients with renal impairment and monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Hydrocodone Bitartrate Extended-Release Capsules contain hydrocodone bitartrate, a Schedule II controlled substance.

Hydrocodone Bitartrate Extended-Release Capsules contain hydrocodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Hydrocodone Bitartrate Extended-Release Capsules can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended release formulations adds to the risk of adverse outcomes from abuse and misuse.

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

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people with untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

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

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

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

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

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

Do not abruptly discontinue Hydrocodone Bitartrate Extended-Release Capsules in a patient physically dependent on opioids. Rapid tapering of Hydrocodone Bitartrate Extended-Release Capsules in a patient physically dependent on opioids may lead to 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. 

When discontinuing Hydrocodone Bitartrate Extended-Release Capsules, gradually taper the dosage using a patient- specific plan that considers the following: the dose of Hydrocodone Bitartrate Extended-Release Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.13)].

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

Hydrocodone Bitartrate Extended-Release Capsules are hard gelatin capsules for oral administration. Hydrocodone bitartrate is an opioid agonist and occurs as fine, white crystals, or as a crystalline powder.

The chemical name is 4,5(alpha)-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5) or morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5 alpha)-, [R (R*, R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It has the following structural formula:

Structure (Structure)

Each Hydrocodone Bitartrate Extended-Release Capsule contains either 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg of hydrocodone bitartrate USP. All capsule strengths include the following inactive ingredients: ammonio methacrylate copolymer Type B, copovidone, gelatin, silicon dioxide, sodium lauryl sulfate, sugar spheres, and talc.

The capsule shells contain the following colorants: black iron oxide (50 mg capsule), D&C yellow #10 (all capsule strengths), FD&C blue #1 (10 mg, 15 mg, and 30 mg capsules), FD&C red #3 (15 mg and 30 mg capsules), FD&C red #40 (30 mg capsule), FD&C yellow #6 (all capsule strengths) and titanium dioxide (all capsule strengths).

The imprinting ink for all capsule strengths contains: black iron oxide, D&C yellow #10, FD&C blue #1, FD&C blue #2, FD&C red # 40, n-butyl alcohol, propylene glycol and shellac.

Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

The efficacy and safety of Hydrocodone Bitartrate Extended-Release Capsules have been evaluated in a randomized double-blind, placebo-controlled, multi-center clinical trial in opioid-experienced subjects with moderate to severe chronic low back pain.

Hydrocodone Bitartrate Extended-Release Capsules are supplied in bottles with child-resistant closures as follows:

Hydrocodone Bitartrate Extended-Release Capsules contain hydrocodone bitartrate which is a controlled substance and is controlled under Schedule II of the Controlled Substances Act. Hydrocodone, like all opioids, is liable to diversion and misuse and should be handled accordingly. Patients and their families should be instructed to dispose of any Hydrocodone Bitartrate Extended-Release Capsules that are no longer needed.

Hydrocodone Bitartrate Extended-Release Capsules may be targeted for theft and diversion. Healthcare professionals should contact their State Medical Board, State Board of Pharmacy, or State Control Board for information on how to detect or prevent diversion of this product.

Healthcare professionals should advise patients to store Hydrocodone Bitartrate Extended-Release Capsules in a secure place, preferably locked and out of the reach of children and other non-caregivers.

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].

Dispense in tight container as defined in the USP, with a child-resistant closure.

Advise patients to dispose of any unused capsules from a prescription as soon as they are no longer needed in accordance with local State guidelines and/or regulations [see Patient Counseling Information (17)].

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

NDC 47781-409-60
Hydrocodone Bitartrate Extended-Release Capsules CII

10 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Lbl-10mg 60-count (Lbl 10mg 60s)

NDC 47781-410-60
Hydrocodone Bitartrate Extended-Release Capsules CII

15 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole. 
Do not chew, crush, or dissolve.

60 Capsules 
Rx only

Lbl-15mg 60-count (Lbl 15mg 60s)

NDC 47781-411-60
Hydrocodone Bitartrate Extended-Release Capsules CII

20 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Lbl-20mg 60-count (Lbl 20mg 60s)

NDC 47781-412-60
Hydrocodone Bitartrate Extended-Release Capsules CII

30 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Lbl-30mg 60-count (Lbl 30mg 60s)

NDC 47781-413-60
Hydrocodone Bitartrate Extended-Release Capsules CII

40 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Lbl-40mg 60-count (Lbl 40mg 60s)

NDC 47781-414-60
Hydrocodone Bitartrate Extended-Release Capsules CII

50 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Lbl-50mg 60-count (Lbl 50mg 60s)