1 INDICATIONS AND USAGE Hydromorphone hydrochloride extended-release tablets are indicated in opioid-tolerant patients for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

Patients considered opioid tolerant are those who are 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.

Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including hydromorphone hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• Hydromorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic.

Hydromorphone hydrochloride extended-release tablets are an opioid agonist indicated in opioid-tolerant patients for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

Patients considered opioid tolerant are those who are taking, 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.

( 1 ) Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including hydromorphone hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

( 1 , 5.1 ) • Hydromorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic.

( 1 )

6 ADVERSE REACTIONS 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 ( 5.2 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] • Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Opioid-Induced Hyperalgesia and Allodynia [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 )] Most common adverse reactions (incidence >10%) are: constipation, nausea, vomiting, somnolence, headache, and dizziness.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

Hydromorphone hydrochloride extended-release tablets was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies.

Of these, 423 patients were exposed to hydromorphone hydrochloride extended-release tablets for greater than 6 months and 141 exposed for greater than one year.

The most common adverse reactions leading to study discontinuation were nausea, vomiting, constipation, somnolence, and dizziness.

The most common treatment-related serious adverse reactions from controlled and uncontrolled chronic pain studies were drug withdrawal syndrome, overdose, confusional state, and constipation.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients.

The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies ( 14 )] .

A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase.

The adverse reactions that were reported in at least 2% of the patients are contained in Table 2 .

Table 2.

Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Titration Phase Hydromorphone Hydrochloride Extended-Release Tablets (N = 447) Double-Blind Treatment Phase Hydromorphone Hydrochloride Extended-Release Tablets (N = 134) Placebo (N = 134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Insomnia 13 (3) 7 (5) 5 (4) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) Anorexia/Decreased Appetite 10 (2) 2 (1) 0 (0) Arthralgia 9 (2) 8 (6) 3 (2) Abdominal Pain 9 (2) 4 (3) 3 (2) Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 3 .

Table 3.

Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Chronic Pain Receiving Hydromorphone Hydrochloride Extended-Release Tablets in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N = 2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia/Fatigue 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia/Decreased Appetite 139 (6) Dry Mouth 121 (5) Abdominal Pain 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia* 88 (4) Depression 81 (3) Dyspnea 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Pain 51 (2) * Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia The following Adverse Reactions occurred in patients with an overall frequency of < 2% and are listed in descending order within each System Organ Class: Cardiac disorders : palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders : vertigo, tinnitus Endocrine disorders : hypogonadism Eye disorders : vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders : flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions : chills, malaise, feeling abnormal, feeling of body temperature change, feeling jittery, hangover, gait disturbance, feeling drunk, body temperature decreased Infections and infestations : gastroenteritis, diverticulitis Injury, poisoning and procedural complications : contusion, overdose Investigations : weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased Metabolism and nutrition disorders : dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders : myalgia Nervous system disorders : tremor, sedation, hypoesthesia, paresthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, crying, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, suicide ideation, libido decreased, aggression Renal and urinary disorders : dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders : erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders : rhinorrhea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders : erythema Vascular disorders : flushing, hypertension, hypotension 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of hydromorphone.

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 [see Drug Interactions ( 7 )].

Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use [see Warnings and Precautions ( 5.8 )].

Anaphylaxis : Anaphylactic reaction has been reported with ingredients contained in hydromorphone hydrochloride extended-release tablets [see Contraindications ( 4 ) and Warnings and Precautions ( 5.14 )].

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )].

Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.6 )].

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).

Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.11 )] .

Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.

Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).

Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).

Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.

New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.

Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.

Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal.

Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.

Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.