Hysingla ER (Page 5 of 11)

5.8 Adrenal Insufficiency

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

5.9 Severe Hypotension

HYSINGLA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased 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 HYSINGLA ER. In patients with circulatory shock, HYSINGLA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYSINGLA ER in patients with circulatory shock.

5.10 QTc Interval Prolongation

QTc prolongation has been observed with HYSINGLA ER following daily doses of 160 mg [see Clinical Pharmacology (12.2)]. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing HYSINGLA ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval.

HYSINGLA ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33 – 50%, or changing to an alternate analgesic.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

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), HYSINGLA ER 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 HYSINGLA ER.

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

5.12 Gastrointestinal Obstruction, Dysphagia, and Choking

In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 11 out of 2476 subjects reported difficulty swallowing HYSINGLA ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet [see Adverse Reactions (6)].

Instruct patients not to pre-soak, lick, or otherwise wet HYSINGLA ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)].

Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen.

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER [see Use in Specific Populations (8.4)].

5.13 Risks of Use in Patients with Gastrointestinal Conditions

HYSINGLA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The hydrocodone in HYSINGLA ER 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 symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in HYSINGLA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during HYSINGLA ER therapy.

5.15 Withdrawal

Do not abruptly discontinue HYSINGLA ER in a patient physically dependent on opioids. When discontinuing HYSINGLA ER 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 (2.7), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including HYSINGLA ER. 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)].

5.16 Risks of Driving and Operating Machinery

HYSINGLA ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14 – 16 hours (range 6 – 30 hours) after initial dosing of HYSINGLA ER tablet administration. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of HYSINGLA ER and know how they will react to the medication [see Clinical Pharmacology (12.3), Patient Counseling Information (17)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described 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 Benzodiazepine or 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 (5.12, 5.13)]
  • Seizures [see Warnings and Precautions (5.14)]
  • Withdrawal [see Warnings and Precautions (5.15)]

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 practice.

A total of 1,827 patients were treated with HYSINGLA ER in controlled and open-label chronic pain clinical trials. Five hundred patients were treated for 6 months and 364 patients were treated for 12 months. The clinical trial population consisted of opioid-naïve and opioid-experienced patients with persistent moderate to severe chronic pain.

The common adverse reactions (≥2%) reported by patients in clinical trials comparing HYSINGLA ER (20-120 mg/day) with placebo are shown in Table 2 below:

Table 2: Adverse Reactions Reported in ≥2% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve and Opioid-Experienced Patients
Open-labelTitrationPeriod Double-blindTreatment Period
MedDRA Preferred Term (N=905)(%) Placebo(N=292)(%) HYSINGLA ER(N=296)(%)
Nausea 16 5 8
Constipation 9 2 3
Vomiting 7 3 6
Dizziness 7 2 3
Headache 7 2 2
Somnolence 5 1 1
Fatigue 4 1 1
Pruritus 3 <1 0
Tinnitus 2 1 2
Insomnia 2 2 3
Decreased appetite 1 1 2
Influenza 1 1 3

The adverse reactions seen in controlled and open-label chronic pain studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%).

The most common adverse reactions (≥5%) reported by patients treated with HYSINGLA ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, somnolence.

The common (≥1% to <5%) adverse events reported by patients treated with HYSINGLA ER in the chronic pain clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were:

Ear and labyrinth disorders tinnitus
Gastrointestinal disorders abdominal pain, abdominal pain upper, diarrhea, dry mouth, dyspepsia, gastroesophageal reflux disease
General disorders and administration site conditions chest pain, chills, edema peripheral, pain, pyrexia
Infections and infestations bronchitis, gastroenteritis, gastroenteritis viral, influenza, nasopharyngitis, sinusitis, urinary tract infection
Injury, poisoning and procedural complications fall, muscle strain
Metabolism and nutrition disorders decreased appetite
Musculoskeletal and connective tissue disorders arthralgia, back pain, muscle spasms, musculoskeletal pain, myalgia, pain in extremity
Nervous system disorders lethargy, migraine, sedation
Psychiatric disorders anxiety, depression, insomnia
Respiratory, thoracic and mediastinal disorders cough, nasal congestion, oropharyngeal pain
Skin and subcutaneous tissue disorders hyperhidrosis, pruritus, rash
Vascular disorders hot flush, hypertension

Other less common adverse reactions that were seen in <1% of the patients in the HYSINGLA ER chronic pain clinical trials include the following in alphabetical order: abdominal discomfort, abdominal distention, agitation, asthenia, choking, confusional state, depressed mood, drug hypersensitivity, drug withdrawal syndrome, dysphagia, dyspnea, esophageal obstruction, flushing, hypogonadism, hypotension, hypoxia, irritability, libido decreased, malaise, mental impairment, mood altered, muscle twitching, edema, orthostatic hypotension, palpitations, presyncope, retching, syncope, thinking abnormal, thirst, tremor, and urinary retention.

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