Hysingla ER

Hysingla ER is a prescription medication used to relieve severe pain. Hysingla ER belongs to a group of drugs called narcotic analgesics. These work by changing the way that the brain and nervous system respond to pain.

This medication comes in an extended release tablet form and is taken once a day.

Do not chew, divide, crush, dissolve, or break Hysingla ER tablets. Swallow tablets whole.

Common side effects of Hysingla ER include nausea, vomiting, constipation, lightheadedness, anxiety, mood changes, rash, and itching.

Hysingla ER can also cause drowsiness and dizziness. Do not drive or operate heavy machinery until you know how Hysingla ER affects you.

If you take too much Hysingla ER, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Hysingla ER is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; and CYTOCHROME P450 3A4 INTERACTION

Addiction, Abuse, and Misuse
Hysingla ER 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 Hysingla ER and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Hysingla ER. Monitor for respiratory depression, especially during initiation of Hysingla ER or following a dose increase. Instruct patients to swallow Hysingla ER tablets whole; crushing, chewing, or dissolving Hysingla ER tablets can cause rapid release and absorption of a potentially fatal dose of Hysingla ER.

Accidental Ingestion
Accidental ingestion of even one dose of Hysingla ER, especially by children, can result in a fatal overdose of Hysingla ER.

Neonatal Opioid Withdrawal Syndrome
Prolonged use of Hysingla ER 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.

The concomitant use of Hysingla ER with all cytochrome P450 3A4 inhibitors may result in an increase in Hysingla ER 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 Hysingla ER plasma concentration. Monitor patients receiving Hysingla ER and any CYP3A4 inhibitor or inducer.

You should not use hydrocodone if you are allergic to it, or if you have:

• severe asthma or breathing problems; or

• a blockage in your stomach or intestines.

Some medicines can interact with hydrocodone and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, herbal products, or medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

To make sure hydrocodone is safe for you, tell your doctor if you have ever had:

• any type of breathing problem or lung disease;

• a head injury, brain tumor, or seizures;

• drug or alcohol addiction, or mental illness;

• urination problems;

• liver or kidney disease;

• a heart rhythm disorder called long QT syndrome;

• problems with your gallbladder, pancreas, or thyroid; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

If you use hydrocodone while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Do not breast-feed while taking hydrocodone. This medicine can pass into breast milk and cause drowsiness, breathing problems, or death in a nursing baby.

Do not drink alcohol. Dangerous side effects or death can occur when alcohol is combined with hydrocodone.

This medication may impair your thinking or reactions. Avoid driving or operating machinery until you know how hydrocodone will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

This section provides information on the proper use of a number of products that contain hydrocodone. It may not be specific to Hysingla ER. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of this medicine is taken for a long time, it may become habit-forming (causing mental or physical dependence) or cause an overdose.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Swallow the extended-release capsule or tablet whole with water. Do not crush, break, chew, or dissolve it. Do not pre-soak, lick, or wet the tablet before placing it in the mouth, or take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.

Take this medicine at the same time each day.

Hydrocodone should only be used by patients who have already been taking narcotic pain medicines, also called opioids. These patients are called opioid-tolerant. If you are uncertain whether or not you are opioid-tolerant, check with your doctor before using this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For severe pain:
  • For oral dosage form (extended-release capsules):
    • Patients who are not taking narcotic medicines:
      • Adults—At first, 10 milligrams (mg) every 12 hours. Your doctor may adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • Patients switching from other narcotic medicines:
      • Adults—The capsule is given every 12 hours. Your doctor will determine your dose and adjust the dose as needed.
      • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (extended-release tablets):
    • Patients who are not taking narcotic medicines:
      • Adults—
        • Hysingla: At first, 20 milligrams (mg) every 24 hours. Your doctor may adjust your dose as needed.
        • Vantrela™: At first, 15 mg every 12 hours. Your doctor may adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • Patients switching from other narcotic medicines:
      • Adults—
        • Hysingla: The tablet is given every 24 hours. Your doctor will determine your dose and adjust the dose as needed.
        • Vantrela™: The tablet is given every 12 hours. Your doctor will determine your dose and adjust the dose as needed.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Hydrocodone can cause serious unwanted effects or fatal overdose if taken by children, pets, or adults who are not used to strong narcotic pain medicines. Make sure you store the medicine in a safe and secure place to prevent others from getting it.

Do not throw unused medicine in the trash. Ask your pharmacist about the best way to dispose of medicine you do not use.

• If you have an allergy to hydrocodone or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Lung or breathing problems like asthma, trouble breathing, or sleep apnea; high levels of carbon dioxide in the blood; or stomach or bowel block or narrowing.
• If you have a long QT on ECG.
• If you have liver disease.
• If you are taking any of these drugs: Buprenorphine, butorphanol, nalbuphine, or pentazocine.
• If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last 14 days. Taking Hysingla ER within 14 days of those drugs can cause very bad high blood pressure.
• If you are taking any of these drugs: Linezolid or methylene blue.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Hysingla ER.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Hysingla ER is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11, (5.12))]
• Hypersensitivity to hydrocodone or any component of Hysingla ER.

Addiction, Abuse, and Misuse

Hysingla ER contains hydrocodone, a Schedule II controlled substance. As an opioid, Hysingla ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as Hysingla ER 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 Hysingla ER. 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 Hysingla ER, and monitor all patients receiving Hysingla ER 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 Hysingla ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hysingla ER, but use in such patients necessitates intensive counseling about the risks and proper use of Hysingla ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Hysingla ER 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), and 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 HYSINGLA ER. 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.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (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 Hysingla ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of Hysingla ER.

To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the Hysingla ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Hysingla ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hysingla ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for 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).

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of HYSINGLA ER 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 (5.4)], particularly when an inhibitor is added after a stable dose of Hysingla ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hysingla ER treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using Hysingla ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Hysingla ER treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Hysingla ER until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of Hysingla ER 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 Hysingla ER 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)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hysingla ER 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 durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. 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 Hysingla ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Hysingla ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Hysingla ER-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 Hysingla ER[see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating Hysingla ER and when Hysingla ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

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

Severe Hypotension

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.

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.

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.

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)].

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.

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.

Withdrawal

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)].

When discontinuing Hysingla ER, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue Hysingla ER [see Drug Abuse and Dependence (9.3)].

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)].

Pregnancy

Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. Available data with Hysingla ER in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure [see Data].

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 2-4% and 15-20%, 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 neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor and Delivery
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. Hysingla ER is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Hysingla ER, 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 dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data
Animal Data
No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in in rabbit at 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons.

Lactation

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 HYSINGLA, 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 Hysingla ER.

Clinical Considerations
Monitor infants exposed to Hysingla ER 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.

Females and Males of Reproductive Potential

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 [see Adverse Reactions (6.2)].

Pediatric Use

The safety and effectiveness of Hysingla ER in pediatric patients have not been established.

HYSINGLA ER gradually forms a viscous hydrogel (i.e., a gelatinous mass) when exposed to water or other fluids. 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 Warnings and Precautions (5.11)]

Geriatric Use

In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology (12.3)]. Of the 1827 subjects exposed to Hysingla ER in the pooled chronic pain studies, 241 (13%) were age 65 and older (including those age 75 and older), while 42 (2%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received Hysingla ER.

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 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 Hysingla ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Hydrocodone is known to be substantially excreted by the kidney, and the risk of 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.

Hepatic Impairment

No adjustment in starting dose with Hysingla ER 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 these patients [see Dosage and Administration (2.4)]. Monitor closely for respiratory depression, sedation, and hypotension

Renal Impairment

No dose adjustment is needed in patients with mild renal impairment. Patients with moderate or severe renal impairment or end stage renal disease have higher plasma concentrations than those with normal renal function [see Clinical Pharmacology (12.3)]. Therefore, a dosage reduction is recommended for these patients [see Dosage and Administration (2.5)]. Monitor closely for respiratory depression, sedation, and hypotension.

Hysingla ER can slow or stop your breathing. Never use hydrocodone in larger amounts, or for longer than prescribed. Do not crush, break, or open an extended-release Hysingla ER tablet. Swallow it whole to avoid exposure to a potentially fatal dose. Hydrocodone may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

MISUSE OF NARCOTIC MEDICATION CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription.

You should not use this medicine if you have severe asthma or breathing problems, or a blockage in your stomach or intestines.

Tell your doctor if you are pregnant. Hydrocodone may cause life-threatening withdrawal symptoms in a newborn if the mother has taken this medicine during pregnancy.

Do not drink alcohol. Dangerous side effects or death could occur when alcohol is combined with hydrocodone.

You should not use Hysingla ER if you are allergic to hydrocodone, or if you have:

• severe asthma or breathing problems; or

• a blockage in your stomach or intestines.

Hysingla ER may be habit forming. Never share Hysingla ER with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Selling or giving away Hysingla ER is against the law.

Some medicines can interact with hydrocodone and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, herbal products, or medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

To make sure Hysingla ER is safe for you, tell your doctor if you have ever had:

• any type of breathing problem or lung disease;

• a head injury, brain tumor, or seizures;

• drug or alcohol addiction, or mental illness;

• urination problems;

• liver or kidney disease;

• a heart rhythm disorder called long QT syndrome;

• problems with your gallbladder, pancreas, or thyroid; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

If you use Hysingla ER while you are pregnant, your baby could become dependent on hydrocodone. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Do not breast-feed while you are using Hysingla ER. Hydrocodone can pass into breast milk and cause drowsiness, breathing problems, or death in a nursing baby.

Applies to hydrocodone: compounding powder, oral capsule extended release, oral tablet extended release

General

The most commonly reported side effects included constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, cough, bronchitis, nasopharyngitis, sinusitis, nasal congestion
Uncommon (0.1% to 1%): Dyspnea[Ref]

Cardiovascular

Common (1 to 10%): Hot flush, hypertension, chest pain, peripheral edema
Rare (less than 0.1%): Hypotension, orthostatic hypotension, palpitations, presyncope, syncope
Frequency not reported: QTC interval prolongation[Ref]

QT interval prolongation has been observed in healthy subjects following daily dosing with hydrocodone extended-release tablets. The difference in QT interval at steady state was found to be 6 milliseconds, 7 milliseconds, and 10 milliseconds at doses of 80 mg, 120 mg and 160 mg, daily, respectively.[Ref]

Gastrointestinal

Very common (10% or more): Constipation (up to 11%), nausea (up to 10%)
Common (1% to 10%): Dry mouth, vomiting, abdominal pain or discomfort, gastroesophageal reflux disease, diarrhea, dyspepsia
Rare (less than 0.1%): Dysphagia, esophageal obstruction, retching, chocking
Very rare (less than 0.01%): Difficulty swallowing tablet[Ref]

In clinical trials with extended release tablets, 11 or 2476 subjects reported difficulty swallowing the tablets. These reports included esophageal obstruction, dysphagia, and choking. One case required medical intervention to remove the tablet.[Ref]

Nervous system

Common (1% to 10%): Somnolence, fatigue, headache, tremor, dizziness, lethargy, migraine, paresthesia, sedation
Uncommon (0.1% to 1%): Abnormal thinking[Ref]

Other

Common (1% to 10%): Pain, pyrexia, fatigue, tinnitus, chills
Uncommon (0.1% to 1%): Asthenia, neonatal abstinence syndrome, drug withdrawal[Ref]

Psychiatric

Common (1 to 10%): Anxiety, depression, insomnia
Uncommon (0.1% to 1%): Agitation, altered mood, irritability, libido decreased[Ref]

Metabolic

Common (1% to 10%): Dehydration, hypokalemia, increased blood cholesterol, decreased appetite
Uncommon (0.1% to 1%): Thirst[Ref]

Hepatic

Common (1 to 10%): Increased gamma-glutamyltransferase[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, muscle spasms , contusion, fall, foot fracture, joint injury or sprain, muscle strain, arthralgia, musculoskeletal pain, myalgia, neck pain, osteoarthritis, pain in extremity
Uncommon (0.1% to 1%): Muscle twitching[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Drug hypersensitivity[Ref]

Endocrine

Uncommon (0.1% to 1%): Hypogonadism[Ref]

Dermatologic

Common (1% to 10%): Pruritus, skin laceration, hyperhidrosis, night sweats, rash[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Uncommon (0.1% to 1%): Urinary retention[Ref]

Some side effects of Hysingla ER may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.